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Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:15301838 (Michelakakis et al, 2004) decribe a female patient of healthy unrelated patients. Her diagnosis of Leber congenital amaurosis was subsequently demonstrated to be a PEX1 defect. Myoclonic seizures began age 2. The patient is heterozygous for G843D variant and an additional second variant that is not yet identified.
Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:28432012 (Ge et al., 2017) report 2 Chinese newborns with Zellweger phenotypes and compound het variants in PEX1 (Arg577Thrfs*15 and Asn830Thrfx*61). Although the authors note that seizures are in the clinical spectrum of ZS patients, seizures were not reported for the Chinese newborns.
Early onset or syndromic epilepsy v1.417 PEX1 Rebecca Foulger commented on gene: PEX1: PMID:21844578 (Cho et al., 2011) report a Korean patient who was compound het for variants in the PEX1 gene (p.H678QfsX3 and p.R949W) inherited from the parents. He had typical features of ZS including seizures (starting 4 days old), dysmorphic face and a poor suck.
Early onset or syndromic epilepsy v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:28666289 (Komulainen-Ebrahim et al., 2017) describe a homozygous MTR p.P1173L variant in a patient with drug-resistant seizures associated with hyperhomocysteinemia and hypomethioninemia.
Early onset or syndromic epilepsy v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:9683607 (Wilson et al., 1998) report 3 cblG patients, including 2 siblings who presented with neonatal seizures.
Early onset or syndromic epilepsy v1.417 MTR Rebecca Foulger commented on gene: MTR: PMID:25526710 (Huemer et al., 2015) summarise clinical features of 13 patients with the cblG defect (caused by defects in MTR): 5/13 had seizures.
Early onset or syndromic epilepsy v1.417 IDH2 Rebecca Foulger commented on gene: IDH2: A number of papers note that IDH1 and IDH2 variants have an established association with preoperative seizures in patients with grade II-IV diffuse gliomas (PMID:29172136, 29288860, 22217666).
Early onset or syndromic epilepsy v1.417 IDH2 Rebecca Foulger Publications for gene: IDH2 were set to 20847235
Early onset or syndromic epilepsy v1.416 IDH2 Rebecca Foulger commented on gene: IDH2: PMID:24049096 (Nota et al., 2013) report 3 cases, with seizures reported in 2/3. Case 2 was a 9 year old Caucasian girl with tonic-clonic seizures and mosaic IDH2 variants. Case 3 was a Caucasian girl with seizures age 3 months- her seizures responded well to anticonvulsants. The patient died from sudden cardiac arrest age 8, and was found to have a heterozygous IDH2 c.419G>A variant. Germline mosaicism in the mother was suggested to explain the inheritance pattern in this family.
Early onset or syndromic epilepsy v1.416 HLCS Rebecca Foulger commented on gene: HLCS: PMID:27114915 (Donti et al., 2016) describe a cohort of 5 patients. Case 5 had focal seizures age 5 months which have continued since. He has compound het variants in HLCS (N570K and c.1519+5G>A). The authors note that the phenotypic spectrum of HCLS is broad, from intractable seizures and ID to normal growth and development.
Early onset or syndromic epilepsy v1.416 GSS Rebecca Foulger Publications for gene: GSS were set to 26984560
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:26669244 (Gunduz et al., 2016) report 4 patients with GS deficiency. Case I and Case IV had seizures noted together with homozygous variants (splicing variant in I and p.R125H in IV): Table 1.
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: Seizures are recorded in OMIM Clinical synopsis for MIM:266130 based on Marstein et al., 1976 (no PubMed).
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:15990954 (Njallson et al 2005) summarise the phenotypes of patients with glutathione synthetase deficiency, but don't mention seizures or epilepsy (as noted in review by Tracy Lester).
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:11445798 (Ristoff et al,. 2001) examined 28 patients with Glutathione synthetase deficiency (GSSD). Diagnosis was based on metabolic tests. 16/28 had neurological symptoms such as seizures/psychomotor retardation. In 16 patients with severe GS deficiency, 7 had seizures.
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger commented on gene: GSS: PMID:26984560 (Atwal et al. 2016) present a 19 year old female with Glutathione synthetase deficiency (GSSD). She was diagnosed with a mild seizure disorder age 10, and treated with the antiepileptic lamotrigine, which was discontinued once she was seizure free for 5 years. The authors note it is possible her seizures were unrelated to the underlying GSSD.
Early onset or syndromic epilepsy v1.415 GSS Rebecca Foulger Publications for gene: GSS were set to
Early onset or syndromic epilepsy v1.414 GLYCTK Rebecca Foulger Publications for gene: GLYCTK were set to 3588091; 30637540; 28462797; 20949620
Early onset or syndromic epilepsy v1.413 GLYCTK Rebecca Foulger Publications for gene: GLYCTK were set to 3588091
Early onset or syndromic epilepsy v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:30637540 (Zehavi et al., 2019) report a male from a consanguineous Arab family with intractable seizures and a homozygous missense pathogenic variant in GLYCTK (p.Leu152Pro).
Early onset or syndromic epilepsy v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:28462797 (Swanson et al., 2017) reviewed the Serbian patient from Sass et al., 2010. In addition to p.Phe483SerfsX2 variant in GLYCTK, the patient had an additional Ser117Leu variant in AMT highlighting the co-occurence of two metabolic conditions (D-glyceric aciduria and nonketotic hyperglycinemia).
Early onset or syndromic epilepsy v1.412 GLYCTK Rebecca Foulger commented on gene: GLYCTK: PMID:20949620 (Sass et al., 2010) report 3 patients of Serbian, Mexican and Turkish origin, including the original 1974 (Serbian) patient. All had homozygous variant in GLYTCK:
Patient A was a Serbian boy with generalized seizures beginning age 8 weeks (p.Phe483SerfsX2 variant).
Patient B was a Mexican girl with focal clonic seizures and a Phe493Cys variant.
Patient C was a Turkish boy where seizures were not noted (p.Leu520CysfsX108 variant).
Early onset or syndromic epilepsy v1.412 GFM1 Rebecca Foulger Publications for gene: GFM1 were set to 25852744; 26937387; 28216230; 23430926; 21986555
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:28216230 (Simon et al., 2017) report 2 brothers with compound het variants in GFM1 (maternally-inherited p.Arg250Trp and paternally-inherited p.Gly230_231Glnins19). The younger brother (P1) developed seizures by 4.5 months, characterised as infantile spasms. He has remained seizure free on treatment with topiramate. No seizures were noted for the brother who died age 10 months from multiple organ failure. The authors suggest additional modifier genes may be responsible for the different in severity between the brothers.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:26937387 (Ravn et al., 2015) describe 3 patients with novel GFM1 variants. Patient 3 (a girl of non-consanguineous parents) had epileptic seizures beginning at 2 months old. She died at 3 months during a febrile episode.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:21986555. Galmiche et al., 2012 report two unrelated patients with homozygous GFM1 variants (R671C). The parents were both heterozygous for this variant For the first patient (an Algerian boy from consanguineous parents), no clinical seizures were noted but EEG showed burst of multifocal spikes.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:25852744. Brito et al., 2015 report an infant born to unrelated Caucasian parents with seizures amongst her phenotype (starting age 7 months) and compound het variants in GFM1 (Gly469Valfs*84 and Arg671Cys). The authors summarise clinical features of previous GFM1-deficient patients and note seizures in 5/12 patients.
Early onset or syndromic epilepsy v1.411 GFM1 Rebecca Foulger commented on gene: GFM1: PMID:21119709. In a girl, born of consanguineous parents, with combined oxidative phosphorylation deficiency, Smits et al. (2011) identified a homozygous R250W variant in GFM1. The patient had refractory seizures amongst her phenotypes. This paper is referred to in the review by Tracy Lester.
Early onset or syndromic epilepsy v1.411 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057; 7730309; 31202265
Early onset or syndromic epilepsy v1.410 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057; 7730309
Early onset or syndromic epilepsy v1.409 GCH1 Rebecca Foulger commented on gene: GCH1: Additional evidence for seizures being part of the metabolic disorder comes from PMID:31202265 (Dayasiri et al, 2019) who report a S. Asian child with AR GTPCH (GCH1) deficiency, diagnosed from metabolic testing and family consanguinity. Features included recurrent seizures since 3 months old.
Early onset or syndromic epilepsy v1.409 GCH1 Rebecca Foulger Publications for gene: GCH1 were set to 7869202; 17407085; 12552057
Thoracic aortic aneurysm or dissection (GMS) v0.54 COL3A1 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed from Monoallelic to Both monoallelic and biallelic based on expert reviews provided.
Thoracic aortic aneurysm or dissection (GMS) v0.54 COL3A1 Ivone Leong Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Fetal anomalies v0.351 SIK3 Rebecca Foulger Phenotypes for gene: SIK3 were changed from ?Spondyloepimetaphyseal dysplasia, Krakow type, 618162 to Spondyloepimetaphyseal dysplasia, Krakow type, 618162
Fetal anomalies v0.350 SIK3 Rebecca Foulger Classified gene: SIK3 as Green List (high evidence)
Fetal anomalies v0.350 SIK3 Rebecca Foulger Added comment: Comment on list classification: Added SIK3 to panel as a Green gene following communication with Rhiannon Mellis. A mouse model (PMID:22318228) provides additional support: mice show skeletal anomalies (plus dwarfism postnatally).
Fetal anomalies v0.350 SIK3 Rebecca Foulger Gene: sik3 has been classified as Green List (High Evidence).
Fetal anomalies v0.349 SIK3 Rebecca Foulger gene: SIK3 was added
gene: SIK3 was added to Fetal anomalies. Sources: Other
Mode of inheritance for gene: SIK3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIK3 were set to 30232230; 22318228
Phenotypes for gene: SIK3 were set to ?Spondyloepimetaphyseal dysplasia, Krakow type, 618162
Added comment: Added to panel as suggested by Rhinannon Mellis. One pair of siblings with spondyloepimetaphyseal dysplasia reported in PMID:30232230 (Csukasi et al., 2018) plus one clinical case of suspected skeletal dysplasia prenatally.
Sources: Other
Paroxysmal central nervous system disorders v1.0 Rebecca Foulger promoted panel to version 1.0
Paroxysmal central nervous system disorders v0.174 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Paroxysmal central nervous system disorders v0.173 CACNB4 Rebecca Foulger changed review comment from: Reviews by Andrea Nemeth and Jonathan William were uploaded (September 29th 2019) on their behalf based on email discussion of these genes to reach a consensus on the rating. Comments were received over email, and I uploaded an Amber review based on their comments.; to: Reviews by Andrea Nemeth and Jonathan Williams were uploaded (September 29th 2019) on their behalf based on email discussion of these genes to reach a consensus on the rating. Comments were received over email, and I uploaded an Amber review based on their comments.
Paroxysmal central nervous system disorders v0.173 CACNB4 Rebecca Foulger changed review comment from: Comment on list classification: Downgraded CACNB4 rating from Green to Amber based on GLH review. The most recent comments from Andrea Nemeth and Jonathan William agree that there is only weak evidence to support a gene:disease association. The current evidence comes from PMID:10762541 which reports 1 family (plus another family with epilepsy), and a mouse model.; to: Comment on list classification: Downgraded CACNB4 rating from Green to Amber based on GLH review. The most recent comments from Andrea Nemeth and Jonathan Williams agree that there is only weak evidence to support a gene:disease association. The current evidence comes from PMID:10762541 which reports 1 family (plus another family with epilepsy), and a mouse model.
Skeletal dysplasia v1.230 KMT2D Eleanor Williams Classified gene: KMT2D as Green List (high evidence)
Skeletal dysplasia v1.230 KMT2D Eleanor Williams Added comment: Comment on list classification: Promoting from red to green as >3 cases reported and phenotype is relevant.
Skeletal dysplasia v1.230 KMT2D Eleanor Williams Gene: kmt2d has been classified as Green List (High Evidence).
Skeletal dysplasia v1.229 KMT2D Eleanor Williams Mode of inheritance for gene: KMT2D was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v1.228 KMT2D Eleanor Williams commented on gene: KMT2D: Associated with Kabuki syndrome 1 #147920 (AD) in OMIM. Short stature and some skeletal features (spine, hips) listed as clinical features.

> 3 cases reported in OMIM.
Skeletal dysplasia v1.228 KMT2D Eleanor Williams commented on gene: KMT2D: Associated with Kabuki syndrome 1 #147920 (AD) in OMIM. Short stature and some skeletal features (spine, hips) listed as clinical features.

> 3 cases reported in OMIM.
Skeletal dysplasia v1.228 KAT6B Eleanor Williams Classified gene: KAT6B as Green List (high evidence)
Skeletal dysplasia v1.228 KAT6B Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported.
Skeletal dysplasia v1.228 KAT6B Eleanor Williams Gene: kat6b has been classified as Green List (High Evidence).
Skeletal dysplasia v1.227 KAT6B Eleanor Williams Mode of inheritance for gene: KAT6B was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v1.226 KAT6B Eleanor Williams commented on gene: KAT6B: Associated with Genitopatellar syndrome #606170 (AD) in OMIM. Abnormalities of the pelvis, limbs, hands and feet listed. >3 cases reported in OMIM.
Skeletal dysplasia v1.226 KAT6A Eleanor Williams commented on gene: KAT6A: Associated with Mental retardation, autosomal dominant 32 #616268 (AD) in OMIM.

PMID: 25728777 -Tham et al 2015 - report six individuals from five unrelated families, with mutations in KAT6A detected by whole-exome sequencing. 5 different de novo heterozygous truncating mutations were identified. An additional subject with a 0.23 MB microdeletion including the entire KAT6A reading frame was identified with genome-wide array comparative genomic hybridization. Craniosynostosis was reported in 2 families. No other major skeletal abnormalities were reported.
Skeletal dysplasia v1.226 IGF1R Eleanor Williams commented on gene: IGF1R: Associated with Insulin-like growth factor I, resistance to #270450 (AD, AR). More than 3 cases with variants in IFG1R reported in OMIM. Clinical features include short stature due to lack of response to IGF. Clinodactyly and short hands and feet also listed.
Skeletal dysplasia v1.226 IFIH1 Eleanor Williams Classified gene: IFIH1 as Green List (high evidence)
Skeletal dysplasia v1.226 IFIH1 Eleanor Williams Added comment: Comment on list classification: 4 cases reported. All have the same gain of function variant. Genomics England clinicians confirm the phenotype is relevant.
Skeletal dysplasia v1.226 IFIH1 Eleanor Williams Gene: ifih1 has been classified as Green List (High Evidence).
Skeletal dysplasia v1.225 IFIH1 Eleanor Williams Phenotypes for gene: IFIH1 were changed from Singleton-Merten syndrome 1 (182250) to Singleton-Merten syndrome 1, 182250
Skeletal dysplasia v1.224 IFIH1 Eleanor Williams Publications for gene: IFIH1 were set to 25620204
Skeletal dysplasia v1.223 IFIH1 Eleanor Williams Added comment: Comment on mode of pathogenicity: A single variant, thought to act as a gain of function, has been identified.
Skeletal dysplasia v1.223 IFIH1 Eleanor Williams Mode of pathogenicity for gene: IFIH1 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
Skeletal dysplasia v1.222 IFIH1 Eleanor Williams Mode of inheritance for gene: IFIH1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal dysplasia v1.221 IFIH1 Eleanor Williams changed review comment from: Associated with Singleton-Merten syndrome 1 #182250 (AD) in OMIM with short stature and various skeletal abnormalities listed as clinical features.

PMID: 25620204 - Rutsch et al 2015 - identified the same missense mutation, c.2465G>A (p.Arg822Gln), in IFIH1 in Singleton-Merten syndrome (SMS) patients from two families and a simplex case. Functional studies suggest this is a a gain-of-function IFIH1 mutation. Patients showed early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis .; to: Associated with Singleton-Merten syndrome 1 #182250 (AD) in OMIM with short stature and various skeletal abnormalities listed as clinical features.

PMID: 25620204 - Rutsch et al 2015 - identified the same missense mutation, c.2465G>A (p.Arg822Gln), in IFIH1 in Singleton-Merten syndrome (SMS) patients from two families and a simplex case. Functional studies suggest this is a a gain-of-function IFIH1 mutation. Patients showed early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis .

PMID: 28319323 - Pettersson et al 2018 - identified the same mutation c.2465G>A p.(Arg822Gln), in IFIH1in a mother and daughter with Singleton-Merten syndrome. Patient 1 presented with congenital glaucoma, spastic paraplegia, severe dental anomalies, kyphosis, osteoporosis, recurrent infections, muscle weakness, aortic insufficiency, pericarditis, short stature, and SLE. Her mother presented with milder dental anomalies and finger deformities.
Skeletal dysplasia v1.221 IFIH1 Eleanor Williams commented on gene: IFIH1: Associated with Singleton-Merten syndrome 1 #182250 (AD) in OMIM with short stature and various skeletal abnormalities listed as clinical features.

PMID: 25620204 - Rutsch et al 2015 - identified the same missense mutation, c.2465G>A (p.Arg822Gln), in IFIH1 in Singleton-Merten syndrome (SMS) patients from two families and a simplex case. Functional studies suggest this is a a gain-of-function IFIH1 mutation. Patients showed early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis .
Skeletal dysplasia v1.221 IDH2 Eleanor Williams changed review comment from: Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome; to: Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G). Phenotypes of the patients are not given.

PMID: 24049096 - Nota et al. (2013) reported two patients with D-2-hydroxyglutaric aciduria-2, one in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo. In the other the mother also had mosacism for R140Q variant. No skeletal phenotypes are reported.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome
Skeletal dysplasia v1.221 IDH2 Eleanor Williams changed review comment from: PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.; to: Associated with D-2-hydroxyglutaric aciduria 2 #613657 in OMIM. No inheritance pattern given. Clinical features do not list skeletal characteristics.

PMID: 20847235 - Kranendijk et al. (2010) - 15 of 17 cases of D-2-hydroxyglutaric aciduria without mutation in the D2HGDH gene a heterozygous mutation was found in the IDH2 gene. 14 had an arg140-to-gln mutation (R140Q) and 1 had an arg140-to-gly mutation (R140G).

PMID: 24049096 - Nota et al. (2013) reported a patient with D-2-hydroxyglutaric aciduria-2 in whom mosaicism for the R140Q mutation in IDH2 had occurred de novo.

PMID: 22057234 - Pansuriya etal 2011 - state that 'Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). They report somatic heterozygous mutations IDH2 (c.516G>C encoding R172S) in enchondromas (benign cartilage tumors) and in spindle cell hemangiomas (benign vascular lesions).

Conclusion - associated with D-2-hydroxyglutaric aciduria but this does not have a skeletal phenotype. Also associated with somatic mutations which can result in Ollier disease and Maffucci syndrome
Skeletal dysplasia v1.221 EP300 Eleanor Williams commented on gene: EP300: Associated with Rubinstein-Taybi syndrome 2 #613684 (AD) in OMIM with Broad thumbs, Square distal fingertips, Syndactyly (in some patients) and Broad great toes listed as skeletal clinical features.

Heterozygous mutations reported in > 3 cases in OMIM.
Skeletal dysplasia v1.221 COG1 Eleanor Williams Classified gene: COG1 as Green List (high evidence)
Skeletal dysplasia v1.221 COG1 Eleanor Williams Added comment: Comment on list classification: 3 unrelated cases with plausible disease causing variants in the gene reported and a relevant phenotype.
Skeletal dysplasia v1.221 COG1 Eleanor Williams Gene: cog1 has been classified as Green List (High Evidence).
Skeletal dysplasia v1.220 COG1 Eleanor Williams changed review comment from: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM.; to: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM. Clinical features include short stature, several skeletal features such as scoliosis and vertebral abnormalities.

PMID: 16537452 - Foulquier et al 2006 - describe a patient with a mild form of congenital disorder of glycosylation type II with a homozygous insertion of a single nucleotide (2659-2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids. Both parents were shown to be heterozygous for this mutation. Her skeletal features included small hands and feet, rhizomelic short stature.

PMID: 19008299 - Zeevaert et al 2009 - two patients (one with consanguineous Greek-Turkish parents, the other with unrelated Bulgarian parents) with a cerebrocostomandibular-like syndrome and an intronic mutation, c.1070+5G>A, that disrupts a splice donor site and leads to skipping of exon 6, a frameshift and a premature stopcodon in exon 7. Patient 1's characteristics included multiple congenital abnormalities including Pierre-Robin sequence (cleft palate, micrognathia and glossoptosis), costovertebral anomalies including osteopenia, ribfusions and posterior rib gaps, butterfly vertebrae, misalignment of the vertebrae and a clubfoot on the right. Patient 2 presented with rhizomelic shortening of upper limbs, ulnar deviation of fingers, thoracic scoliosis, hypospadias-I and left-side cryptorchidism among other features.

3 unrelated cases.
Skeletal dysplasia v1.220 COG1 Eleanor Williams commented on gene: COG1: Associated with Congenital disorder of glycosylation, type IIg #611209 (AR) in OMIM.
Additional findings health related v0.90 RET Ellen McDonagh Transcript for gene RET was changed from ENST00000355710.7 to ENST00000355710.8
Additional findings health related v0.89 MSH6 Ellen McDonagh Source Additional Findings was removed from MSH6.
Source ACMG was removed from MSH6.
Source Other was added to MSH6.
Phenotypes for gene: MSH6 were changed from ENST00000234420.9; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Transcript for gene MSH6 was changed from None to ENST00000234420.9
Additional findings health related v0.88 MUTYH Ellen McDonagh Source Additional Findings was removed from MUTYH.
Source ACMG was removed from MUTYH.
Source Other was added to MUTYH.
Phenotypes for gene: MUTYH were changed from ENST00000450313.5; Bowel cancer predisposition; MYH-associated polyposis; Adult only to Bowel cancer predisposition; MYH-associated polyposis; Adult only
Transcript for gene MUTYH was changed from None to ENST00000450313.5
Additional findings health related v0.87 PCSK9 Ellen McDonagh Source Additional Findings was removed from PCSK9.
Source ACMG was removed from PCSK9.
Source Other was added to PCSK9.
Phenotypes for gene: PCSK9 were changed from ENST00000302118.5; Familial hypercholesterolaemia; Adult and child to Familial hypercholesterolaemia; Adult and child
Transcript for gene PCSK9 was changed from None to ENST00000302118.5
Additional findings health related v0.86 RET Ellen McDonagh Phenotypes for gene: RET were changed from ENST00000355710.7; Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child to Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child
Transcript for gene RET was changed from None to ENST00000355710.7
Additional findings health related v0.85 VHL Ellen McDonagh Source Additional Findings was removed from VHL.
Source ACMG was removed from VHL.
Source Other was added to VHL.
Phenotypes for gene: VHL were changed from ENST00000256474.2; Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child to Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child
Transcript for gene VHL was changed from None to ENST00000256474.2
Skeletal dysplasia v1.220 SULF1 Eleanor Williams Tag deletions tag was added to gene: SULF1.
Tag currently-ngs-unreportable tag was added to gene: SULF1.
Skeletal dysplasia v1.220 SLCO5A1 Eleanor Williams Tag deletions tag was added to gene: SLCO5A1.
Tag currently-ngs-unreportable tag was added to gene: SLCO5A1.
Familial hypercholesterolaemia (GMS) v1.0 Ellen McDonagh promoted panel to version 1.0
Familial hypercholesterolaemia (GMS) v0.7 Ellen McDonagh Panel types changed to GMS Rare Disease; GMS signed-off
Familial hypercholesterolaemia (GMS) v0.6 Ellen McDonagh List of related panels changed from to R134
Skeletal dysplasia v1.220 OAT Eleanor Williams changed review comment from: Associated with Gyrate atrophy of choroid and retina with or without ornithinemia #258870 (AR) in OMIM but no skeletal phenotypes listed in clinical features.

This gene is not listed in Bonafe et al 2015 (Nosology and Classification of Genetic Skeletal Disorders: 2015 Revision) PMID: 26394607 or Mortier et al 2019 (Nosology and classification of genetic skeletal disorders: 2019 revision). PMID: 31633310; to: Associated with Gyrate atrophy of choroid and retina with or without ornithinemia #258870 (AR) in OMIM but no skeletal phenotypes listed in clinical features.

This gene is not listed in Bonafe et al 2015 (Nosology and Classification of Genetic Skeletal Disorders: 2015 Revision) PMID: 26394607 or Mortier et al 2019 (Nosology and classification of genetic skeletal disorders: 2019 revision). PMID: 31633310

A PubMed search did not find any relevant publications.
Skeletal dysplasia v1.220 SULF1 Eleanor Williams commented on gene: SULF1: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 20602915 - Isidor et al 2010 - using whole-genome oligonucleotide array CGH, they identified an interstitial deletion at 8q13 in 5 patients from 4 unrelated families with Mesomelia-synostoses syndrome. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1 and SLCO5A1. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Codeletion of SULF1 and SLCO5A1was found in all patients, suggesting that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.

PMID: 28328141 - Kohmoto et al 2017 - report the first Japanese case with MSS diagnosed by detecting an 8q13 deletion (581 Kb monoallelic deletion) that resulted from a unique, distant L1s‐mediated unequal NAHR event, which is different from the possible mechanisms proposed in previously reported cases. The deletion encompasses SULF1, SLCO5A1, and LINC01603. The size of the 8q13 deletion was different from those of any of the four reported deletions responsible for MSS (Isidor et al., 2010). The deletion could not be confirmed as de novo because of the unavailability of parental DNA.

PMID: 30450550 - Dardis et al 2019 - describe the first patient affected by MSS without the previously described 8q13 deletions. Patient is an 8‐year‐old 46,XY male presenting the radiological and clinical hallmarks of MSS. Microdeletions of SULF1 and SLCO5A1 genes at 8q13 were absent. Sequencing of SULF1 and SLCO5A1 found 4 polymorphisms but no pathogenic mutations. However, it was found that there was monoallelic expression of SULF1 in the patient's cells, likely leading to SULF1 haploinsufficiency. There may be either a deletion of a portion of SULF1 gene not detectable by PCR or CGH array or mutations or epigenetic alterations in sequences that contribute to the regulation of SULF1 expression.

Summary, there are 5 cases where deletions covering both SULF1 and SLCO5A1 are found in patients with MSS. There is one case of MSS in a patient with no detectable deletions of SULF1 and SLCO5A1, but with monoallelic expression of SULF1. There is no current regions curated by ClinGen that cover these genes.
Skeletal dysplasia v1.220 SLCO5A1 Eleanor Williams commented on gene: SLCO5A1: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 20602915 - Isidor et al 2010 - using whole-genome oligonucleotide array CGH, they identified an interstitial deletion at 8q13 in 5 patients from 4 unrelated families with Mesomelia-synostoses syndrome. The deletions vary from 582 Kb to 738 Kb in size, but invariably encompass only two genes: SULF1 and SLCO5A1. Breakpoint sequence analyses performed in two families showed nonrecurrent deletions. Codeletion of SULF1 and SLCO5A1was found in all patients, suggesting that haploinsufficiency of SULF1 combined with haploinsufficiency of SLCO5A1 (or the altered expression of a neighboring gene through position effect) could be necessary in the pathogenesis of MSS.

PMID: 28328141 - Kohmoto et al 2017 - report the first Japanese case with MSS diagnosed by detecting an 8q13 deletion (581 Kb monoallelic deletion) that resulted from a unique, distant L1s‐mediated unequal NAHR event, which is different from the possible mechanisms proposed in previously reported cases. The deletion encompasses SULF1, SLCO5A1, and LINC01603. The size of the 8q13 deletion was different from those of any of the four reported deletions responsible for MSS (Isidor et al., 2010). The deletion could not be confirmed as de novo because of the unavailability of parental DNA.

PMID: 30450550 - Dardis et al 2019 - describe the first patient affected by MSS without the previously described 8q13 deletions. Patient is an 8‐year‐old 46,XY male presenting the radiological and clinical hallmarks of MSS. Microdeletions of SULF1 and SLCO5A1 genes at 8q13 were absent. Sequencing of SULF1 and SLCO5A1 found 4 polymorphisms but no pathogenic mutations. However, it was found that there was monoallelic expression of SULF1 in the patient's cells, likely leading to SULF1 haploinsufficiency. There may be either a deletion of a portion of SULF1 gene not detectable by PCR or CGH array or mutations or epigenetic alterations in sequences that contribute to the regulation of SULF1 expression.

Summary, there are 5 cases where deletions covering both SULF1 and SLCO5A1 are found in patients with MSS. There is one case of MSS in a patient with no detectable deletions of SULF1 and SLCO5A1, but with monoallelic expression of SULF1. There is no current regions curated by ClinGen that cover these genes.
Rare genetic inflammatory skin disorders v0.15 CARD9 Catherine Snow Mode of inheritance for gene: CARD9 was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.220 RAD21 Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants:

PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.

PMID: 24378232 - Minor et al., 2014 - 2 patients with atypic Cornelia de Lange. Patient 1 - in frame deletion of exon 13 - presented with developmental delay, hypospadias, inguinal hernia and dysmorphic features, mild 5th finger clinodactyly. This deletion was found to be inherited from the mother who had a history of melanoma and other unspecified medical problems.
Patient 2 - c.592_593dup frameshift mutation - presented with developmental delay, characteristic facial features, hirsutism, and hand and feet anomalies (clinodactyly, syndactyly). The mother had the same frameshift mutation showing incomplete penetrance.

PMID: 27882533 - Boyle et al., 2017 - patient with microcephaly and classical CdLS facial features with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance.

PMID: 27620904 - Martinez et al., 2017 - 92 patients recruited with syndromic intellectual disability. 1 patient identified with a variant in RAD21. A diagnosis of CdLS was made.
Hypertrophic cardiomyopathy v1.78 MYBPC3 Ivone Leong Added comment: Comment on mode of inheritance: MOI changed due to evidence in OMIM that there are patients who are biallelic for variants in this gene.
Hypertrophic cardiomyopathy v1.78 MYBPC3 Ivone Leong Mode of inheritance for gene: MYBPC3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal dysplasia v1.220 RAD21 Eleanor Williams Classified gene: RAD21 as Amber List (moderate evidence)
Skeletal dysplasia v1.220 RAD21 Eleanor Williams Added comment: Comment on list classification: Promoted from red to amber. 2 cases reported in OMIM with SNV and short stature (1 case) and limb defects (2 cases). Other cases of deletions covering this gene and a similar phenotype are also reported.
Skeletal dysplasia v1.220 RAD21 Eleanor Williams Gene: rad21 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v1.219 RAD21 Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM. Clinical features listed include short stature and limb defects.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient
Skeletal dysplasia v1.219 RAD21 Eleanor Williams changed review comment from: Associated with Cornelia de Lange syndrome 4 614701 in OMIM.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short and thin fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short (1 patients) and thin (1 patient) fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient
Skeletal dysplasia v1.219 RAD21 Eleanor Williams changed review comment from: OMIM: - 2 cases reported in OMIM (PMID: 22633399, Deardorff et al 2012) plus 3 patients with overlapping deletions covering RAD21 (aswell as other genes).

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient; to: Associated with Cornelia de Lange syndrome 4 614701 in OMIM.

OMIM: - 2 cases reported in OMIM with Cornelia de Lange syndrome-4 (PMID: 22633399, Deardorff et al 2012) with de novo heterozygous missense mutations in RAD21. Phenotypic features include Clinodactyly, short and thin fingers and additional skeletal features of pectus carinatum, coxa vara, short femoral neck in one case. An additional 3 patients with overlapping deletions covering RAD21 (aswell as other genes) were identified.

Other publications with patients with Cornelia de Lange and RAD21 variants
PMID: 30716475 - Dorval et al 2019 - 1 patient - mild phenotype - gastro-oesophageal reflux, progressive microcephaly, which stabilised at about – 3SD, moderate fine motor delay and speech delay.
PMID: 24378232 - Minor et al., 2014 - 2 patients. In one case the mother had the same frameshift mutation showing incomplete penetrance.
PMID: 27882533 - Boyle et al., 2017 - patient with a single bp deletion (c.704delG) in RAD21 predicted to result in a premature stop codon [p.(Ser235Ilefs*19)]. The deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study - suggests incomplete penetrance
PMID: 27620904 - Martinez et al., 2017 - 1 patient
Skeletal dysplasia v1.219 OAT Eleanor Williams commented on gene: OAT: Associated with Gyrate atrophy of choroid and retina with or without ornithinemia #258870 (AR) in OMIM but no skeletal phenotypes listed in clinical features.

This gene is not listed in Bonafe et al 2015 (Nosology and Classification of Genetic Skeletal Disorders: 2015 Revision) PMID: 26394607 or Mortier et al 2019 (Nosology and classification of genetic skeletal disorders: 2019 revision). PMID: 31633310
Skeletal dysplasia v1.219 CKAP2L Eleanor Williams commented on gene: CKAP2L: Associated with Filippi syndrome #272440 (AR) in OMIM. Mainly a digital phenotype.

PMID: 25439729 - Hussain et al 2014 - performed homozygosity mapping and whole-exome sequencing in a Sardinian family with two children with Filippi syndrome and identified a homozygous frameshift mutation, c.571dupA (p.Ile191Asnfs∗6), in CKAP2L which segregated with the disease in the family. They then sequenced CKAP2L in eight additional Filippi-syndrome-affected families (one from Italy, one from Poland, one from Turkey, and five from the UK) and identified five additional mutations in four of the further eight families affected by Filippi syndrome.

Sufficient cases reported, but need to assess whether the phenotype is appropriate for the skeletal dysplasia panel. It is green on the Limb disorders panel.
Skeletal dysplasia v1.219 ARID1B Eleanor Williams commented on gene: ARID1B: Associated with Coffin-Siris syndrome 1 #135900 (AD) in OMIM. Clinical features list short stature in some patients, but mainly a limb phenotype including hypoplastic digits and nails.

OMIM lists many cases of variants in ARID1B reported in patients with Coffin-Siris syndrome.
Skeletal dysplasia v1.219 AKT1 Eleanor Williams changed review comment from: Associated with several phenotypes in OMIM including Proteus syndrome, somatic # 176920. Proteus syndrome features overgrowth of body parts and is associated with mosaicism for a somatic activating mutation in the AKT1 gene.

The Genomics England clinical team do not consider this appropriate for a green rating on the skeletal dysplasia panel.; to: Associated with several phenotypes in OMIM including Proteus syndrome, somatic # 176920. Proteus syndrome features overgrowth of body parts and is associated with mosaicism for a somatic activating mutation in the AKT1 gene.

PMID: 21793738 - Lindhurst et al 2011 - Of 29 patients with the Proteus syndrome, 26 had a somatic activating mutation (c.49G→A, p.Glu17Lys) in the oncogene AKT1. Tissues and cell lines from patients with the Proteus syndrome harbored admixtures of mutant alleles that ranged from 1% to approximately 50%. Mutant cell lines showed greater AKT phosphorylation than did control cell lines.

The Genomics England clinical team do not consider this appropriate for a green rating on the skeletal dysplasia panel.
Skeletal dysplasia v1.219 AKT1 Eleanor Williams commented on gene: AKT1: Associated with several phenotypes in OMIM including Proteus syndrome, somatic # 176920. Proteus syndrome features overgrowth of body parts and is associated with mosaicism for a somatic activating mutation in the AKT1 gene.

The Genomics England clinical team do not consider this appropriate for a green rating on the skeletal dysplasia panel.
Skeletal dysplasia v1.219 TWIST2 Eleanor Williams Classified gene: TWIST2 as No list
Skeletal dysplasia v1.219 TWIST2 Eleanor Williams Added comment: Comment on list classification: Removing this gene from the panel as the OMIM phenotypes to not have a clear skeletal phenotype.
Skeletal dysplasia v1.219 TWIST2 Eleanor Williams Gene: twist2 has been removed from the panel.
Limb disorders v1.63 THPO Eleanor Williams Classified gene: THPO as Amber List (moderate evidence)
Limb disorders v1.63 THPO Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. Two cases of Thrombocythemia with limb defects and variants in THPO reported.
Limb disorders v1.63 THPO Eleanor Williams Gene: thpo has been classified as Amber List (Moderate Evidence).
Limb disorders v1.62 THPO Eleanor Williams gene: THPO was added
gene: THPO was added to Limb disorders. Sources: Literature
Mode of inheritance for gene: THPO was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: THPO were set to 19553636; 22453305
Phenotypes for gene: THPO were set to Thrombocythemia 1, 187950
Review for gene: THPO was set to AMBER
Added comment: Associated with Thrombocythemia 1 #187950 (AD) in OMIM.


PMID: 19553636 - Graziano et al 2009 - report where the father has thrombocythemia and limb defects (absence of forearm and hand, absence of foot). Two sons had milder lower limb defects. A G185T heterozygous mutation was detected in THPO. The grandfather was found to have the variant and had thrombocythemia but no limb defect.

PMID: 22453305 - Stockklausner et al 2012 - report two families with Hereditary thrombocythemia resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects in 2 out of 4 individuals with thrombocythemia (complex limb defects of the left hand in one individual, and absent proximal, middle, and distal phalanges at digits 3–5, a dysplastic proximal phalanx at digit 2 with absent middle and distal phalanx and shortened metacarpal bones at digits 3 and 4, carpal bones were partly fused to metacarpal bones at digits 2–5 in the other).

Two cases reported with a limb defect and no clear wider skeletal phenotype.
Sources: Literature
Skeletal dysplasia v1.218 THPO Eleanor Williams Classified gene: THPO as Red List (low evidence)
Skeletal dysplasia v1.218 THPO Eleanor Williams Added comment: Comment on list classification: Demoted from Green to red. Only two cases reported with a limb defect and no clear wider skeletal phenotype.
Skeletal dysplasia v1.218 THPO Eleanor Williams Gene: thpo has been classified as Red List (Low Evidence).
Skeletal dysplasia v1.217 THPO Eleanor Williams commented on gene: THPO: Associated with Thrombocythemia 1 #187950 (AD) in OMIM.


PMID: 19553636 - Graziano et al 2009 - report where the father has thrombocythemia and limb defects (absence of forearm and hand, absence of foot). Two sons had milder lower limb defects. A G185T heterozygous mutation was detected in THPO. The grandfather was found to have the variant and had thrombocythemia but no limb defect.

PMID: 22453305 - Stockklausner et al 2012 - report two families with Hereditary thrombocythemia resulting from a THPO c.13+1 G>C mutation in the splice donor of intron 3. In one family there were coexisting distal limb defects in 2 out of 4 individuals with thrombocythemia (complex limb defects of the left hand in one individual, and absent proximal, middle, and distal phalanges at digits 3–5, a dysplastic proximal phalanx at digit 2 with absent middle and distal phalanx and shortened metacarpal bones at digits 3 and 4, carpal bones were partly fused to metacarpal bones at digits 2–5 in the other).
Skeletal dysplasia v1.217 ASXL1 Eleanor Williams changed review comment from: Associated with Bohring-Opitz syndrome #605039 (AD) in OMIM. Clinical features listed include short stature and a number of skeletal features including upper limb rhizomelia.; to: Associated with Bohring-Opitz syndrome #605039 (AD) in OMIM. Clinical features listed include short stature and a number of skeletal features including upper limb rhizomelia.

Genomics England clinical team feel that there are sufficient relevant phenotypes to leave green.
Skeletal dysplasia v1.217 ASXL1 Eleanor Williams commented on gene: ASXL1: Associated with Bohring-Opitz syndrome #605039 (AD) in OMIM. Clinical features listed include short stature and a number of skeletal features including upper limb rhizomelia.
Skeletal dysplasia v1.217 TGDS Eleanor Williams commented on gene: TGDS: Associated with Catel-Manzke syndrome #616145 (AR) in OMIM.

PMID: 25480037 - Ehmke et al 2014 - Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. They identified homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction they showed that the mutation c.298G>T is probably a founder mutation


In 7 patients with Catel-Manzke syndrome (616145), Ehmke et al. (2014) identified homozygosity or compound heterozygosity for mutations in the TGDS gene
Skeletal dysplasia v1.217 WRN Eleanor Williams Mode of inheritance for gene: WRN was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.217 WRN Eleanor Williams Mode of inheritance for gene: WRN was changed from to BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.216 WRN Eleanor Williams commented on gene: WRN: Associated with Werner syndrome #277700 (AR) in OMIM with Osteoporosis and slender limbs listed as clinical features.
From Genetics Home Reference "Werner syndrome is characterized by the dramatic, rapid appearance of features associated with normal aging. Individuals with this disorder typically grow and develop normally until they reach puberty. Affected teenagers usually do not have a growth spurt, resulting in short stature".

Numerous variants reported in the RECQL2/WRN gene in association with Werner syndrome in OMIM.
Arrhythmogenic right ventricular cardiomyopathy v1.43 FLNC Ellen McDonagh Classified gene: FLNC as Green List (high evidence)
Arrhythmogenic right ventricular cardiomyopathy v1.43 FLNC Ellen McDonagh Added comment: Comment on list classification: Promoted from Amber to Green based on two expert reviews and Definitive gene validity curation by ClinGen Expert Panel.
Arrhythmogenic right ventricular cardiomyopathy v1.43 FLNC Ellen McDonagh Gene: flnc has been classified as Green List (High Evidence).
Arrhythmogenic right ventricular cardiomyopathy v1.42 FLNC Ellen McDonagh Mode of inheritance for gene: FLNC was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.64 PRDM16 Ellen McDonagh Classified gene: PRDM16 as Amber List (moderate evidence)
Dilated Cardiomyopathy and conduction defects v1.64 PRDM16 Ellen McDonagh Added comment: Comment on list classification: Promoted to Amber as not enough evidence at this stage to be Green.
Dilated Cardiomyopathy and conduction defects v1.64 PRDM16 Ellen McDonagh Gene: prdm16 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.408 HCN2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept MOI as 'BOTH monoallelic and biallelic' as supported by reviews from Helen Lord and Alison Callaway, and literature (PMID:22131395).
Early onset or syndromic epilepsy v1.408 HCN2 Rebecca Foulger Mode of inheritance for gene: HCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Intellectual disability v2.1102 IL3RA Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1102 IL3RA Eleanor Williams Mode of inheritance for gene: IL3RA 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 Unknown
Intellectual disability v2.1101 DHRSX Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1101 DHRSX Eleanor Williams Mode of inheritance for gene: DHRSX 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 Unknown
Intellectual disability v2.1100 CRLF2 Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1100 CRLF2 Eleanor Williams Mode of inheritance for gene: CRLF2 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 Unknown
Intellectual disability v2.1099 AKAP17A Eleanor Williams Added comment: Comment on mode of inheritance: This gene is in the pseudoautosomal region shared between chromosomes X and Y. The mode of inheritance should therefore be set to Biallelic or Monoallelic once more cases establish the inheritance pattern.
Intellectual disability v2.1099 AKAP17A Eleanor Williams Mode of inheritance for gene: AKAP17A 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 Unknown
Laterality disorders and isomerism v0.51 CCDC39 Matthew Edwards reviewed gene: CCDC39: Rating: GREEN; Mode of pathogenicity: None; Publications: 21131972, 23255504; Phenotypes: OMIM 613807 Ciliary dyskinesia, primary, 14; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Thoracic aortic aneurysm or dissection (GMS) v0.53 TGFB3 Ivone Leong Publications for gene: TGFB3 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.52 SKI Ivone Leong Publications for gene: SKI were set to
Thoracic aortic aneurysm or dissection (GMS) v0.51 PRKG1 Ivone Leong Publications for gene: PRKG1 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.50 NOTCH1 Ivone Leong Publications for gene: NOTCH1 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.49 MYLK Ivone Leong Publications for gene: MYLK were set to
Thoracic aortic aneurysm or dissection (GMS) v0.48 FBN2 Ivone Leong Publications for gene: FBN2 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.47 EFEMP2 Ivone Leong Publications for gene: EFEMP2 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.46 COL5A2 Ivone Leong Publications for gene: COL5A2 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.45 CBS Ivone Leong Publications for gene: CBS were set to 747076; 18799873; 16733360; 2041851; 23525608
Thoracic aortic aneurysm or dissection v1.109 COL5A2 Ivone Leong Publications for gene: COL5A2 were set to 26188975; 29543232
Thoracic aortic aneurysm or dissection v1.108 COL5A2 Ivone Leong Publications for gene: COL5A2 were set to 26188975
Thoracic aortic aneurysm or dissection v1.107 COL5A1 Ivone Leong Publications for gene: COL5A1 were set to 26188975; 10946364
Thoracic aortic aneurysm or dissection v1.106 COL3A1 Ivone Leong Publications for gene: COL3A1 were set to 25758994
Thoracic aortic aneurysm or dissection v1.105 COL1A2 Ivone Leong Publications for gene: COL1A2 were set to
Thoracic aortic aneurysm or dissection v1.104 BGN Ivone Leong Publications for gene: BGN were set to 27632686
Structural eye disease v1.0 Ivone Leong promoted panel to version 1.0
Structural eye disease v0.99 HMX1 Ivone Leong Added comment: Comment on mode of inheritance: MOI corrected from Both monoallelic and biallelic to Biallelic based on reviewers comments and OMIM.
Structural eye disease v0.99 HMX1 Ivone Leong Mode of inheritance for gene: HMX1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Additional findings health related v0.84 MSH2 Ellen McDonagh Source Additional Findings was removed from MSH2.
Source ACMG was removed from MSH2.
Source Expert list was added to MSH2.
Phenotypes for gene: MSH2 were changed from ENST00000233146.6; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Transcript for gene MSH2 was changed from None to ENST00000233146.6
Additional findings health related v0.83 MLH1 Ellen McDonagh Source Additional Findings was removed from MLH1.
Source ACMG was removed from MLH1.
Source Expert list was added to MLH1.
Phenotypes for gene: MLH1 were changed from ENST00000231790.6; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Transcript for gene MLH1 was changed from None to ENST00000231790.6
Additional findings health related v0.82 MEN1 Ellen McDonagh Source Additional Findings was removed from MEN1.
Source ACMG was removed from MEN1.
Source Expert list was added to MEN1.
Phenotypes for gene: MEN1 were changed from ENST00000394374.6; Other cancer predisposition; Myltiple endocrine Neoplasia Type 1; Adult and child to Other cancer predisposition; Myltiple endocrine Neoplasia Type 1; Adult and child
Transcript for gene MEN1 was changed from None to ENST00000394374.6
Additional findings health related v0.81 LDLR Ellen McDonagh Source Additional Findings was removed from LDLR.
Source ACMG was removed from LDLR.
Source Expert list was added to LDLR.
Phenotypes for gene: LDLR were changed from ENST00000558518.5; Familial hypercholesterolaemia; Adult and child to Familial hypercholesterolaemia; Adult and child
Transcript for gene LDLR was changed from None to ENST00000558518.5
Additional findings reproductive carrier status v0.3 CFTR Ellen McDonagh Phenotypes for gene: CFTR were changed from ENST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only to Carrier status; Cystic Fibrosis; Adult-only
Transcript for gene CFTR was changed from None to ENST00000003084.10
Additional findings health related v0.80 BRCA2 Ellen McDonagh Source Additional Findings was removed from BRCA2.
Source ACMG was removed from BRCA2.
Source Expert list was added to BRCA2.
Phenotypes for gene: BRCA2 were changed from ENST00000544455.5; Breast and ovarian cancer predisposition; Adult only to Breast and ovarian cancer predisposition; Adult only
Transcript for gene BRCA2 was changed from None to ENST00000544455.5
Additional findings health related v0.79 BRCA1 Ellen McDonagh Source Additional Findings was removed from BRCA1.
Source ACMG was removed from BRCA1.
Source Expert list was added to BRCA1.
Transcript for gene BRCA1 was changed from None to ENST00000357654.8
Additional findings health related v0.78 APOB Ellen McDonagh Phenotypes for gene: APOB were changed from ENST00000233242.5; Familial hypercholesterolaemia; Adult and child to Familial hypercholesterolaemia; Adult and child
Transcript for gene APOB was changed from None to ENST00000233242.5
Additional findings health related v0.77 APC Ellen McDonagh Source Additional Findings was removed from APC.
Source ACMG was removed from APC.
Source Expert list was added to APC.
Phenotypes for gene: APC were changed from ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Transcript for gene APC was changed from None to ENST00000257430.9
Structural eye disease v0.98 WDR37 Ivone Leong Classified gene: WDR37 as Red List (low evidence)
Structural eye disease v0.98 WDR37 Ivone Leong Added comment: Comment on list classification: New gene submitted by reviewer. I have made this gene a Red gene as the current panel has already been finalised. This gene can be considered for a new gene rating in the next review iteration.
Structural eye disease v0.98 WDR37 Ivone Leong Gene: wdr37 has been classified as Red List (Low Evidence).
Fetal anomalies v0.348 GLA Rebecca Foulger changed review comment from: Added GLA to panel based on Green rating on Fetal hydrops panel V1.16, following email communication from Dominic McMullan (West Midlands, Oxford and Wessex GLH).
Sources: Other; to: Added GLA to panel as a Green gene based on Green rating on Fetal hydrops panel V1.16, following email communication from Dominic McMullan (West Midlands, Oxford and Wessex GLH).
Sources: Other
Fetal anomalies v0.348 GLA Rebecca Foulger Classified gene: GLA as Green List (high evidence)
Fetal anomalies v0.348 GLA Rebecca Foulger Gene: gla has been classified as Green List (High Evidence).
Fetal anomalies v0.347 GLA Rebecca Foulger gene: GLA was added
gene: GLA was added to Fetal anomalies. Sources: Other
Mode of inheritance for gene: GLA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: GLA were set to Fabry disease, 301500
Added comment: Added GLA to panel based on Green rating on Fetal hydrops panel V1.16, following email communication from Dominic McMullan (West Midlands, Oxford and Wessex GLH).
Sources: Other
Structural eye disease v0.97 WDR37 Ivone Leong Publications for gene: WDR37 were set to PMID:31327510, PMID:31327508
Structural eye disease v0.96 Ivone Leong Panel types changed to GMS Rare Disease; GMS signed-off
Retinal disorders v2.1 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Retinal disorders v2.0 Ivone Leong promoted panel to version 2.0
Retinal disorders v1.228 RDH12 Ivone Leong Added comment: Comment on mode of inheritance: MOI has been updated from Biallelic to BOTH monoallelic and biallelic based on PMID: 31505163, which describes both autosomal dominant and recessive retinal phenotypes.
Retinal disorders v1.228 RDH12 Ivone Leong Mode of inheritance for gene: RDH12 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v1.227 RDH12 Ivone Leong Publications for gene: RDH12 were set to
Retinal disorders v1.226 NMNAT1 Ivone Leong Publications for gene: NMNAT1 were set to
Retinal disorders v1.225 CSPP1 Ivone Leong Phenotypes for gene: CSPP1 were changed from Genetic Retinal Degeneration Conditions; Joubert syndrome 21 to Genetic Retinal Degeneration Conditions; Joubert syndrome 21,615636
Retinal disorders v1.224 COL18A1 Ivone Leong Phenotypes for gene: COL18A1 were changed from Knobloch Syndrome Type I to Knobloch Syndrome Type I, 267750
Retinal disorders v1.223 CNGA3 Ivone Leong Phenotypes for gene: CNGA3 were changed from Achromatopsia; Achromatopsia-2; Eye Disorders; Achromatopsia, Cone, and Cone-rod Dystrophy to Achromatopsia; Achromatopsia-2, 216900; Eye Disorders; Achromatopsia, Cone, and Cone-rod Dystrophy
Retinal disorders v1.222 CLRN1 Ivone Leong Phenotypes for gene: CLRN1 were changed from Eye Disorders; ?Usher syndrome, type 3A, 276902Retinitis pigmentosa 61, 614180; Retinitis Pigmentosa, Dominant; Retinitis pigmentosa to Eye Disorders; ?Usher syndrome, type 3A, 276902; Retinitis pigmentosa 61, 614180
Retinal disorders v1.221 CEP290 Ivone Leong Publications for gene: CEP290 were set to
Retinal disorders v1.220 CDHR1 Ivone Leong Phenotypes for gene: CDHR1 were changed from Achromatopsia, Cone, and Cone-rod Dystrophy; Eye Disorders; Cone-Rod Dystrophy, Recessive; Cone-rod dystrophy 15, 613660 to Achromatopsia, Cone, and Cone-rod Dystrophy; Eye Disorders; Cone-Rod Dystrophy, Recessive; Cone-rod dystrophy 15, 613660; Retinitis pigmentosa 65, 613660
Retinal disorders v1.219 CC2D2A Ivone Leong Phenotypes for gene: CC2D2A were changed from COACH syndrome; Joubert syndrome 9; Meckel syndrome 6; Eye Disorders to COACH syndrome, 216360; Joubert syndrome 9, 612285; Meckel syndrome 6, 612284; Eye Disorders
Retinal disorders v1.218 BBS9 Ivone Leong Phenotypes for gene: BBS9 were changed from Eye Disorders to Eye Disorders; Bardet-Biedl syndrome 9, 615986
Retinal disorders v1.217 BBS7 Ivone Leong Phenotypes for gene: BBS7 were changed from Eye Disorders to Eye Disorders; Bardet-Biedl syndrome 7, 615984
Retinal disorders v1.216 BBS5 Ivone Leong Phenotypes for gene: BBS5 were changed from Eye Disorders; Bardet-Biedl syndrome 5 to Eye Disorders; Bardet-Biedl syndrome 5, 615983
Retinal disorders v1.215 BBS4 Ivone Leong Phenotypes for gene: BBS4 were changed from Eye Disorders; Bardet-Biedl syndrome 4 to Eye Disorders; Bardet-Biedl syndrome 4, 615982
Retinal disorders v1.214 BBS2 Ivone Leong Phenotypes for gene: BBS2 were changed from Eye Disorders; Bardet-Biedl syndrome 2; Retinitis pigmentosa 74 to Eye Disorders; Bardet-Biedl syndrome 2, 615981; Retinitis pigmentosa 74, 616562
Retinal disorders v1.213 BBS12 Ivone Leong Phenotypes for gene: BBS12 were changed from Eye Disorders; Bardet-Biedl syndrome 12 to Eye Disorders; Bardet-Biedl syndrome 12, 615989
Retinal disorders v1.212 BBS1 Ivone Leong Phenotypes for gene: BBS1 were changed from Eye Disorders; Retinitis pigmentosa to Eye Disorders; Retinitis pigmentosa; Bardet-Biedl syndrome 1, 209900
Retinal disorders v1.211 BBS10 Ivone Leong Phenotypes for gene: BBS10 were changed from Eye Disorders; Bardet-Biedl syndrome 10 to Eye Disorders; Bardet-Biedl syndrome 10, 615987
Retinal disorders v1.210 ATOH7 Ivone Leong Phenotypes for gene: ATOH7 were changed from Persistent hyperplastic primary vitreous, autosomal recessive; multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus to Persistent hyperplastic primary vitreous, autosomal recessive, 221900; multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus
Retinal disorders v1.209 ATF6 Ivone Leong Phenotypes for gene: ATF6 were changed from Achromatopsia 7 to Achromatopsia 7, 616517
Retinal disorders v1.208 ALMS1 Ivone Leong Phenotypes for gene: ALMS1 were changed from Eye Disorders; Alstrom syndrome to Eye Disorders; Alstrom syndrome, 203800
Retinal disorders v1.207 AHI1 Ivone Leong Phenotypes for gene: AHI1 were changed from Eye Disorders; Joubert syndrome 17 to Eye Disorders; Joubert syndrome 3, 608629
Retinal disorders v1.206 AGBL5 Ivone Leong Phenotypes for gene: AGBL5 were changed from Retinitis pigmentosa; Retinitis pigmentosa 75 617023 to Retinitis pigmentosa 75, 617023
Retinal disorders v1.205 ADAMTS18 Ivone Leong Phenotypes for gene: ADAMTS18 were changed from Genetic Retinal Degeneration Conditions; Microcornea, myopic chorioretinal atrophy, and telecanthus to Genetic Retinal Degeneration Conditions; Microcornea, myopic chorioretinal atrophy, and telecanthus, 615458
Retinal disorders v1.204 ADGRV1 Ivone Leong Phenotypes for gene: ADGRV1 were changed from Usher syndrome, type 2C; Eye Disorders to Usher syndrome, type 2C, 605472; Eye Disorders; Usher syndrome, type 2C, GPR98/PDZD7 digenic, 605472
Thoracic aortic aneurysm or dissection (GMS) v0.44 FOXE3 Ivone Leong Phenotypes for gene: FOXE3 were changed from {Aortic aneurysm, familial thoracic 11, susceptibility to} to Aortic aneurysm, familial thoracic 11, (susceptibility to) 617349
Thoracic aortic aneurysm or dissection (GMS) v0.43 FOXE3 Ivone Leong Publications for gene: FOXE3 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.42 FLNA Ivone Leong Phenotypes for gene: FLNA were changed from Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders to Marfan Syndrome, Thoracic Aortic Aneurysm & Dissection (TAAD), and Related Disorders; Cardiac valvular dysplasia, X-linked 314400
Thoracic aortic aneurysm or dissection (GMS) v0.41 FLNA Ivone Leong Publications for gene: FLNA were set to
Thoracic aortic aneurysm or dissection (GMS) v0.40 FKBP14 Ivone Leong Phenotypes for gene: FKBP14 were changed from to Ehlers-Danlos syndrome, kyphoscoliotic type, 2 614557
Thoracic aortic aneurysm or dissection (GMS) v0.39 FKBP14 Ivone Leong Publications for gene: FKBP14 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.38 ELN Ivone Leong Publications for gene: ELN were set to
Thoracic aortic aneurysm or dissection (GMS) v0.37 ABL1 Ivone Leong Publications for gene: ABL1 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.36 LOX Ivone Leong Publications for gene: LOX were set to
Thoracic aortic aneurysm or dissection (GMS) v0.35 ZNF469 Ivone Leong reviewed gene: ZNF469: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 TNXB Ivone Leong reviewed gene: TNXB: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 SLC39A13 Ivone Leong reviewed gene: SLC39A13: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 PKD2 Ivone Leong reviewed gene: PKD2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 PKD1 Ivone Leong reviewed gene: PKD1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 MYLK2 Ivone Leong reviewed gene: MYLK2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 MAT2A Ivone Leong reviewed gene: MAT2A: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 LTBP2 Ivone Leong reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 KCNN1 Ivone Leong reviewed gene: KCNN1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 HNRNPK Ivone Leong reviewed gene: HNRNPK: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 EMILIN1 Ivone Leong reviewed gene: EMILIN1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL9A3 Ivone Leong reviewed gene: COL9A3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL9A2 Ivone Leong reviewed gene: COL9A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL9A1 Ivone Leong reviewed gene: COL9A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL4A1 Ivone Leong reviewed gene: COL4A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL2A1 Ivone Leong reviewed gene: COL2A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL1A2 Ivone Leong reviewed gene: COL1A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL1A1 Ivone Leong reviewed gene: COL1A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL11A2 Ivone Leong reviewed gene: COL11A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL11A1 Ivone Leong reviewed gene: COL11A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 CHST14 Ivone Leong reviewed gene: CHST14: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 B4GALT7 Ivone Leong reviewed gene: B4GALT7: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ATP7A Ivone Leong reviewed gene: ATP7A: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ATP6V0A2 Ivone Leong reviewed gene: ATP6V0A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ALDH18A1 Ivone Leong reviewed gene: ALDH18A1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ADAMTS2 Ivone Leong reviewed gene: ADAMTS2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ACVR1 Ivone Leong reviewed gene: ACVR1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ABCC6 Ivone Leong reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 MED12 Ivone Leong reviewed gene: MED12: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 FLCN Ivone Leong reviewed gene: FLCN: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 SMAD6 Ivone Leong reviewed gene: SMAD6: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 SMAD4 Ivone Leong reviewed gene: SMAD4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 SMAD2 Ivone Leong reviewed gene: SMAD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 PLOD1 Ivone Leong reviewed gene: PLOD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 MFAP5 Ivone Leong reviewed gene: MFAP5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 FOXE3 Ivone Leong reviewed gene: FOXE3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 FLNA Ivone Leong edited their review of gene: FLNA: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.; Changed rating: AMBER
Thoracic aortic aneurysm or dissection (GMS) v0.35 FKBP14 Ivone Leong reviewed gene: FKBP14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 FBLN5 Ivone Leong reviewed gene: FBLN5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ELN Ivone Leong reviewed gene: ELN: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 ABL1 Ivone Leong reviewed gene: ABL1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 TGFBR2 Ivone Leong reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 TGFBR1 Ivone Leong reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 TGFB3 Ivone Leong edited their review of gene: TGFB3: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 TGFB2 Ivone Leong reviewed gene: TGFB2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 SMAD3 Ivone Leong reviewed gene: SMAD3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 SLC2A10 Ivone Leong edited their review of gene: SLC2A10: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 SKI Ivone Leong reviewed gene: SKI: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 PRKG1 Ivone Leong reviewed gene: PRKG1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 NOTCH1 Ivone Leong reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 MYLK Ivone Leong reviewed gene: MYLK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 MYH11 Ivone Leong reviewed gene: MYH11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 LOX Ivone Leong reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 FBN2 Ivone Leong edited their review of gene: FBN2: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 FBN1 Ivone Leong reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 EFEMP2 Ivone Leong reviewed gene: EFEMP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL5A2 Ivone Leong edited their review of gene: COL5A2: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel. Therefore this gene has been promoted from Amber to Green; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL5A1 Ivone Leong edited their review of gene: COL5A1: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel. Therefore this gene has been promoted from Amber to Green; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 COL3A1 Ivone Leong reviewed gene: COL3A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.35 CBS Ivone Leong edited their review of gene: CBS: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 BGN Ivone Leong edited their review of gene: BGN: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel. Therefore this gene has been promoted from Amber to Green; Changed rating: GREEN
Thoracic aortic aneurysm or dissection (GMS) v0.35 ACTA2 Ivone Leong reviewed gene: ACTA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.34 MED12 Ivone Leong Source NHS GMS was added to MED12.
Source Expert Review Red was added to MED12.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 FLCN Ivone Leong Source NHS GMS was added to FLCN.
Source Expert Review Red was added to FLCN.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 SMAD6 Ivone Leong Source NHS GMS was added to SMAD6.
Source Expert Review Amber was added to SMAD6.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 PLOD1 Ivone Leong Source NHS GMS was added to PLOD1.
Source Expert Review Amber was added to PLOD1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 FKBP14 Ivone Leong Source NHS GMS was added to FKBP14.
Source Expert Review Amber was added to FKBP14.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 FBLN5 Ivone Leong Source NHS GMS was added to FBLN5.
Source Expert Review Amber was added to FBLN5.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 PRKG1 Ivone Leong Source Expert Review Green was added to PRKG1.
Source NHS GMS was added to PRKG1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 NOTCH1 Ivone Leong Source Expert Review Green was added to NOTCH1.
Source NHS GMS was added to NOTCH1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 LOX Ivone Leong Source Expert Review Green was added to LOX.
Source NHS GMS was added to LOX.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 EFEMP2 Ivone Leong Source Expert Review Green was added to EFEMP2.
Source NHS GMS was added to EFEMP2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 COL5A2 Ivone Leong Source Expert Review Green was added to COL5A2.
Source NHS GMS was added to COL5A2.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 COL5A1 Ivone Leong Source Expert Review Green was added to COL5A1.
Source NHS GMS was added to COL5A1.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.34 BGN Ivone Leong Source Expert Review Green was added to BGN.
Source NHS GMS was added to BGN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Thoracic aortic aneurysm or dissection (GMS) v0.33 FBLN5 Ivone Leong Publications for gene: FBLN5 were set to
Likely inborn error of metabolism v1.407 UQCC2 Catherine Snow Mode of inheritance for gene: UQCC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.406 YME1L1 Catherine Snow commented on gene: YME1L1
Likely inborn error of metabolism v1.406 TMEM65 Catherine Snow commented on gene: TMEM65
Likely inborn error of metabolism v1.406 TIMMDC1 Catherine Snow commented on gene: TIMMDC1
Likely inborn error of metabolism v1.406 TFAM Catherine Snow commented on gene: TFAM
Likely inborn error of metabolism v1.406 SSBP1 Catherine Snow commented on gene: SSBP1
Likely inborn error of metabolism v1.406 SLC25A32 Catherine Snow commented on gene: SLC25A32: Treatable tag was added based on reports in PMID: 26933868 and 28443623, that riboflavin treatment was effective.
Likely inborn error of metabolism v1.406 SLC25A32 Catherine Snow commented on gene: SLC25A32
Likely inborn error of metabolism v1.406 PTCD3 Catherine Snow commented on gene: PTCD3
Likely inborn error of metabolism v1.406 PET117 Catherine Snow commented on gene: PET117
Likely inborn error of metabolism v1.406 NSUN3 Catherine Snow changed review comment from: PMID: 27356879 - reports on a loss-of-function mutation in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency.; to: PMID: 27356879 - reports on a compound heterozygous variant resulting in a loss-of-function mutation in NSUN3 in a patient presenting with combined mitochondrial respiratory chain complex deficiency.
Likely inborn error of metabolism v1.406 NSUN3 Catherine Snow commented on gene: NSUN3
Likely inborn error of metabolism v1.406 MSTO1 Catherine Snow commented on gene: MSTO1
Likely inborn error of metabolism v1.406 MRPS14 Catherine Snow commented on gene: MRPS14
Likely inborn error of metabolism v1.406 MRM2 Catherine Snow changed review comment from: One proband identified in PMID: 28973171, OMIM currently based on this.; to: One proband identified in PMID: 28973171, OMIM entry currently based on this.
Likely inborn error of metabolism v1.406 MRM2 Catherine Snow commented on gene: MRM2
Likely inborn error of metabolism v1.406 ERAL1 Catherine Snow commented on gene: ERAL1
Likely inborn error of metabolism v1.406 YME1L1 Catherine Snow gene: YME1L1 was added
gene: YME1L1 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: YME1L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: YME1L1 were set to 27495975
Phenotypes for gene: YME1L1 were set to ?Optic atrophy 11, 617302
Likely inborn error of metabolism v1.406 TMEM65 Catherine Snow gene: TMEM65 was added
gene: TMEM65 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: TMEM65 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM65 were set to 28295037
Phenotypes for gene: TMEM65 were set to TMEM65 related mitochondrial encephalopmyopathy
Likely inborn error of metabolism v1.406 TIMMDC1 Catherine Snow gene: TIMMDC1 was added
gene: TIMMDC1 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: TIMMDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TIMMDC1 were set to 28604674
Phenotypes for gene: TIMMDC1 were set to Mitochondrial complex I deficiency, nuclear type 31, 618251
Likely inborn error of metabolism v1.406 TFAM Catherine Snow gene: TFAM was added
gene: TFAM was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: TFAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFAM were set to 27448789
Phenotypes for gene: TFAM were set to ?Mitochondrial DNA depletion syndrome 15 (hepatocerebral type), 617156
Likely inborn error of metabolism v1.406 SSBP1 Catherine Snow gene: SSBP1 was added
gene: SSBP1 was added to Inborn errors of metabolism. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: SSBP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SSBP1 were set to 31298765
Likely inborn error of metabolism v1.406 SLC25A32 Catherine Snow gene: SLC25A32 was added
gene: SLC25A32 was added to Inborn errors of metabolism. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: SLC25A32 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A32 were set to 26933868; 28443623
Phenotypes for gene: SLC25A32 were set to ?Exercise intolerance, riboflavin-responsive
Likely inborn error of metabolism v1.406 PTCD3 Catherine Snow gene: PTCD3 was added
gene: PTCD3 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: PTCD3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCD3 were set to 30607703; 30706245
Phenotypes for gene: PTCD3 were set to low birth weight, mental retardation, and optic atrophy
Likely inborn error of metabolism v1.406 PET117 Catherine Snow gene: PET117 was added
gene: PET117 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: PET117 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PET117 were set to 28386624
Phenotypes for gene: PET117 were set to lesions in the medulla oblongata
Likely inborn error of metabolism v1.406 NSUN3 Catherine Snow gene: NSUN3 was added
gene: NSUN3 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: NSUN3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSUN3 were set to 27356879
Phenotypes for gene: NSUN3 were set to Combined mitochondrial respiratory chain complex deficiency
Likely inborn error of metabolism v1.406 MSTO1 Catherine Snow gene: MSTO1 was added
gene: MSTO1 was added to Inborn errors of metabolism. Sources: Expert Review Green,Expert list
Mode of inheritance for gene: MSTO1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MSTO1 were set to 28554942; 28544275
Phenotypes for gene: MSTO1 were set to Myopathy, mitochondrial, and ataxia, 617675
Likely inborn error of metabolism v1.406 MRPS14 Catherine Snow gene: MRPS14 was added
gene: MRPS14 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: MRPS14 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPS14 were set to 30358850
Phenotypes for gene: MRPS14 were set to ?Combined oxidative phosphorylation deficiency 38, 618378
Likely inborn error of metabolism v1.406 MRM2 Catherine Snow gene: MRM2 was added
gene: MRM2 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: MRM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRM2 were set to 28973171
Phenotypes for gene: MRM2 were set to ?Mitochondrial DNA depletion syndrome 17, 618567
Likely inborn error of metabolism v1.406 ERAL1 Catherine Snow gene: ERAL1 was added
gene: ERAL1 was added to Inborn errors of metabolism. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: ERAL1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERAL1 were set to 28449065
Phenotypes for gene: ERAL1 were set to Perrault syndrome 6, 617565
Catecholaminergic polymorphic VT v1.25 CALM3 Ivone Leong reviewed gene: CALM3: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Catecholaminergic polymorphic VT v1.25 TECRL Ivone Leong reviewed gene: TECRL: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Catecholaminergic polymorphic VT v1.25 TRDN Ivone Leong reviewed gene: TRDN: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Catecholaminergic polymorphic VT v1.25 RYR2 Ivone Leong edited their review of gene: RYR2: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Catecholaminergic polymorphic VT v1.25 CASQ2 Ivone Leong reviewed gene: CASQ2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Catecholaminergic polymorphic VT v1.25 CALM2 Ivone Leong reviewed gene: CALM2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Catecholaminergic polymorphic VT v1.25 CALM1 Ivone Leong reviewed gene: CALM1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Short QT syndrome v1.23 SLC22A5 Ivone Leong edited their review of gene: SLC22A5: Changed rating: RED
Short QT syndrome v1.23 SLC22A5 Ivone Leong edited their review of gene: SLC22A5: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Red on this panel.; Changed rating: AMBER
Short QT syndrome v1.23 SLC4A3 Ivone Leong edited their review of gene: SLC4A3: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.; Changed rating: AMBER
Short QT syndrome v1.23 CACNB2 Ivone Leong edited their review of gene: CACNB2: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.; Changed rating: AMBER
Short QT syndrome v1.23 CACNA2D1 Ivone Leong edited their review of gene: CACNA2D1: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.; Changed rating: AMBER
Short QT syndrome v1.23 KCNQ1 Ivone Leong reviewed gene: KCNQ1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Short QT syndrome v1.23 KCNJ2 Ivone Leong edited their review of gene: KCNJ2: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Short QT syndrome v1.23 KCNH2 Ivone Leong reviewed gene: KCNH2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Short QT syndrome v1.23 CACNA1C Ivone Leong reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Brugada syndrome and cardiac sodium channel disease v1.45 SCN5A Ivone Leong edited their review of gene: SCN5A: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Long QT syndrome v1.45 CALM3 Ivone Leong Mode of inheritance for gene: CALM3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Long QT syndrome v1.44 CAV3 Ivone Leong reviewed gene: CAV3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 KCNJ5 Ivone Leong reviewed gene: KCNJ5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 SCN4B Ivone Leong reviewed gene: SCN4B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 ANK2 Ivone Leong reviewed gene: ANK2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 SCN5A Ivone Leong edited their review of gene: SCN5A: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Long QT syndrome v1.44 KCNQ1 Ivone Leong edited their review of gene: KCNQ1: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Long QT syndrome v1.44 KCNJ2 Ivone Leong reviewed gene: KCNJ2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 KCNH2 Ivone Leong reviewed gene: KCNH2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 KCNE2 Ivone Leong reviewed gene: KCNE2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 KCNE1 Ivone Leong edited their review of gene: KCNE1: Added comment: Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.; Changed rating: GREEN
Long QT syndrome v1.44 CALM3 Ivone Leong reviewed gene: CALM3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 CALM2 Ivone Leong reviewed gene: CALM2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 CALM1 Ivone Leong reviewed gene: CALM1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.44 CACNA1C Ivone Leong reviewed gene: CACNA1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Long QT syndrome v1.43 TECRL Ivone Leong gene: TECRL was added
gene: TECRL was added to Long QT syndrome. Sources: NHS GMS
Mode of inheritance for gene: TECRL was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: TECRL were set to Ventricular tachycardia, catecholaminergic polymorphic, 3, 614021
Review for gene: TECRL was set to AMBER
Added comment: New gene submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Amber on this panel.
Sources: NHS GMS
Likely inborn error of metabolism v1.405 COASY Catherine Snow Classified gene: COASY as Amber List (moderate evidence)
Likely inborn error of metabolism v1.405 COASY Catherine Snow Gene: coasy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.405 COASY Catherine Snow Classified gene: COASY as Amber List (moderate evidence)
Likely inborn error of metabolism v1.405 COASY Catherine Snow Gene: coasy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.405 COASY Catherine Snow Classified gene: COASY as Amber List (moderate evidence)
Likely inborn error of metabolism v1.405 COASY Catherine Snow Gene: coasy has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.404 COASY Catherine Snow gene: COASY was added
gene: COASY was added to Inborn errors of metabolism. Sources: Expert list
Mode of inheritance for gene: COASY was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COASY were set to 30089828
Phenotypes for gene: COASY were set to Neurodegeneration with brain iron accumulation 6, 615643; Pontocerebellar hypoplasia, type 12, 618266
Review for gene: COASY was set to AMBER
Added comment: COASY has sufficient evidence to be made Green however as it has been purposefully not rated by experts as Green on Mitochondrial Panels COASY will be rated as Amber.
Sources: Expert list
Likely inborn error of metabolism v1.403 MRPS7 Catherine Snow Publications for gene: MRPS7 were set to
Likely inborn error of metabolism v1.402 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.402 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.402 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.402 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.402 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.402 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.401 MRPS7 Catherine Snow Classified gene: MRPS7 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.401 MRPS7 Catherine Snow Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.401 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.401 MRPS7 Catherine Snow Mode of inheritance for gene: MRPS7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.401 MRPS7 Catherine Snow Classified gene: MRPS7 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.401 MRPS7 Catherine Snow Gene: mrps7 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.400 UQCC3 Catherine Snow Publications for gene: UQCC3 were set to
Likely inborn error of metabolism v1.400 UQCC3 Catherine Snow changed review comment from: Comment on list classification: Promoting to Amber as some evidence is avaliable; to: Comment on list classification: Promoting to Amber as some evidence is available
Likely inborn error of metabolism v1.400 UQCC3 Catherine Snow Mode of inheritance for gene: UQCC3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.399 UQCC3 Catherine Snow Classified gene: UQCC3 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.399 UQCC3 Catherine Snow Gene: uqcc3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.399 UQCC3 Catherine Snow Classified gene: UQCC3 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.399 UQCC3 Catherine Snow Added comment: Comment on list classification: Promoting to Amber as some evidence is avaliable
Likely inborn error of metabolism v1.399 UQCC3 Catherine Snow Gene: uqcc3 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.398 UQCC2 Catherine Snow Deleted their comment
Intellectual disability v2.1098 ZNF292 Konstantinos Varvagiannis gene: ZNF292 was added
gene: ZNF292 was added to Intellectual disability. Sources: Radboud University Medical Center, Nijmegen,Literature
Mode of inheritance for gene: ZNF292 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZNF292 were set to 31723249; 29904178
Phenotypes for gene: ZNF292 were set to Intellectual disability; Autism; Attention deficit hyperactivity disorder; Abnormality of the face; Abnormal muscle tone; Abnormality of nervous system morphology; Growth abnormality; Feeding difficulties; Abnormality of the skeletal system; Abnormality of the cardiovascular system; Microcephaly; Seizures
Penetrance for gene: ZNF292 were set to Incomplete
Review for gene: ZNF292 was set to GREEN
gene: ZNF292 was marked as current diagnostic
Added comment: Mirzaa et al. (2019 - PMID: 31723249) report on 28 individuals (from 27 families) with putatively pathogenic ZNF292 variants.

Main features consisted of DD and ID (27/28 - mild in 40%, moderate in 22%, severe in 11%) with or without ASD and ADHD. A single individual had no evidence of ID but had speech delay and ASD at the age of 6. Additional features (by diminishing order of frequency) included presence of non-specific dysmorphic features (~45%), abnormal tone, brain MRI abnormalities, growth failure, feeding difficulties, skeletal and cardiac anomalies, microcephaly and epilepsy (~11%).

As the authors comment, ZNF292 encodes a zinc finger protein, acting as a transcription factor.

Evidence is provided that gene has high expression in the developing human brain, with its expression being higher in prenatal development and diminishing postnatally. Znf292 is also expressed in adult mouse brain (highest in hippocampus/Purkinje cells).

Variants were identified by exome or targeted panel sequencing (targeted capture/molecular inversion probes). Previous investigations (eg. aCGH, analysis of relevant genes) had probably ruled out alternative causes in most with few having VUS or possibly relevant additional variants (eg. a KDM5C stopgain variant in a male).

24 putatively pathogenic variants were observed in this cohort, all predicting LoF (stopgain, frameshift or splice variants). All were de novo with the exception of one family where the variant was inherited from an affected parent. Almost all were absent from gnomAD and had CADD scores > 35.

Most variants lied within the last and largest exon that encodes a DNA binding domain. RT-PCR on RNA from 2 individuals harboring such variants confirmed that NMD does not apply. This exon however represents ~88% of the total coding length so the distribution of variants in this (NMD escaping) region was consistent with what would also be expected by chance.

ZNF292 has a pLI of 1 in gnomAD. Manual review of some relevant LoF variants in gnomAD suggested that they represent false positive calls.

As a result, the effect of variants is not clear although haploinsufficiency is still possible based also on phenotype of (larger) deletions spanning this gene (cited: Engwerda et al - PMID: 29904178 / The study focuses on deletions of the broader 6q. A possible role of ZNF292 is discussed as autism was present in 4/10 individuals with deletions encompassing this gene).

Based on the aforementioned cohort with one individual being diagnosed with mild ID only as an adult and/or presence of 5 pLoF variants in gnomAD the authors propose that some variants may be incompletely penetrant or associated with only mild features.

Finally, 15 additional individuals (belonging to 12 families) harbored variants for which pathogenicity was suspected (but could not be concluded) due to insufficient phenotypic information, lack of sufficient parental studies or missense variants. In this cohort variants were mostly pLoF, while 3 individuals (incl. 2 sibs) had a de novo missense SNV.
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Other studies were not here reviewed as some of the individuals reported were published previously in larger cohorts.
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There is no associated phenotype in OMIM / G2P. SysID includes this gene among the candidate ID ones.
ZNF292 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx).
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Overall ZNF292 could be added to the ID panel probably with green (or amber) rating.

[Please consider inclusion in other possibly relevant panels eg. autism, epilepsy]
Sources: Radboud University Medical Center, Nijmegen, Literature
Skeletal dysplasia v1.216 PIK3C2A Eleanor Williams Classified gene: PIK3C2A as Green List (high evidence)
Skeletal dysplasia v1.216 PIK3C2A Eleanor Williams Added comment: Comment on list classification: After further assessment of the phenotype in the supplementary data for PMID: 31034465 (scoliosis, short stature etc) it was decided to promote this gene to green
Skeletal dysplasia v1.216 PIK3C2A Eleanor Williams Gene: pik3c2a has been classified as Green List (High Evidence).
Skeletal dysplasia v1.215 TMEM67 Eleanor Williams Classified gene: TMEM67 as Red List (low evidence)
Skeletal dysplasia v1.215 TMEM67 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team demoting this gene to red as the skeletal phenotype is not strong.
Skeletal dysplasia v1.215 TMEM67 Eleanor Williams Gene: tmem67 has been classified as Red List (Low Evidence).
Skeletal dysplasia v1.214 KIAA0753 Eleanor Williams Classified gene: KIAA0753 as Green List (high evidence)
Skeletal dysplasia v1.214 KIAA0753 Eleanor Williams Added comment: Comment on list classification: Adding this ciliopathy gene to the skeletal dysplasia panel after consultation with the Genomics England clinical team. The reported phenotypes include skeletal dysplasias.
Skeletal dysplasia v1.214 KIAA0753 Eleanor Williams Gene: kiaa0753 has been classified as Green List (High Evidence).
Skeletal dysplasia v1.213 KIAA0753 Eleanor Williams gene: KIAA0753 was added
gene: KIAA0753 was added to Skeletal dysplasia. Sources: Other
Mode of inheritance for gene: KIAA0753 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIAA0753 were set to 29138412; 28220259; 26643951
Phenotypes for gene: KIAA0753 were set to ?Orofaciodigital syndrome XV 617127; Joubert syndrome; Short-rib skeletal dysplasia
Review for gene: KIAA0753 was set to GREEN
Added comment: Provisionally associated with ?Orofaciodigital syndrome XV (617127) in OMIM

PMID: 26643951 - Chevrier et al 2016 - 1 case of a newborn female presenting with an oral-facial-digital (OFD) VI syndrome in which they identified two causal heterozygous mutations in the KIAA0753 gene. Both KIAA0753 mutations, one nonsense variant (c.1891A>T; p.Lys631*) and one substitution in Intron 8 (c.1546-3C>A), were confirmed by Sanger sequencing, as well as the maternal heterozygous status for the non-sense variant.

PMID: 28220259 - Stephen et al 2017 - 2 siblings with Joubert syndrome associated with growth hormone deficiency but no oral or digital anomalies. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C).

PMID: 29138412 - Hammarsjö et al 2017 - report biallelic pathogenic variants in KIAA0753 in four patients from 3 families with short-rib type skeletal dysplasia - ranging from prenatal lethality in one fetus to viability with moderate skeletal dysplasia in three children. 2 families had the same homozygous nonsense variant but are not thought to be related. In the 3rd family the index patient was compound heterogyzous. KIAA0753 is expressed in normal fetal human growth plate and they show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. In family 1, they also identified an additional homozygous missense variant, c.425 C > T (p.Thr142Met) in SLC13A5 and conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant.
Sources: Other
Skeletal dysplasia v1.212 ZSWIM6 Eleanor Williams Classified gene: ZSWIM6 as Green List (high evidence)
Skeletal dysplasia v1.212 ZSWIM6 Eleanor Williams Added comment: Comment on list classification: This cililiopathy gene has been added to the skeletal dysplasia panel after consultation with the Genomics England clinical team. There is sufficient skeletal involvement to include on this panel.
Skeletal dysplasia v1.212 ZSWIM6 Eleanor Williams Gene: zswim6 has been classified as Green List (High Evidence).
Skeletal dysplasia v1.211 ZSWIM6 Eleanor Williams gene: ZSWIM6 was added
gene: ZSWIM6 was added to Skeletal dysplasia. Sources: Other
Mode of inheritance for gene: ZSWIM6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ZSWIM6 were set to 25105228
Phenotypes for gene: ZSWIM6 were set to Acromelic frontonasal dysostosis 603671
Review for gene: ZSWIM6 was set to GREEN
Added comment: Associated with Acromelic frontonasal dysostosis #603671 (AD) and Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features #617865 (AD) in OMIM. Acromelic frontonasal dysostosis - OMIM lists the skeletal phenotypes of Patellar hypoplasia or aplasia (in some patients), Tibial hypoplasia, polydactyly of hands and feet, Talipes equinovarus. Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features - OMIM lists the skeletal phenotype of Foot deformities (in some patients) only
Sources: Other
Skeletal dysplasia v1.210 DHCR7 Eleanor Williams Classified gene: DHCR7 as Green List (high evidence)
Skeletal dysplasia v1.210 DHCR7 Eleanor Williams Added comment: Comment on list classification: This ciliopathy gene is being added to the Skeletal dysplasia panel after discussion with the Genomics England clinical team. Smith-Lemli-Optiz syndrome includes features such as limb shortening as well as abnormalities of the hands and feet.
Skeletal dysplasia v1.210 DHCR7 Eleanor Williams Gene: dhcr7 has been classified as Green List (High Evidence).
Skeletal dysplasia v1.209 DHCR7 Eleanor Williams gene: DHCR7 was added
gene: DHCR7 was added to Skeletal dysplasia. Sources: Other
Mode of inheritance for gene: DHCR7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHCR7 were set to 9634533
Phenotypes for gene: DHCR7 were set to Smith-Lemli-Opitz syndrome 270400
Review for gene: DHCR7 was set to GREEN
Added comment: Associated with Smith-Lemli-Opitz syndrome in OMIM. They describe this as "an autosomal recessive multiple congenital malformation and mental retardation syndrome." Several skeletal features are listed in the clinical features in OMIM including limb shortening, Hip dislocation and subluxation, and abnormalities of the hands and feet.
Sources: Other
Skeletal ciliopathies v0.19 KIAA0753 Eleanor Williams changed review comment from: Provisionally associated with ?Orofaciodigital syndrome XV (617127) in OMIM

PMID: 26643951 - Chevrier et al 2016 - 1 case of a newborn female presenting with an oral-facial-digital (OFD) VI syndrome in which they identified two causal heterozygous mutations in the KIAA0753 gene. Both KIAA0753 mutations, one nonsense variant (c.1891A>T; p.Lys631*) and one substitution in Intron 8 (c.1546-3C>A), were confirmed by Sanger sequencing, as well as the maternal heterozygous status for the non-sense variant. The sporadic occurrence of the c.1546-3C>A variant was confirmed by samples concordance. cDNA analysis indicates the intronic variant results in skipping of Exon 8 that caused a frameshift, changed the amino acids sequence and led to the occurrence of a premature stop codon. Because both mutations appeared truncating and probably compound heterozygous, they were considered as potentially causal.

PMID: 28220259 - Stephen et al 2017 - 2 siblings with Joubert syndrome associated with growth hormone deficiency. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). Brain MRI of the younger sibling revealed the “molar tooth sign”, and she had global developmental delay. The older sibling was diagnosed after the younger sibling, and brain MRI showed an ectopic posterior pituitary gland in addition to the molar tooth sign. Hypotonia and global developmental delay were noted at 10 months. The parents were each heterozygous for one of the variants. Cilia formation in primary fibroblasts from patients was signficantly lower than in controls.

PMID: 29138412 - Hammarsjö et al 2017 - report biallelic pathogenic variants in KIAA0753 in four patients from 3 families with short-rib type skeletal dysplasia - ranging from prenatal lethality in one fetus to viability with moderate skeletal dysplasia in three children. 2 families had the same homozygous nonsense variant but are not thought to be related. In the 3rd family the index patient was compound heterogyzous. KIAA0753 is expressed in normal fetal human growth plate and they show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. In family 1, they also identified an additional homozygous missense variant, c.425 C > T (p.Thr142Met) in SLC13A5 and conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant. ; to: Provisionally associated with ?Orofaciodigital syndrome XV (617127) in OMIM

PMID: 26643951 - Chevrier et al 2016 - 1 case of a newborn female presenting with an oral-facial-digital (OFD) VI syndrome in which they identified two causal heterozygous mutations in the KIAA0753 gene. Both KIAA0753 mutations, one nonsense variant (c.1891A>T; p.Lys631*) and one substitution in Intron 8 (c.1546-3C>A), were confirmed by Sanger sequencing, as well as the maternal heterozygous status for the non-sense variant. The sporadic occurrence of the c.1546-3C>A variant was confirmed by samples concordance. cDNA analysis indicates the intronic variant results in skipping of Exon 8 that caused a frameshift, changed the amino acids sequence and led to the occurrence of a premature stop codon. Because both mutations appeared truncating and probably compound heterozygous, they were considered as potentially causal.

PMID: 28220259 - Stephen et al 2017 - 2 siblings with Joubert syndrome associated with growth hormone deficiency but no oral or digital anomalies. Whole exome sequencing of the family identified compound heterozygous mutations in KIAA0753, i.e., a missense mutation (p.Arg257Gly) and an intronic mutation (c.2359-1G>C). Brain MRI of the younger sibling revealed the “molar tooth sign”, and she had global developmental delay. The older sibling was diagnosed after the younger sibling, and brain MRI showed an ectopic posterior pituitary gland in addition to the molar tooth sign. Hypotonia and global developmental delay were noted at 10 months. The parents were each heterozygous for one of the variants. Cilia formation in primary fibroblasts from patients was signficantly lower than in controls.

PMID: 29138412 - Hammarsjö et al 2017 - report biallelic pathogenic variants in KIAA0753 in four patients from 3 families with short-rib type skeletal dysplasia - ranging from prenatal lethality in one fetus to viability with moderate skeletal dysplasia in three children. 2 families had the same homozygous nonsense variant but are not thought to be related. In the 3rd family the index patient was compound heterogyzous. KIAA0753 is expressed in normal fetal human growth plate and they show that the affected fetus, with a compound heterozygous frameshift and a nonsense mutation in KIAA0753, has an abnormal proliferative zone and a broad hypertrophic zone. The importance of KIAA0753 for normal skeletal development is further confirmed by findings that zebrafish embryos homozygous for a nonsense mutation in kiaa0753 display altered cartilage patterning. In family 1, they also identified an additional homozygous missense variant, c.425 C > T (p.Thr142Met) in SLC13A5 and conclude that the seizures and teeth hypoplasia in P1 and P2 are due to the homozygous SLC13A5 variant.
Skeletal ciliopathies v0.19 PMM2 Eleanor Williams commented on gene: PMM2
Skeletal ciliopathies v0.19 TXNDC15 Eleanor Williams Classified gene: TXNDC15 as No list
Skeletal ciliopathies v0.19 TXNDC15 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team, removing this gene from the skeletal ciliopathies panel as the skeletal phenotype is polydactyly only.
Skeletal ciliopathies v0.19 TXNDC15 Eleanor Williams Gene: txndc15 has been removed from the panel.
Skeletal ciliopathies v0.18 SCLT1 Eleanor Williams Classified gene: SCLT1 as No list
Skeletal ciliopathies v0.18 SCLT1 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team, removing this gene from the skeletal ciliopathies panel as the skeletal phenotype is not strong.
Skeletal ciliopathies v0.18 SCLT1 Eleanor Williams Gene: sclt1 has been removed from the panel.
Skeletal ciliopathies v0.17 DDX59 Eleanor Williams Classified gene: DDX59 as No list
Skeletal ciliopathies v0.17 DDX59 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team, removing this gene from the skeletal ciliopathies panel as the skeletal phenotype is mainly polydactyly.
Skeletal ciliopathies v0.17 DDX59 Eleanor Williams Gene: ddx59 has been removed from the panel.
Skeletal ciliopathies v0.16 CENPF Eleanor Williams Classified gene: CENPF as No list
Skeletal ciliopathies v0.16 CENPF Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team, removing this gene from the skeletal ciliopathies panel as the phenotype is polydactyly only.
Skeletal ciliopathies v0.16 CENPF Eleanor Williams Gene: cenpf has been removed from the panel.
Monogenic hearing loss v2.4 PIK3C2A Eleanor Williams gene: PIK3C2A was added
gene: PIK3C2A was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: PIK3C2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3C2A were set to 31034465
Phenotypes for gene: PIK3C2A were set to Oculoskeletodental syndrome 618440
Review for gene: PIK3C2A was set to AMBER
Added comment: Associated with Oculoskeletodental syndrome 618440 (AR) in OMIM based on evidence from PMID: 31034465 - Tiosano et al 2019 - report 5 individuals from 3 unrelated consanguineous families with a similar set of clinical features including dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts. 3 out 5 indviduals (one from each family) showed hearing loss (non-progressive hearing deficiency, bilateral moderate conductive hearing loss and sensorineural hearing loss, hearing aids at 22 years old). Homozygous loss-of-function mutations in PIK3C2A were identified in each family.
Sources: Literature
Skeletal dysplasia v1.208 PIK3C2A Eleanor Williams Phenotypes for gene: PIK3C2A were changed from to Oculoskeletodental syndrome 618440
Skeletal dysplasia v1.207 PIK3C2A Eleanor Williams Classified gene: PIK3C2A as Amber List (moderate evidence)
Skeletal dysplasia v1.207 PIK3C2A Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team, decided to rate this gene Amber for now. Not clear how relevant the skeletal phenotypes are to this panel.
Skeletal dysplasia v1.207 PIK3C2A Eleanor Williams Gene: pik3c2a has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v1.206 PIK3C2A Eleanor Williams gene: PIK3C2A was added
gene: PIK3C2A was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: PIK3C2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3C2A were set to 31034465
Review for gene: PIK3C2A was set to AMBER
Added comment: Associated with Oculoskeletodental syndrome #618440 (AR) in OMIM. This is based on evidence from PMID: 31034465 - Tiosano et al 2019 - report 5 individuals from 3 unrelated consanguineous families with a similar set of clinical features including dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts. The skeletal findings included "scoliosis, delayed bone age, diminished ossification of femoral heads, cervical lordosis, shortened fifth digits with mild metaphyseal dysplasia and clinodactyly". Homozygous loss-of-function mutations in PIK3C2A were identified in each family.
Sources: Literature
Skeletal dysplasia v1.205 RPL13 Eleanor Williams changed review comment from: PMID: 31630789 - Le Caignec et al 2019 - report one de novo missense variant (c.548G>C [p.Arg183Pro]) and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477þ1G>T, c.477þ1G>A, and c.477þ2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion.
Sources: Literature; to: Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 31630789 - Le Caignec et al 2019 - report one de novo missense variant (c.548G>C [p.Arg183Pro]) and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477þ1G>T, c.477þ1G>A, and c.477þ2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion.
Sources: Literature
Skeletal dysplasia v1.205 RPL13 Eleanor Williams Classified gene: RPL13 as Green List (high evidence)
Skeletal dysplasia v1.205 RPL13 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to green as 4 cases, one with a missense variant but 3 with splice variants that lead to an 18 amino acid insertion in the protein have been reported.
Skeletal dysplasia v1.205 RPL13 Eleanor Williams Gene: rpl13 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.398 UQCC2 Catherine Snow Classified gene: UQCC2 as Green List (high evidence)
Likely inborn error of metabolism v1.398 UQCC2 Catherine Snow Added comment: Comment on list classification: This gene was promoted from Amber to Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter. Two unrelated cases reported, with functional supporting evidence.
Likely inborn error of metabolism v1.398 UQCC2 Catherine Snow Gene: uqcc2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.397 UQCC2 Catherine Snow Publications for gene: UQCC2 were set to
Likely inborn error of metabolism v1.397 UQCC2 Catherine Snow Classified gene: UQCC2 as Green List (high evidence)
Likely inborn error of metabolism v1.397 UQCC2 Catherine Snow Added comment: Comment on list classification: This gene was promoted from Amber to Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter. Two unrelated cases reported, with functional supporting evidence.
Likely inborn error of metabolism v1.397 UQCC2 Catherine Snow Gene: uqcc2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.396 UQCC2 Catherine Snow Deleted their comment
Skeletal ciliopathies v0.15 ZSWIM6 Eleanor Williams commented on gene: ZSWIM6
Skeletal ciliopathies v0.15 SCLT1 Eleanor Williams changed review comment from: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 15797711 - this paper does not appear to be about SCLT1 or ciliopathies

PMID: 23348840 - Tanos et al 2013 - identified SCLT1 as a component of distal appendages (DAPs) of centrioles that have been proposed to anchor cilia to the plasma membrane. It is one of five DAP components and is essential for ciliogenesis.

PMID: 24285566 - Adly et al 2014 - 1 case with index patient with consanguineous Saudi parents and a severe ciliopathy phenotype. He had severe midline cleft lip and palate, microcephaly and choanal atresia. He also had significant eye involvement in the form of severe coloboma, and congenital heart disease (ASD and VSD). He had micropenis. Brain imaging revealed pachygyria and absent corpus callosum. He had abnormal inner ear structures. A splicing mutation was identified in SCLT1 (, NM_144643.2:exon5:c.290+2T>C). This mutation completely abolishes the consensus donor site of exon 5 as confirmed by RTPCR, which showed complete skipping of exon 5 resulting in a frameshift and introduction of a premature stop codon (p.Lys79Valfs*4),

PMID: 28005958 - de Castro-Miró et al 2016 - A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. 1 case with compound heterozygosity (one missense and one splicing altering mutations) in SCLT1 that segregates with the condition in the family (2 affected siblings). Proposed to be causative of early-onset Retinitis Pigmentosa. SCLT1 is a member of the centrosomal/ciliary protein family.

PMID: 28486600 - Li et al 2017 - report a mouse model with mutated Sclt1 gene. The Sclt1-/- mice exhibit typical ciliopathy phenotypes, including cystic kidney, cleft palate and polydactyly.

PMID: 30425282 - Katagiri et al 2018 - a patient with Senior Løken syndrome and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts. Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein.

3 cases plus a mouse model and functional evidence that the protein is a ciliary protein.; to: Not associated with any phenotype in OMIM or Gene2Phenotype.

PMID: 15797711 - this paper does not appear to be about SCLT1 or ciliopathies

PMID: 23348840 - Tanos et al 2013 - identified SCLT1 as a component of distal appendages (DAPs) of centrioles that have been proposed to anchor cilia to the plasma membrane. It is one of five DAP components and is essential for ciliogenesis.

PMID: 24285566 - Adly et al 2014 - 1 case with index patient with consanguineous Saudi parents and a severe ciliopathy phenotype consistent with oro-facio-digital syndrome type IX. He had severe midline cleft lip and palate, microcephaly and choanal atresia. He also had significant eye involvement in the form of severe coloboma, and congenital heart disease (ASD and VSD). He had micropenis. Brain imaging revealed pachygyria and absent corpus callosum. He had abnormal inner ear structures. A splicing mutation was identified in SCLT1 (, NM_144643.2:exon5:c.290+2T>C). This mutation completely abolishes the consensus donor site of exon 5 as confirmed by RTPCR, which showed complete skipping of exon 5 resulting in a frameshift and introduction of a premature stop codon (p.Lys79Valfs*4),

PMID: 28005958 - de Castro-Miró et al 2016 - A cohort of 33 pedigrees affected with a variety of retinal disorders was analysed by WES. 1 case with compound heterozygosity (one missense and one splicing altering mutations) in SCLT1 that segregates with the condition in the family (2 affected siblings). Proposed to be causative of early-onset Retinitis Pigmentosa. SCLT1 is a member of the centrosomal/ciliary protein family.

PMID: 28486600 - Li et al 2017 - report a mouse model with mutated Sclt1 gene. The Sclt1-/- mice exhibit typical ciliopathy phenotypes, including cystic kidney, cleft palate and polydactyly.

PMID: 30425282 - Katagiri et al 2018 - a patient with Senior Løken syndrome and her unaffected parents revealed that the patient had infantile-onset retinal dystrophy and juvenile-onset nephronophthisis. Other systemic abnormalities included hepatic dysfunction, megacystis, mild learning disability, autism, obesity, and hyperinsulinemia. Whole-exome sequencing identified compound heterozygous SCLT1 variants (c.1218 + 3insT and c.1631A > G) in the patient. The unaffected parents were heterozygous for each variant. Transcript analysis using reverse transcription PCR demonstrated that the c.1218 + 3insT variant leads to exon 14 skipping (p.V383_M406del), while the other variant (c.1631A > G) primarily leads to exon 17 skipping (p.D480EfsX11) as well as minor amounts of two transcripts. Immunohistochemical analysis demonstrated that the Sclt1 protein was localized to the distal appendage of the photoreceptor basal body, indicating a ciliary protein.

3 cases plus a mouse model and functional evidence that the protein is a ciliary protein.
Skeletal ciliopathies v0.15 LZTFL1 Eleanor Williams commented on gene: LZTFL1: Associated with Bardet-Biedl syndrome 17 #615994 (AR) in OMIM with polydactyly of hands and feet listed as clinical features.
Skeletal ciliopathies v0.15 DHCR7 Eleanor Williams commented on gene: DHCR7
Likely inborn error of metabolism v1.396 SLC25A4 Catherine Snow Added comment: Comment on mode of inheritance: The MOI was changed for consistency between panels Mitochondrial DNA maintenance disorder (code: 533) and Possible mitochondrial disorder - nuclear genes (code: 539).
Likely inborn error of metabolism v1.396 SLC25A4 Catherine Snow Mode of inheritance for gene: SLC25A4 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.395 ABCB7 Catherine Snow Added comment: Comment on mode of inheritance: Changed MOI for consistency amongst other panels. XLR in OMIM.
Likely inborn error of metabolism v1.395 ABCB7 Catherine Snow Mode of inheritance for gene: ABCB7 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Skeletal ciliopathies v0.15 CENPF Eleanor Williams commented on gene: CENPF
Likely inborn error of metabolism v1.395 ABCB7 Catherine Snow Added comment: Comment on mode of inheritance: Changed MOI for consistency amongst other panels. XLR in OMIM.
Likely inborn error of metabolism v1.395 ABCB7 Catherine Snow 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
Nephrocalcinosis or nephrolithiasis v1.51 SLC9A3R1 Eleanor Williams Classified gene: SLC9A3R1 as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v1.51 SLC9A3R1 Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene to Amber in light of the expert review that highlights that the proposed pathogenic variants are found at higher than expected frequency in the general population.
Nephrocalcinosis or nephrolithiasis v1.51 SLC9A3R1 Eleanor Williams Gene: slc9a3r1 has been classified as Amber List (Moderate Evidence).
Non-syndromic familial congenital anorectal malformations v1.6 Rebecca Foulger Panel types changed to Rare Disease 100K
VACTERL-like phenotypes v1.25 Rebecca Foulger Panel types changed to Rare Disease 100K
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Detlef Bockenhauer changed review comment from: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. They find variants in SLC9A3R1 in 4 patients from 3 families. These 3 variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, there are several lines of evidence arguing against SLC9A3R1 being a disease causing gene:
1) the frequency of variants in SLC9A3R in itself higher than expected for a dominant disease gene (3% combined frequency of missense and pLoF in gnomAD)
2) there are 231 missende variants in this gene listed in gnomAD versus 211.7 expected, based on gene length (Z=-0.48), thus the gene is not constrained against missense variants
3) the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population

The clinical relevance of any variants identified in SLC9A3R1 is thus questionable.; to: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. They find variants in SLC9A3R1 in 4 patients from 3 families. These 3 variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, there are several lines of evidence arguing against SLC9A3R1 being a disease causing gene:
1) the frequency of variants in SLC9A3R in itself is higher than expected for a dominant disease gene (3% combined frequency of missense and pLoF in gnomAD)
2) there are 231 missense variants in this gene listed in gnomAD versus 211.7 expected, based on gene length (Z=-0.48), thus the gene is not constrained against missense variants
3) the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population

The clinical relevance of any variants identified in SLC9A3R1 is thus questionable.
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Detlef Bockenhauer changed review comment from: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. they find variants in SLC9A3R1 in 4 patients from 3 families. These variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, not only is the frequency of variants in SLC9A3R in itself higher than expected for a dominant disease gene, but the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population and the likelihood that they disease causing is thus very unlikely.; to: In the original publication (PMID: 18784102 - Karim et al 2008), Karim et al examine 159 patients with either nephrolithiasis or bone demineralisation. They find variants in SLC9A3R1 in 4 patients from 3 families. These 3 variants are now listed in gnomAD with a combined frequency of just over 2%. Thus, the frequency of these variants in the patient cohort is essentially the same as in the general population.
Several publications subsequently report variants in this gene in cohorts with nephrolithiasis/calcinosis, but again essentially with either the same or even lower frequency as in the normal population:
1) Daga et al (Kidney Int. 2018 Jan;93(1):204-213. doi: 10.1016/j.kint.2017.06.025): 1 out of 51 families
2) Braun et al (Clin J Am Soc Nephrol. 2016 Apr 7;11(4):664-72. doi: 10.2215/CJN.07540715): 1 out of 143
3) Halbritter et al (J Am Soc Nephrol. 2015 Mar; 26(3): 543–551doi: 10.1681/ASN.2014040388): 2 out of 268

Thus, there are several lines of evidence arguing against SLC9A3R1 being a disease causing gene:
1) the frequency of variants in SLC9A3R in itself higher than expected for a dominant disease gene (3% combined frequency of missense and pLoF in gnomAD)
2) there are 231 missende variants in this gene listed in gnomAD versus 211.7 expected, based on gene length (Z=-0.48), thus the gene is not constrained against missense variants
3) the frequency of variants in patients with nephrolithiasis/calcinosis is essentially the same as in the general population

The clinical relevance of any variants identified in SLC9A3R1 is thus questionable.
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Detlef Bockenhauer commented on gene: SLC9A3R1
Skeletal dysplasia v1.204 TMEM67 Eleanor Williams changed review comment from: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361).

RHYNS syndrome - 1 case:

PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents.

PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done.

Meckel syndrome 3 - 3 out of 22 cases show polydactyly:

PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families.

PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.; to: Associated with several phenotypes in OMIM but ?RHYNS syndrome (#609884) is the main disease phenotype that has a skeletal component. Polydactyly may also be seen in Meckel syndrome 3 (#607361).

RHYNS syndrome - 1 case:

PMID: 9375913 - Di Rocco et al. (1997) - 1 case. 17.5-year-old boy with short stature, severe bone-age retardation and exhibited mild signs of skeletal dysplasia, including generalized osteopenia, epiphyseal hypoplasia, hypoplastic iliac bones with irregular acetabular margins, and thin tubular bones. He later developed nephronophthisis. Brancati et al. (2018) (PMID: 29891882) re-assessed this patient at age 38 years and reported he exhibited short stature and severe generalized osteoporosis. Skeletal survey showed moderately shortened long bones, bowed radii, short femoral neck, brachydactyly of the hands and feet with more severe involvement of middle phalanges, distal phalanx of the thumbs, and metacarpals, moderately thickened calvarium, and rotoscoliosis. Compound heterozygous variants in TMEM67 were identified, one inherited from each of his parents.

PMID: 11391657 - Hedera and Gorski (2001) described 2 brothers, who had early onset retinitis pigmentosa, short stature with GH deficiency, mild facial asymmetry, and acromelic shortening of the distal extremities. They suggest this phenotype is consistent with RHYNS syndrome but no genome analysis was done.

Meckel syndrome 3 - 3 out of 22 cases show polydactyly:

PMID: 16415887 - Smith et al. 2006 - detected 5 different homozygous mutations in the TMEM67 in 5 consanguineous families with Meckel syndrome. The mutations were not found in over 120 ethnically matched normal control chromosomes. Polydactyly was observed in 2 out of the 5 families.

PMID: 17377820 - Consugar et al. 2007 - identified 7 novel pathogenic mutations in the TMEM67 gene in 5 of 17 families with a clinical diagnosis of Meckel syndrome. All cases were compound heterogygous. Polydactyly is reported in 1 family.
Neurodegenerative disorders, adult onset v1.107 Louise Daugherty Panel types changed to GMS Rare Disease
Dystonia, chorea or related movement disorder, adult onset v0.130 PDE2A Louise Daugherty changed review comment from: PMID: 29392776 Only identified in one family with infantile onset chorea predominant movement disorder, not enough evidence to rate Green unless additional evidence from labs.; to: PMID: 29392776 Only identified in one family with infantile onset chorea predominant movement disorder, not enough evidence to rate Green unless additional evidence from labs. it is currently not associated with any phenotypes in OMIM or G2P
Dystonia, chorea or related movement disorder, adult onset v0.130 PDE2A Louise Daugherty commented on gene: PDE2A: PMID: 29392776 Only identified in one family with infantile onset chorea predominant movement disorder, not enough evidence to rate Green unless additional evidence from labs.
Dystonia, chorea or related movement disorder, adult onset v0.130 PDE2A Louise Daugherty Classified gene: PDE2A as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v0.130 PDE2A Louise Daugherty Added comment: Comment on list classification: downgraded to Amber until evidence from GLH
Dystonia, chorea or related movement disorder, adult onset v0.130 PDE2A Louise Daugherty Gene: pde2a has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v0.129 VAMP2 Louise Daugherty Classified gene: VAMP2 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v0.129 VAMP2 Louise Daugherty Added comment: Comment on list classification: downgraded to amber until evidence from the GLH
Dystonia, chorea or related movement disorder, adult onset v0.129 VAMP2 Louise Daugherty Gene: vamp2 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v0.128 VAMP2 Louise Daugherty edited their review of gene: VAMP2: Changed rating: AMBER
Dystonia, chorea or related movement disorder, adult onset v0.128 VAMP2 Louise Daugherty edited their review of gene: VAMP2: Added comment: PMID: 30929742 : Literature reports 5 individuals, all with heterozygous de novo variants in VAMP2, it is currently not associated with any phenotypes in OMIM or G2P; Changed rating: GREEN; Changed publications: 30929742; Changed phenotypes: Cortical visual impairment, Seizures, Stereotypic behavior, Generalized hypotonia, Intellectual disability, Abnormality of movement, Global developmental delay, Generalized hypotonia, Global developmental delay, Intellectual disability, Autistic behavior, Stereotypic behavior, Seizures, Abnormality of movement, Cortical visual impairment, Autistic behavior; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.0 ALG8 Eleanor Williams edited their review of gene: ALG8: Changed rating: GREEN; Changed publications: 28375157; Changed phenotypes: Polycystic liver disease 3 with or without kidney cysts, 617874; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.0 ALG8 Eleanor Williams changed review comment from: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM.

PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts (1, at least 3, 3-4 and 9). 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently.

PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.

Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel. ; to: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM.

PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts (1, at least 3, 3-4 and 9). 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently. The proband with 3-4 kidney cysts has a daughter who shares the ALG8 variants and who has no liver cysts but 8 kidney cysts.

PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.
Cystic kidney disease v2.0 SEC61A1 Eleanor Williams changed review comment from: Associated with Hyperuricemic nephropathy, familial juvenile, 4, #617056 (AD) in OMIM.

PMID: 27392076 - Bolar et al 2016 - report on two families with Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. The father in family B had multiple bilateral simple cysts throughout the kidney. In both families heterozygous missense variants in SEC61A1 were identified - c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly) -both affecting functionally important and conserved residues in SEC61. Functional studies support the renal function for this gene.

PMID: 31488840- Devuyst et al 2019 - a primer that highlights the different types of ADTKD - no new cases

Summary - 1 case reported with kidney cysts; to: Associated with Hyperuricemic nephropathy, familial juvenile, 4, #617056 (AD) in OMIM.

PMID: 27392076 - Bolar et al 2016 - report on two families with Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. The father in family B had multiple bilateral simple cysts throughout the kidney. In both families heterozygous missense variants in SEC61A1 were identified - c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly) -both affecting functionally important and conserved residues in SEC61. Functional studies support the renal function for this gene.

PMID: 31488840- Devuyst et al 2019 - a primer that highlights the different types of ADTKD - no new cases

PMID: 30586318 - Groopman et al 2018 - report 1 case with a heterozygous missense variant in SEC61A1 (p.I428M). The clinical diagnosis was 'Congenital or cystic renal disease' and the genetic diagnosis 'Hyperuricemic nephropathy familial juvenile 4' (See TableS7).

Summary - 2 cases reported with kidney cysts
Tubulointerstitial kidney disease v1.0 SEC61A1 Eleanor Williams edited their review of gene: SEC61A1: Added comment: Upgrading review rating to green, the Groopman paper increases the number of cases to 3.; Changed rating: GREEN
Sarcoma cancer susceptibility v1.15 Louise Daugherty List of related panels changed from Sarcoma;Sarcoma pertinent cancer susceptibility to Sarcoma; Sarcoma pertinent cancer susceptibility
Hydrocephalus v2.1 Louise Daugherty List of related panels changed from Hydrocephalus; R86 to Hydrocephalus; R86
Haematological malignancies cancer susceptibility v1.20 Louise Daugherty List of related panels changed from Haemonc;Haematological malignancies pertinent cancer susceptibility to Haemonc; Haematological malignancies pertinent cancer susceptibility
Childhood solid tumours cancer susceptibility v1.6 Louise Daugherty List of related panels changed from Childhood;Childhood solid tumours pertinent cancer susceptibility to Childhood; Childhood solid tumours pertinent cancer susceptibility
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Eleanor Williams changed review comment from: Associated with Nephrolithiasis/osteoporosis, hypophosphatemic, 2 #612287 (AD) in OMIM. A previous name for SLC9A3R1 is NHERF1.

Evidence for association comes from PMID: 18784102 - Karim et al 2008 - sequencing of the coding region of NHERF1 in 92 patients who presented with either renal stones or bone demineralization, together with normal serum PTH concentrations and who had no evidence of any usual causes of these disorders (e.g., hyperparathyroidism, hyperthyroidism, or an increased FGF-23 plasma concentration). These were group 1 patients. They identified three distinct missense mutations in the NHERF1 gene in four unrelated patients from group 1 (328C->G, L110V; 458G->A, R153Q; 673G->A, E225K).

They also studied patients who did not have renal stones or bone demineralization (group 2) who were referred to the clinical investigation department for renal assessment before undergoing a potentially nephrotoxic treatment for psoriasis. One patient in group 2 had an NHERF1 mutation (L110V). This patient had a low TmP/GFR value.; to: Associated with Nephrolithiasis/osteoporosis, hypophosphatemic, 2 #612287 (AD) in OMIM. A previous name for SLC9A3R1 is NHERF1.

Evidence for association comes from PMID: 18784102 - Karim et al 2008 - sequencing of the coding region of NHERF1 in 92 patients who presented with either renal stones or bone demineralization, together with normal serum PTH concentrations and who had no evidence of any usual causes of these disorders (e.g., hyperparathyroidism, hyperthyroidism, or an increased FGF-23 plasma concentration). These were group 1 patients. They identified three distinct missense mutations in the NHERF1 gene in four unrelated patients from group 1 (328C->G, L110V; 458G->A, R153Q; 673G->A, E225K).

They also studied patients who did not have renal stones or bone demineralization (group 2) who were referred to the clinical investigation department for renal assessment before undergoing a potentially nephrotoxic treatment for psoriasis. One patient in group 2 had an NHERF1 mutation (L110V). This patient had a low TmP/GFR value.


PMID: 28893421 - Daga et al 2018 - performed WES in 65 individuals from 51 families with nephrolithiasis and/or a finding of nephrocalcinosis on renal ultrasound, who manifested before the age of 25 years. They found 1 individual with a heterozygous pathogenic variant in SLC9A3R1 (c.673G>A, p.E225K).
Nephrocalcinosis or nephrolithiasis v1.50 SLC9A3R1 Eleanor Williams commented on gene: SLC9A3R1
Early onset or syndromic epilepsy v1.407 Ellen McDonagh Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS Rare Disease Virtual
Early onset or syndromic epilepsy v1.406 Ellen McDonagh List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy; R59
Holoprosencephaly v2.1 Ellen McDonagh List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85 to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85
Other rare neuromuscular disorders v1.12 Ellen McDonagh List of related panels changed from Other rare neuromuscular disorders; R381 to Other rare neuromuscular disorders; R381
Hereditary spastic paraplegia, childhood onset v2.6 Ellen McDonagh List of related panels changed from Childhood onset hereditary spastic paraplegia; Childhood onset hereditary spastic paraplegia; R61 to Childhood onset hereditary spastic paraplegia; R61
Hereditary spastic paraplegia, childhood onset v2.5 Ellen McDonagh List of related panels changed from Childhood onset hereditary spastic paraplegia; R61 to Childhood onset hereditary spastic paraplegia; Childhood onset hereditary spastic paraplegia; R61
Paediatric disorders v4.353 Ellen McDonagh List of related panels changed from Acutely unwell children with a likely monogenic disorder; Congenital malformation and dysmorphism syndromes - microarray and sequencing; R14; R27 to Acutely unwell children with a likely monogenic disorder; Congenital malformation and dysmorphism syndromes - microarray and sequencing; Congenital malformation and dysmorphism syndromes; R14; R27
Likely inborn error of metabolism v1.393 Ellen McDonagh List of related panels changed from Likely inborn error of metabolism - targeted testing not possible to Likely inborn error of metabolism - targeted testing not possible; Likely inborn error of metabolism; R98
Skeletal dysplasia v1.204 RPL13 Eleanor Williams gene: RPL13 was added
gene: RPL13 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: RPL13 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RPL13 were set to 31630789
Phenotypes for gene: RPL13 were set to Spondyloepimetaphyseal Dysplasia with Severe Short Stature
Review for gene: RPL13 was set to GREEN
Added comment: PMID: 31630789 - Le Caignec et al 2019 - report one de novo missense variant (c.548G>C [p.Arg183Pro]) and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13, in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477þ1G>T, c.477þ1G>A, and c.477þ2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion.
Sources: Literature
Cystic kidney disease v2.0 SEC61A1 Eleanor Williams reviewed gene: SEC61A1: Rating: AMBER; Mode of pathogenicity: None; Publications: 27392076; Phenotypes: Hyperuricemic nephropathy, familial juvenile, 4, 617056; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Cystic kidney disease v2.0 ALG8 Eleanor Williams changed review comment from: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM.

PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts. 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently.

PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.

Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel. ; to: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM.

PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts (1, at least 3, 3-4 and 9). 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently.

PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.

Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel.
Possible mitochondrial disorder, nuclear genes v1.12 SSBP1 Carl Fratter changed review comment from: The publications above indicate that pathogenic variants cause disease via a dominant negative effect.
7 different variants have been reported in 9 unrelated families/individuals.
Only one variant has been reported in association with biallelic (autosomal recessive) inheritance to date; i.e. the majority of reported cases are of monoallelic (autosomal dominant) inheritance.; to: The publications above indicate that pathogenic variants cause disease via a dominant negative effect.
7 different variants have been reported in 9 unrelated families/individuals.
Only one variant has been reported in association with biallelic (autosomal recessive) inheritance to date; i.e. the majority of reported cases are of monoallelic (autosomal dominant) inheritance.
Green rating has been proposed by the GMS Mitochondrial specialist test group on the basis of the evidence summarised here.
Mitochondrial DNA maintenance disorder v1.0 SSBP1 Carl Fratter reviewed gene: SSBP1: 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: 31298765, 31550240; Phenotypes: optic atrophy, optic atrophy with additional features (including retinal degeneration); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Possible mitochondrial disorder, nuclear genes v1.12 SSBP1 Carl Fratter reviewed gene: SSBP1: 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: 31298765, 31550240; Phenotypes: optic atrophy, optic atrophy with additional features (including retinal degeneration); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v2.0 Louise Daugherty promoted panel to version 2.0
Primary immunodeficiency or monogenic inflammatory bowel disease v1.138 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 USP18 Louise Daugherty commented on gene: USP18: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 PSMB9 Louise Daugherty commented on gene: PSMB9: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 PSMB4 Louise Daugherty commented on gene: PSMB4: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 PSMA3 Louise Daugherty commented on gene: PSMA3: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 NRAS Louise Daugherty commented on gene: NRAS: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 NLRP1 Louise Daugherty commented on gene: NLRP1: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 CFB Louise Daugherty commented on gene: CFB: Gene was flagged as requiring further clinical input from the Immunology Test Group, but no additional information was submitted to support the Green rating. In view of a lack of clear evidence the current recommendation is Amber.
Cystic kidney disease v2.0 ALG8 Eleanor Williams changed review comment from: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM.

PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts. 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently.

PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.; to: Associated with Polycystic liver disease 3 with or without kidney cysts, 617874 (AD) in OMIM.

PMID: 28375157 - Besse et al 2017 - report 5 probands with 3 different heterozygous variants in ALG8 and liver cysts. 4 of the probands also had between 1 and 9 kidney cysts. 3 of the probands share the same c.1090C>T, p.R364X variant, but the shared haplotype block among any 2 of these individuals is approximately 87 kb which is too small to be indicative of a cryptic relationship between any of the probands and instead suggests that the mutation in each arose independently.

PMID: 30135240 - Lanktree et al 2018 - looked for rare variants in gnomAD and BRAVO in genes involved in ADPKD (PKD1, PKD2), ADPLD (PRKCSH, SEC63, GANAB, ALG8, SEC61B, LRP5). ADPLD protein truncating variants in ALG8 are found in 1 in 1,429 people in these two databases. But this paper does not give numbers of people with ADPLD or if those people also have kidney cysts.

Will check with the Genomics England clinical team whether the level of kidney cysts seen in Besse et al is sufficient to rate this gene green on the panel.
Cytopenia - NOT Fanconi anaemia v1.0 Louise Daugherty promoted panel to version 1.0
Cystic kidney disease v2.0 ALG9 Eleanor Williams edited their review of gene: ALG9: Changed rating: GREEN; Changed publications: 31395617, 28932688; Changed phenotypes: Gillessen-Kaesbach-Nishimura syndrome, 263210; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Cystic kidney disease v2.0 ALG9 Eleanor Williams changed review comment from: Associated with Gillessen-Kaesbach-Nishimura syndrome, 263210 (AR) in OMIM in which Polycystic kidneys is listed as a clinical feature.

PMID: 31395617 - Besse et al 2019 - report 2 patients in a clinically defined cohort with genetically unresolved polycystic liver and kidney disease that had rare heterozygous loss-of-function variants in ALG9. Then using a novel ‘genotype-first’ approach to find ALG9 mutation carriers from a large cohort of exome-sequenced individuals, they found that 7/8 (88%) of ALG9 mutation carriers over age 50 had a least 4 kidney cysts (abstract only accessed).

PMID: 28932688 - Davis et al 2017 - report the case of a proband with ALG9-CDG who has a milder phenotype. This female child was born to non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. A homozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) was identified. Both parents were found to carry one copy of the mutation. In a table of phenotypic features from the 11 known patients with ALG9-CDG (including the one here), 3 other patients are reported with polycystic kidneys and homozygous ALG variants.; to: Associated with Gillessen-Kaesbach-Nishimura syndrome, 263210 (AR) in OMIM in which Polycystic kidneys is listed as a clinical feature.

PMID: 31395617 - Besse et al 2019 - report 2 patients in a clinically defined cohort with genetically unresolved polycystic liver and kidney disease that had rare heterozygous loss-of-function variants in ALG9. Then using a novel ‘genotype-first’ approach to find ALG9 mutation carriers from a large cohort of exome-sequenced individuals, they found that 7/8 (88%) of ALG9 mutation carriers over age 50 had a least 4 kidney cysts (abstract only accessed).

PMID: 28932688 - Davis et al 2017 - report the case of a proband with ALG9-CDG who has a milder phenotype. This female child was born to non-consanguineous parents of Scottish decent. Prenatally, dysmorphic features, numerous renal cysts and minor cardiac malformations were detected. Post-natally, dysmorphic features included shallow orbits, micrognathia, hypoplastic nipples, talipes equinovarus, lipodystrophy and cutis marmorata. She developed failure to thrive and seizures. A homozygous mutation in ALG9, c.860A > G (p.Tyr287Cys) was identified. Both parents were found to carry one copy of the mutation. In a table of phenotypic features from the 11 known patients with ALG9-CDG (including the one here), 3 other patients are reported with polycystic kidneys and homozygous ALG variants.
Cystic kidney disease v2.0 ALG9 Eleanor Williams commented on gene: ALG9
Cytopenia - NOT Fanconi anaemia v0.137 Louise Daugherty Panel types changed to GMS Rare Disease; GMS signed-off
Skeletal Muscle Channelopathies v1.21 CNBP_CCTG Louise Daugherty commented on STR: CNBP_CCTG: As discussed in PanelApp team meeting a new tag "NGS Not Validated". This STR currently has not be validated within the Genomics England pipeline.
Distal myopathies v1.11 CNBP_CCTG Louise Daugherty commented on STR: CNBP_CCTG
Skeletal muscle channelopathy v0.26 CNBP_CCTG Louise Daugherty commented on STR: CNBP_CCTG: As discussed in PanelApp team meeting a new tag "NGS Not Validated". This STR currently has not be validated within the Genomics England pipeline.
Skeletal muscle channelopathy v0.26 CNBP_CCTG Louise Daugherty Tag NGS Not Validated tag was added to STR: CNBP_CCTG.
Distal myopathies v1.11 CNBP_CCTG Louise Daugherty Tag NGS Not Validated tag was added to STR: CNBP_CCTG.
Skeletal Muscle Channelopathies v1.21 CNBP_CCTG Louise Daugherty Tag NGS Not Validated tag was added to STR: CNBP_CCTG.
Cystic kidney disease v2.0 ALG8 Eleanor Williams commented on gene: ALG8
Mitochondrial disorders v2.2 ABCB7 Ivone Leong Added comment: Comment on mode of inheritance: Change MOI 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" to reflect the MOI that is given to this gene on the "Possible mitochondrial disorder - nuclear genes" (code: 539, v1.12).
Mitochondrial disorders v2.2 ABCB7 Ivone Leong 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
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 CSF2RA Louise Daugherty Added comment: Comment on mode of inheritance: Changed MOI due to MOI checks carried out by PanelApp team. This gene is on the pseudoautosomal region of chromosome X which is shared with chromoseome Y, so MOI affected cases are biallelic.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.137 CSF2RA Louise Daugherty Mode of inheritance for gene: CSF2RA 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 BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v2.4 RNASEH2B Louise Daugherty Publications for gene: RNASEH2B were set to 30223285; :25243380; 29691679; 28762473
Hereditary spastic paraplegia, childhood onset v2.3 RNASEH2B Louise Daugherty Phenotypes for gene: RNASEH2B were changed from hereditary spastic paraparesis to Aicardi-Goutieres syndrome 2, 610181; spastic paraparesis
DDG2P v1.148 NUP107 Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for EARLY-CHILDHOOD-ONSET STEROID-RESISTANT NEPHROTIC SYNDROME: confirmed. DDG2P Mutation consequence: loss of function. DDG2P Allelic requirement: biallelic.
Hereditary spastic paraplegia, childhood onset v2.2 RNASEH2B Louise Daugherty Classified gene: RNASEH2B as Red List (low evidence)
Hereditary spastic paraplegia, childhood onset v2.2 RNASEH2B Louise Daugherty Added comment: Comment on list classification: New Green rated gene added by reviewer after panel sign off to V1.0- to be reviewed at next panel update with the Neurology Test Group for GMS. The 100,000 Genomes Project has identified one case and recent publications have reported RNASEH2B variants in homozygous status in patients with spastic paraplegia. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Hereditary spastic paraplegia, childhood onset v2.2 RNASEH2B Louise Daugherty Gene: rnaseh2b has been classified as Red List (Low Evidence).
Hereditary spastic paraplegia, childhood onset v2.1 RNASEH2B Louise Daugherty Publications for gene: RNASEH2B were set to PMID:30223285, PMID:25243380, PMID:29691679 and PMID:28762473
Hereditary spastic paraplegia, childhood onset v2.0 RNASEH2B Zerin Hyder gene: RNASEH2B was added
gene: RNASEH2B was added to Hereditary spastic paraplegia - childhood onset. Sources: Other
Mode of inheritance for gene: RNASEH2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEH2B were set to PMID:30223285, PMID:25243380, PMID:29691679 and PMID:28762473
Phenotypes for gene: RNASEH2B were set to hereditary spastic paraparesis
Penetrance for gene: RNASEH2B were set to unknown
Mode of pathogenicity for gene: RNASEH2B was set to Other
Review for gene: RNASEH2B was set to GREEN
Added comment: Above publications report the association of pure, childhood-onset spastic paraparesis in association with missense recessive variants in RNASEH2B.
Sources: Other
Hereditary spastic paraplegia, adult onset v1.2 Louise Daugherty removed gene:RNASEH2B from the panel
Structural eye disease v0.95 WDR37 Zerin Hyder gene: WDR37 was added
gene: WDR37 was added to Structural eye disease. Sources: Other
Mode of inheritance for gene: WDR37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR37 were set to PMID:31327510, PMID:31327508
Phenotypes for gene: WDR37 were set to corneal opacity; Peters anomaly; coloboma; microcornea
Penetrance for gene: WDR37 were set to unknown
Review for gene: WDR37 was set to AMBER
Added comment: Features of WDR37 syndrome include the following: ocular anomalies such as corneal opacity/Peters anomaly, coloboma, and microcornea; dysmorphic facial features; significant neurological impairment with structural brain defects and seizures; poor feeding; poor post-natal growth; variable skeletal, cardiac, and genitourinary defects.

The probands in one paper exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia
Sources: Other
Hereditary spastic paraplegia v1.210 RNASEH2B Louise Daugherty Classified gene: RNASEH2B as Green List (high evidence)
Hereditary spastic paraplegia v1.210 RNASEH2B Louise Daugherty Added comment: Comment on list classification: New gene added. The 100,000 Genomes Project has identified one case and recent publications have reported RNASEH2B variants in homozygous status in patients with spastic paraplegia. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Hereditary spastic paraplegia v1.210 RNASEH2B Louise Daugherty Gene: rnaseh2b has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.209 RNASEH2B Louise Daugherty Phenotypes for gene: RNASEH2B were changed from spastic paraparesis to Aicardi-Goutieres syndrome 2, 610181; spastic paraparesis
Hereditary spastic paraplegia v1.208 RNASEH2B Louise Daugherty Publications for gene: RNASEH2B were set to PMID:30223285, PMID:25243380, PMID:29691679 and PMID:28762473
Hereditary spastic paraplegia, adult onset v1.1 RNASEH2B Zerin Hyder gene: RNASEH2B was added
gene: RNASEH2B was added to Hereditary spastic paraplegia - adult onset. Sources: Other
Mode of inheritance for gene: RNASEH2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEH2B were set to PMID:30223285, PMID:25243380, PMID:29691679 and PMID:28762473
Phenotypes for gene: RNASEH2B were set to hereditary spastic paraparesis
Mode of pathogenicity for gene: RNASEH2B was set to Other
Review for gene: RNASEH2B was set to GREEN
Added comment: Above publications report association of pure, childhood-onset spastic paraparesis in association with missense recessive variants in RNASEH2B.
Sources: Other
Hereditary spastic paraplegia v1.207 RNASEH2B Zerin Hyder gene: RNASEH2B was added
gene: RNASEH2B was added to Hereditary spastic paraplegia. Sources: Other
Mode of inheritance for gene: RNASEH2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEH2B were set to PMID:30223285, PMID:25243380, PMID:29691679 and PMID:28762473
Phenotypes for gene: RNASEH2B were set to spastic paraparesis
Penetrance for gene: RNASEH2B were set to unknown
Mode of pathogenicity for gene: RNASEH2B was set to Other
Review for gene: RNASEH2B was set to GREEN
Added comment: Abovepublications report association of pure, childhood-onset spastic paraparesis in association with missense recessive variants in RNASEH2B.
Sources: Other
Polycystic liver disease v1.0 Ivone Leong promoted panel to version 1.0
Polycystic liver disease v0.9 Ivone Leong Panel types changed to GMS Rare Disease; GMS signed-off
Hereditary neuropathy v1.337 WARS Louise Daugherty Classified gene: WARS as Green List (high evidence)
Hereditary neuropathy v1.337 WARS Louise Daugherty Added comment: Comment on list classification: new gene added from the GLH, this gene was rated as Green due to cases in the 100,000 Genomes Project in addition to the published cases
Hereditary neuropathy v1.337 WARS Louise Daugherty Gene: wars has been classified as Green List (High Evidence).
Hereditary neuropathy v1.336 WARS Louise Daugherty Publications for gene: WARS were set to
Fetal anomalies v0.346 BICD2 Suzanne Drury reviewed gene: BICD2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27751653, 29274205, 28635954; Phenotypes: HP:0002804, HP:0001059; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Respiratory ciliopathies including non-CF bronchiectasis v1.2 FOXJ1 Louise Daugherty Publications for gene: FOXJ1 were set to PMID: 31630787
Respiratory ciliopathies including non-CF bronchiectasis v1.1 FOXJ1 Louise Daugherty Classified gene: FOXJ1 as Red List (low evidence)
Respiratory ciliopathies including non-CF bronchiectasis v1.1 FOXJ1 Louise Daugherty Added comment: Comment on list classification: New gene added by external reviewer after panel sign off to V1.0- to be reviewed at next panel update with the respiratory Test Group for GMS
Respiratory ciliopathies including non-CF bronchiectasis v1.1 FOXJ1 Louise Daugherty Gene: foxj1 has been classified as Red List (Low Evidence).
Unexplained young onset end-stage renal disease v0.162 TCTN3 Eleanor Williams Classified gene: TCTN3 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.162 TCTN3 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.162 TCTN3 Eleanor Williams Gene: tctn3 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.161 TCTN3 Eleanor Williams Mode of inheritance for gene: TCTN3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.160 TCTN3 Eleanor Williams Publications for gene: TCTN3 were set to
Unexplained young onset end-stage renal disease v0.159 TCTN3 Eleanor Williams Phenotypes for gene: TCTN3 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 18 614815
Unexplained young onset end-stage renal disease v0.158 TMEM231 Eleanor Williams Classified gene: TMEM231 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.158 TMEM231 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.158 TMEM231 Eleanor Williams Gene: tmem231 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.157 TMEM138 Eleanor Williams Classified gene: TMEM138 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.157 TMEM138 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.157 TMEM138 Eleanor Williams Gene: tmem138 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.156 TMEM138 Eleanor Williams Mode of inheritance for gene: TMEM138 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.155 TMEM138 Eleanor Williams Publications for gene: TMEM138 were set to
Unexplained young onset end-stage renal disease v0.154 TMEM138 Eleanor Williams Phenotypes for gene: TMEM138 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 16 614465
Unexplained young onset end-stage renal disease v0.153 TMEM216 Eleanor Williams Classified gene: TMEM216 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.153 TMEM216 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.153 TMEM216 Eleanor Williams Gene: tmem216 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.152 TMEM216 Eleanor Williams Mode of inheritance for gene: TMEM216 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.151 TMEM216 Eleanor Williams Publications for gene: TMEM216 were set to
Unexplained young onset end-stage renal disease v0.150 TMEM216 Eleanor Williams Phenotypes for gene: TMEM216 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 2 608091; Meckel syndrome 2 603194
Unexplained young onset end-stage renal disease v0.149 TMEM231 Eleanor Williams Mode of inheritance for gene: TMEM231 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.148 TMEM231 Eleanor Williams Publications for gene: TMEM231 were set to
Unexplained young onset end-stage renal disease v0.147 TMEM231 Eleanor Williams Phenotypes for gene: TMEM231 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 20 614970; Meckel syndrome 11 615397
Unexplained young onset end-stage renal disease v0.146 TMEM237 Eleanor Williams Classified gene: TMEM237 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.146 TMEM237 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.146 TMEM237 Eleanor Williams Gene: tmem237 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.145 TMEM237 Eleanor Williams Mode of inheritance for gene: TMEM237 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.144 TMEM237 Eleanor Williams Publications for gene: TMEM237 were set to
Unexplained young onset end-stage renal disease v0.143 TMEM237 Eleanor Williams Phenotypes for gene: TMEM237 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 14 614424
Unexplained young onset end-stage renal disease v0.142 TTC8 Eleanor Williams Classified gene: TTC8 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.142 TTC8 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.142 TTC8 Eleanor Williams Gene: ttc8 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.141 TTC8 Eleanor Williams Publications for gene: TTC8 were set to
Unexplained young onset end-stage renal disease v0.140 TTC8 Eleanor Williams Phenotypes for gene: TTC8 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 8 615985
Unexplained young onset end-stage renal disease v0.139 TTC8 Eleanor Williams Mode of inheritance for gene: TTC8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.138 WDPCP Eleanor Williams Classified gene: WDPCP as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.138 WDPCP Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.138 WDPCP Eleanor Williams Gene: wdpcp has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.137 WDPCP Eleanor Williams Mode of inheritance for gene: WDPCP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.136 WDPCP Eleanor Williams Phenotypes for gene: WDPCP were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; ?Bardet-Biedl syndrome 15 615992
Unexplained young onset end-stage renal disease v0.135 TCTN1 Eleanor Williams Classified gene: TCTN1 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.135 TCTN1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.135 TCTN1 Eleanor Williams Gene: tctn1 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.134 TCTN1 Eleanor Williams Mode of inheritance for gene: TCTN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.133 TCTN1 Eleanor Williams Phenotypes for gene: TCTN1 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 13 614173
Unexplained young onset end-stage renal disease v0.132 SDCCAG8 Eleanor Williams Classified gene: SDCCAG8 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.132 SDCCAG8 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.132 SDCCAG8 Eleanor Williams Gene: sdccag8 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.131 SDCCAG8 Eleanor Williams Publications for gene: SDCCAG8 were set to
Unexplained young onset end-stage renal disease v0.130 SDCCAG8 Eleanor Williams Phenotypes for gene: SDCCAG8 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 16 615993; Senior-Loken syndrome 7 613615
Unexplained young onset end-stage renal disease v0.129 SDCCAG8 Eleanor Williams Mode of inheritance for gene: SDCCAG8 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.128 PMM2 Eleanor Williams Classified gene: PMM2 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.128 PMM2 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.128 PMM2 Eleanor Williams Gene: pmm2 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.127 PMM2 Eleanor Williams Phenotypes for gene: PMM2 were changed from to Congenital disorder of glycosylation, type Ia 212065
Unexplained young onset end-stage renal disease v0.126 PMM2 Eleanor Williams Added comment: Comment on publications: Publication from the renal ciliopathies panel
Unexplained young onset end-stage renal disease v0.126 PMM2 Eleanor Williams Publications for gene: PMM2 were set to
Unexplained young onset end-stage renal disease v0.125 PMM2 Eleanor Williams Mode of inheritance for gene: PMM2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.124 NEK8 Eleanor Williams Classified gene: NEK8 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.124 NEK8 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.124 NEK8 Eleanor Williams Gene: nek8 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.123 MKS1 Eleanor Williams Classified gene: MKS1 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.123 MKS1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.123 MKS1 Eleanor Williams Gene: mks1 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.122 MKS1 Eleanor Williams Mode of inheritance for gene: MKS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.121 MKS1 Eleanor Williams Publications for gene: MKS1 were set to
Unexplained young onset end-stage renal disease v0.120 MKS1 Eleanor Williams Phenotypes for gene: MKS1 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 13 615990; Meckel syndrome 1 249000
Unexplained young onset end-stage renal disease v0.119 KIF7 Eleanor Williams Classified gene: KIF7 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.119 KIF7 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.119 KIF7 Eleanor Williams Gene: kif7 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.118 KIF7 Eleanor Williams Added comment: Comment on mode of inheritance: Acrocallosal syndrome/Joubert syndrome 12 are listed as AR in OMIM.
Unexplained young onset end-stage renal disease v0.118 KIF7 Eleanor Williams Mode of inheritance for gene: KIF7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.117 KIF7 Eleanor Williams Phenotypes for gene: KIF7 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Acrocallosal syndrome 200990; Joubert syndrome 12 200990
Unexplained young onset end-stage renal disease v0.116 INPP5E Eleanor Williams Classified gene: INPP5E as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.116 INPP5E Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.116 INPP5E Eleanor Williams Gene: inpp5e has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.115 INPP5E Eleanor Williams Mode of inheritance for gene: INPP5E was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.114 INPP5E Eleanor Williams Phenotypes for gene: INPP5E were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 1 213300
Unexplained young onset end-stage renal disease v0.113 CEP41 Eleanor Williams Classified gene: CEP41 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.113 CEP41 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.113 CEP41 Eleanor Williams Gene: cep41 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.112 CEP41 Eleanor Williams Mode of inheritance for gene: CEP41 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.111 CEP41 Eleanor Williams Phenotypes for gene: CEP41 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 15 614464
Unexplained young onset end-stage renal disease v0.110 CEP290 Eleanor Williams Classified gene: CEP290 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.110 CEP290 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.110 CEP290 Eleanor Williams Gene: cep290 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.109 CEP290 Eleanor Williams Publications for gene: CEP290 were set to
Unexplained young onset end-stage renal disease v0.108 CEP290 Eleanor Williams Phenotypes for gene: CEP290 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 5 610188lLeber congenital amaurosis 10 611755
Unexplained young onset end-stage renal disease v0.107 CC2D2A Eleanor Williams Classified gene: CC2D2A as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.107 CC2D2A Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.107 CC2D2A Eleanor Williams Gene: cc2d2a has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.106 CC2D2A Eleanor Williams Mode of inheritance for gene: CC2D2A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.105 CC2D2A Eleanor Williams Publications for gene: CC2D2A were set to
Unexplained young onset end-stage renal disease v0.104 CC2D2A Eleanor Williams Phenotypes for gene: CC2D2A were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 9 612285; Meckel syndrome 6 612284
Unexplained young onset end-stage renal disease v0.103 C5orf42 Eleanor Williams Classified gene: C5orf42 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.103 C5orf42 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.103 C5orf42 Eleanor Williams Gene: c5orf42 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.102 C5orf42 Eleanor Williams Mode of inheritance for gene: C5orf42 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.101 C5orf42 Eleanor Williams Publications for gene: C5orf42 were set to
Unexplained young onset end-stage renal disease v0.100 C5orf42 Eleanor Williams Phenotypes for gene: C5orf42 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome 17 614615
Unexplained young onset end-stage renal disease v0.99 BBS9 Eleanor Williams Classified gene: BBS9 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.99 BBS9 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.99 BBS9 Eleanor Williams Gene: bbs9 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.98 BBS9 Eleanor Williams Mode of inheritance for gene: BBS9 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.97 BBS9 Eleanor Williams Publications for gene: BBS9 were set to
Unexplained young onset end-stage renal disease v0.96 BBS9 Eleanor Williams Phenotypes for gene: BBS9 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 9 615986
Unexplained young onset end-stage renal disease v0.95 BBS5 Eleanor Williams Classified gene: BBS5 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.95 BBS5 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.95 BBS5 Eleanor Williams Gene: bbs5 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.94 BBS5 Eleanor Williams Mode of inheritance for gene: BBS5 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.93 BBS5 Eleanor Williams Publications for gene: BBS5 were set to
Unexplained young onset end-stage renal disease v0.92 BBS5 Eleanor Williams Phenotypes for gene: BBS5 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 5 615983
Unexplained young onset end-stage renal disease v0.91 BBS4 Eleanor Williams Classified gene: BBS4 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.91 BBS4 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.91 BBS4 Eleanor Williams Gene: bbs4 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.90 BBS4 Eleanor Williams Mode of inheritance for gene: BBS4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.89 BBS4 Eleanor Williams Publications for gene: BBS4 were set to
Unexplained young onset end-stage renal disease v0.88 BBS4 Eleanor Williams Phenotypes for gene: BBS4 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 4 615982
Unexplained young onset end-stage renal disease v0.87 BBS2 Eleanor Williams Classified gene: BBS2 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.87 BBS2 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.87 BBS2 Eleanor Williams Gene: bbs2 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.86 BBS2 Eleanor Williams Mode of inheritance for gene: BBS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.85 BBS2 Eleanor Williams Publications for gene: BBS2 were set to
Unexplained young onset end-stage renal disease v0.84 BBS2 Eleanor Williams Phenotypes for gene: BBS2 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 2 615981
Unexplained young onset end-stage renal disease v0.83 BBS12 Eleanor Williams Classified gene: BBS12 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.83 BBS12 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.83 BBS12 Eleanor Williams Gene: bbs12 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.82 BBS12 Eleanor Williams Mode of inheritance for gene: BBS12 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.81 BBS12 Eleanor Williams Publications for gene: BBS12 were set to
Unexplained young onset end-stage renal disease v0.80 BBS12 Eleanor Williams Phenotypes for gene: BBS12 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 12 615989
Unexplained young onset end-stage renal disease v0.79 BBS10 Eleanor Williams Classified gene: BBS10 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.79 BBS10 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.79 BBS10 Eleanor Williams Gene: bbs10 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.78 BBS10 Eleanor Williams Phenotypes for gene: BBS10 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome 10 615987
Unexplained young onset end-stage renal disease v0.77 BBS10 Eleanor Williams Publications for gene: BBS10 were set to
Unexplained young onset end-stage renal disease v0.76 BBS10 Eleanor Williams Mode of inheritance for gene: BBS10 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.75 BBS1 Eleanor Williams Classified gene: BBS1 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.75 BBS1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.75 BBS1 Eleanor Williams Gene: bbs1 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.74 BBS1 Eleanor Williams Phenotypes for gene: BBS1 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardet-Biedl syndrome type 1 209900
Unexplained young onset end-stage renal disease v0.73 BBS1 Eleanor Williams Publications for gene: BBS1 were set to
Unexplained young onset end-stage renal disease v0.72 BBS1 Eleanor Williams Mode of inheritance for gene: BBS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.71 ARL6 Eleanor Williams Classified gene: ARL6 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.71 ARL6 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.71 ARL6 Eleanor Williams Gene: arl6 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.70 ARL6 Eleanor Williams Mode of inheritance for gene: ARL6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.69 ARL6 Eleanor Williams Publications for gene: ARL6 were set to
Unexplained young onset end-stage renal disease v0.68 ARL6 Eleanor Williams Phenotypes for gene: ARL6 were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Bardel-Biedl syndrome type 3 600151
Unexplained young onset end-stage renal disease v0.67 ARL13B Eleanor Williams Classified gene: ARL13B as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.67 ARL13B Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.67 ARL13B Eleanor Williams Gene: arl13b has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.66 ARL13B Eleanor Williams Phenotypes for gene: ARL13B were changed from Ciliopathy genes associated with cystic kidney disease; Joubert syndrome type 8 to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome type 8 612291
Unexplained young onset end-stage renal disease v0.65 ARL13B Eleanor Williams Phenotypes for gene: ARL13B were changed from Ciliopathy genes associated with cystic kidney disease to Ciliopathy genes associated with cystic kidney disease; Joubert syndrome type 8
Unexplained young onset end-stage renal disease v0.64 ARL13B Eleanor Williams Publications for gene: ARL13B were set to
Unexplained young onset end-stage renal disease v0.63 ARL13B Eleanor Williams Mode of inheritance for gene: ARL13B was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.62 ALMS1 Eleanor Williams Classified gene: ALMS1 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.62 ALMS1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.62 ALMS1 Eleanor Williams Gene: alms1 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.61 ALMS1 Eleanor Williams Mode of inheritance for gene: ALMS1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.60 ALMS1 Eleanor Williams Publications for gene: ALMS1 were set to
Unexplained young onset end-stage renal disease v0.59 ALMS1 Eleanor Williams Phenotypes for gene: ALMS1 were changed from to Alstrom Syndrome; Bardet-Biedl Syndrome; 203800; Alstrom syndrome
Unexplained young onset end-stage renal disease v0.58 AHI1 Eleanor Williams Publications for gene: AHI1 were set to
Unexplained young onset end-stage renal disease v0.57 AHI1 Eleanor Williams Classified gene: AHI1 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.57 AHI1 Eleanor Williams Added comment: Comment on list classification: Promoting to green as green on the renal ciliopathies panel https://panelapp.genomicsengland.co.uk/panels/725/
Unexplained young onset end-stage renal disease v0.57 AHI1 Eleanor Williams Gene: ahi1 has been classified as Green List (High Evidence).
Intellectual disability v2.1098 CNOT2 Konstantinos Varvagiannis gene: CNOT2 was added
gene: CNOT2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CNOT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CNOT2 were set to 31512373; 31145527; 28135719; 28159701; 30768759; 21505450; 18076123; 22247066
Phenotypes for gene: CNOT2 were set to Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, MIM 618608
Penetrance for gene: CNOT2 were set to unknown
Review for gene: CNOT2 was set to GREEN
gene: CNOT2 was marked as current diagnostic
Added comment: Heterozygous pathogenic CNOT2 variants cause Intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies (MIM 618608 - recently added disorder in OMIM). Larger 12q15 deletions, spanning CNOT2 have been reported in patients with similar phenotype.

Relevant individuals - most discussed below - include 2 patients with truncating de novo mutation, 1 with de novo intragenic deletion, few with small deletions spanning also 2-3 additional proximal genes and others with larger 12q15 deletions encompassing CNOT2 and several other genes.

Overall the phenotype - summarized by Uehara et al. (Ref1 - below) - seems to consist of language delay, mild motor delay (in most), some suggestive facial features (upslanted palpebral fissures, anteverted nares, thin upper lip and micrognathia). Nasal speech has also been reported in some individuals.

As commented by Uehara et al. (Ref1), CNOT2 (CCR4-NOT transcription complex subunit 2) is a member of the carbon catabolite repressor 4 complex (CCR4-NOT), the latter having an important role in deadenylation of mRNA and global mRNA expression. Disruption of the complex - which can be caused by loss of one of its components - results in various human disorders incl. neural diseases. siRNA CNOT2 depletion has been shown to induce CCR4-NOT disruption (cited PMIDs: 16284618, 29438013, 31006510, 21299754).

The type of variants (truncating, intragenic deletion, larger deletions) and the highly overlapping phenotypes in the respective patients suggest happloinsufficiency as the underlying mechanism. CNOT2 has also a pLI of 1 in gnomAD (o/e =0.06) and a %HI in Decipher of 4.39.

The gene appears to have relevant expression (https://www.proteinatlas.org/ENSG00000111596-CNOT2/tissue).
Animal models have not been discussed (or phenotypes possibly not sufficiently studied - MGI for Cnot2 : http://www.informatics.jax.org/marker/MGI:1919318).

CNOT2 is not associated with any phenotype in G2P. It is listed among the ID candidate genes in SysID.
This gene is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc).

Overall CNOT2 could be considered for inclusion in the ID panel with amber (DD although outcome is not known, presumed dysfunction of the CCR4-NOT complex, variant studies or animal models not available) or green rating (sufficient cases and variants, consistent phenotype).
-----
Individuals with CNOT2-only disruption:
[1] PMID: 31512373 (Uehara et al., 2019) - A 6 y.o. male investigated for hypotonia, feeding problems, DD (speech and motor), macrocephaly (+3 SD) and some possibly suggestive facial/other features was found to harbor a de novo stopgain variant (NM_001199302.1: c.946A>T, p.Lys316Ter) after trio exome sequencing. The variant and its de novo occurrence were confirmed by Sanger sequencing. NMD was the predicted effect (variant in ex11 of 21 / effect not further studied). Previous metabolic work-up and chromosomal testing had not revealed an alternative diagnosis.
[2] PMID: 31145527 (Alesi et al. 2019) - A 13 y.o. boy with hypotonia, failure to thrive, DD and following a specific schooling program for children with learning difficulties is reported. The authors comment on the facial phenotype (incl. upslanted p-f, anteverted nares, etc). Other features included valvular/supravalvular pulm. stenosis, mid aortic insufficiency, renal anomalies/failure, skeletal anomalies. Speech was nasal. CMA revealed an 85-kb 12q15 deletion spanning only CNOT2 (exons 3-15). Real-time PCR in proband and parents confirmed the variant and its de novo occurrence.
[3] PMID: 28135719 (DDD study, 2017) - An individual with developmental disorder and a de novo (validated) frameshift variant was identified [DDD4K.00807 - NM_014515.5:c.1158del / p.(L387Sfs*3)]. Phenotype in Decipher incl. abnormality of head/neck, nervous, skeletal system and growth. [https://decipher.sanger.ac.uk/ddd/research-variant/16b4f7866652f08e25a194f65535b4c5#overview].

Individuals with disruption of additional proximal genes due to CNVs:
[4] PMID: 28159701 (Alesi et al. 2017) - The authors report on a 29 y.o. individual with history of DD, learning difficulties, ID (WAIS-R IQ of 48 at the age of 17 y), some dysmorphic facial features. Additional features incl. recurrent infections, nasal voice as well as skeletal anomalies. CMA revealed a 742 kb microdeletion spanning CNOT2, KCNMB4 and PTPRB. Real-time PCR confirmed deletion and it's de novo occurrence in the proband.
[5] PMID: 30768759 (Uehara et al. 2019) - A female investigated among others for global DD (walking/1st words at 24m), mild ID, submucosal cleft palate with some distinctive facial features (upslanted p-f, micrognathia, etc) was found to harbor a 1.32-Mb deletion of 12q15 encompassing CNOT2 and 14 other genes. Given the phenotypic resemblance to patients with 12q15 deletions, the previously defined smallest region of overlap (ref 4,6), the LoF SNV in Decipher the authors suggested that CNOT2 is the critical gene for the phenotype of 12q15 deletion syndrome.

Larger deletions defining the smallest region of overlap
[6] PMID: 21505450 (Vergult et al. 2011) - 3 patients with de novo microdeletions of ~ 2.5 Mb in size with a 1.34 MB common region of overlap are reported. Learning diability, DD, nasal speech and hypothyroidism were among the common features.
[7] PMID: 18076123 (Schluth et al. 2008) - A girl with large (~10 Mb) de novo deletion of 12q15 - q21.2 identified by BAC array was described. The phenotype consisted of hypotonia, DD, moderate ID, growth delay and facial dysmorphic features.
[8] PMID: 22247066 (Lopez et al. 2012) - A patient with ID and features of Floating-Harbor syndrome was found to harbor a 4.7 Mb de novo 12q15-q21.1 deletion spanning CNOT2 and 18 additional genes.
[..]
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1098 TMX2 Konstantinos Varvagiannis gene: TMX2 was added
gene: TMX2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: TMX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMX2 were set to 31586943; 31270415
Phenotypes for gene: TMX2 were set to Global developmental delay; Intellectual disability; Seizures; Microcephaly; Abnormal cortical gyration
Penetrance for gene: TMX2 were set to Complete
Review for gene: TMX2 was set to AMBER
Added comment: PMID: 31586943 - Ghosh et al. 2019 - reported on 8 individuals from 4 consanguineous families from the Middle East and Central Asia, all with a phenotype of DD/ID, seizures and microcephaly with lissencephaly (microlissencephaly is the term applying to the combination of two) upon brain MRI.

All patients were investigated by exome sequencing and the variant localized within a region of ROH which was common to all 4 families. All were homozygous for a TMX2 missense variant (NM_001144012.2:c.500G>A or p.Arg167Gln / NM_015959.4:c.614G>A p.Arg205Gln or hg38 - Chr11:g.57739039G>A). The variant was considered to be the best candidate, upon review of all other homozygous ones.

Sanger sequencing confirmed homozygosity for the variant in affected subjects, with additional compatible segregation studies including parents in all families as well as unaffected sibs (in two families).

Despite presence of the same mutation in all, several proximal to this variant SNPs did not appear to be shared among the families studied, thus suggesting that the variant had arisen within different haplotype blocks.

The authors comment that the variant was not previously identified in public databases. (The variant seems to correspond to rs370455806, present in 10 htz individuals in gnomAD, as well as in the GME database [GME Genotype Count 992:0:1 (hmz?) | Allele Count: 2,1984] . GME includes primarily - although not necessarily - healthy individuals).

This SNV affecting the last nucleotide of an exon of several transcripts (correct ref. is NM_001144012.2 as appears in the supplement / using NM_001347898.1 as in the fig./text the variant would lie within an intron), an eventual splicing effect was studied. mRNA transcript levels were assessed following RT-PCR using different sets of primers. There was no evidence of novel splice isoforms but mRNA levels were reduced compared to controls (15-50% in affected individuals, to a lesser level in carriers). This led to the hypothesis that NMD of an aberrantly spliced mRNA might apply, although this was not proven.

TMX2 encodes a protein disulfide isomerase (PDI). PDIs are transmembrane ER proteins which have a critical role in protein folding (PMID cited: 12670024). There were no relevant studies carried out in the article.

As for animal models, the authors comment that mice homozygous for null mutations display preweaning lethality with complete penetrance.(http://www.informatics.jax.org/diseasePortal/popup?isPhenotype=true&markerID=MGI:1914208&header=mortality/aging).
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Previously, Schot el al. (ESHG Conference 2018 Oral Presentation - Mutations in the thioredoxin related gene TMX2 cause primary microcephaly, polymicrogyria and severe neurodegeneration with impaired mitochondrial energy metabolism - available in PMID: 31270415 / https://www.nature.com/articles/s41431-019-0407-4 ) reported on 7 individuals from 5 unrelated families with biallelic TMX2 mutations. A newborn with microcephaly, polymicrogyria who died of refractory epilepsy, was compound heterozygous for 2 TMX2 variants. 6 additional individuals (from 4 unrelated families) with similar phenotype were found to harbor biallelic TMX2 mutations. It was commented that TMX2 is enriched in mitochondria-associated membrane of the ER with a role in ER stress protection and regulation of neuronal apoptosis. In line with this, fibroblasts from 2 unrelated patients showed secondary OXPHOS deficiency and increased glycolytic activity (the latter possibly as a compensatory mechanism).
-------
There is no associated phenotype in OMIM/G2P/SysID.
-------
Overall this gene could be considered for inclusion in the ID/epilepsy panel probably with amber (/red) rating pending further evidence.
Sources: Literature
Intellectual disability v2.1098 KCNT2 Konstantinos Varvagiannis gene: KCNT2 was added
gene: KCNT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: KCNT2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNT2 were set to 29069600; 29740868
Phenotypes for gene: KCNT2 were set to ?Epileptic encephalopathy, early infantile 57, MIM 617771
Penetrance for gene: KCNT2 were set to unknown
Review for gene: KCNT2 was set to GREEN
Added comment: Heterozygous pathogenic KCNT2 variants cause ?Epileptic encephalopathy, early infantile, 57 (MIM 617771).

At least 3 unrelated affected individuals have been reported :

- PMID: 29069600 - Gururaj et al. 2017 : a male child with EOEE (hypotonia, profound DD and intractable infantile seizures) due to a de novo KCNT2 missense variant (NM_001287819.1:c.720T>A or p.Phe240Leu) identified by exome sequencing.

- PMID: 29740868 - Ambrosino et al. 2018 : A girl with phenotype corresponding to West syndrome later evolving to Lennox-Gastaut syndrome. At the age of 9 years the girl displayed severe ID. Trio exome sequencing revealed a de novo missense KCNT2 variant (NM_001287820.2:c.569G>A or p.Arg190His). A 14 y.o. female recruited through the DDD study with phenotype corresponding to epilepsy of infancy with migrating focal seizures. The girl had poor language development and severe learning disability. Infective and metabolic causes were initially ruled out. Trio exome sequencing revealed a de novo missense SNV (c.569G>C or Arg190Pro).

Overall KCNT2 has been commented to contribute to a phenotypic spectrum similar and overlapping to that of KCNT1 (Ambrosino et al.). [KCNT1 is rated green in both epilepsy and ID panels].

KCNT2 was recently included in the epilepsy panel as green (functional studies summarized in the respective reviews). The gene was also recently added to G2P, associated with 'Developmental and infantile epileptic encephalopathy'. It is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result, KCNT2 could be considered for inclusion in the ID panel with green (or amber) rating.
Sources: Literature
Early onset or syndromic epilepsy v1.405 NSF Konstantinos Varvagiannis gene: NSF was added
gene: NSF was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Penetrance for gene: NSF were set to unknown
Review for gene: NSF was set to AMBER
Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature
Intellectual disability v2.1098 NSF Konstantinos Varvagiannis gene: NSF was added
gene: NSF was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NSF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NSF were set to 31675180
Phenotypes for gene: NSF were set to Seizures; EEG with burst suppression; Global developmental delay; Intellectual disability
Penetrance for gene: NSF were set to unknown
Mode of pathogenicity for gene: NSF 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: NSF was set to AMBER
Added comment: Suzuki et al. (2019 - PMID: 31675180) report on 2 unrelated individuals with de novo missense NSF variants. Overall the phenotype corresponded to an early infantile epileptic encephalopathy. The first patient developed vomiting and tonic seizures immediately after birth, with burst-suppression pattern upon EEG. Trio exome sequencing, followed by Sanger sequencing of proband and parents, revealed a de novo missense variant (NM_006178.3:c.1375G>A / p.Ala459Thr), absent from public databases and predicted in silico to be deleterious (CADD score of 30). The girl died 36 days after birth due to respiratory failure. Another subject, having necessitated mechanical ventilation due to absence of spontaneous respiration after birth, developed myoclonic seizures. EEG showed a burst-suppression pattern. At the age of 3, she was noted to have persistence of seizures and profound ID. Trio exome sequencing identified a missense NSF variant (c.1688C>T / p.Pro563Leu) also confirmed and shown to be de novo by Sanger sequencing. Again the variant was absent from public datasets and had a CADD score of 34. While expression of wt NSF allele in the developing eye of Drosophila had no effect, expression of mutants severely affected eye development - suggesting a dominant negative effect. NSF encodes a homo-hexameric AAA ATPase, which is recruited by SNAPs (Soluble NSF Attachment Proteins) - and the latter by SNAREs (SNAP REceptors) - thus having a role in vesicular transport and membrane fusion. There is currently no associated phenotype in OMIM/G2P. Overall, this gene could be considered for inclusion probably with amber/red rating pending further evidence (eg. additional work-up or alternative causes/explanations not discussed).
Sources: Literature
Intellectual disability v2.1098 WDFY3 Konstantinos Varvagiannis reviewed gene: WDFY3: Rating: GREEN; Mode of pathogenicity: None; Publications: 27008544, 31327001, 25198012, 28191889; Phenotypes: ?Microcephaly 18, primary, autosomal dominant - MIM 617520; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Early onset or syndromic epilepsy v1.405 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 was set to Other
Review for gene: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures, behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
----------
PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
----------
SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
----------
Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Intellectual disability v2.1098 SCAMP5 Konstantinos Varvagiannis gene: SCAMP5 was added
gene: SCAMP5 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: SCAMP5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SCAMP5 were set to 31439720; 20071347
Phenotypes for gene: SCAMP5 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Behavioral abnormality
Penetrance for gene: SCAMP5 were set to unknown
Mode of pathogenicity for gene: SCAMP5 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: SCAMP5 was set to AMBER
Added comment: PMID: 31439720 (Hubert et al. 2019) reported on 2 unrelated individuals with severe ID, seizures behavioral and brain MRI abnormalities (white matter hyperintensity and mesial temporal sclorosis), both harboring the same missense SCAMP5 mutation as a de novo event (NM_001178111.1:c.538G>T or p.Gly180Trp).

Previously aCGH +/- metabolic workup were non diagnostic.

The occurrence of the same de novo variant in both as well as the similar presentation (incl. MRI images) suggested SCAMP5 as the most probable candidate gene, despite presence of few other variants in both.

SCAMP5 is highly expressed in brain (https://www.proteinatlas.org/ENSG00000198794-SCAMP5) and previous studies have suggested a role in synaptic vesicle trafficking (PMIDs cited: 29562188, 25057210, etc).

Cultured skin fibroblasts from affected individuals failed to express SCAMP5.

Scamp is the Drosophila orthologue, with previous studies having demonstrated that mutants display defects in climbing, olfactory-assisted memory and susceptibility to heat induced seizures (PMIDs cited: 25478561, 19144841). Expression of the Scamp Gly302Trp variant in Drosophila ('equivalent' to the SCAMP5 Gly180Trp) revealed strongly reduced levels for the variant compared with wt upon Western Blot, either due to reduced expression or due to increased turnover. Overall the effect of Gly302Trp expression was similar to Scamp knockdown by RNAi (eg. rough eye phenotype, reduced ability to climb the walls of a graded tube after tapping, less/no flies reaching adult stage) but significantly different compared to wt.

As a result, a dominant-negative effect was presumed.
----------
PMID: 20071347 (Castermans et al. 2010) is cited as a previous report of a relevant affected individual. In this study a 40 y.o. male with early DD, mild ID (IQ of 63) and ASD was found to harbor a de novo apparently balanced t(1;15) translocation affecting CLIC4 and PPCDC (both not associated with ID). [1-Mb resolution aCGH revealed no relevant CNVs].

Studies were however focused on SCAMP5 given that the gene is located downstream of / proximal to PPCDC, has brain-enriched expression as well as involvement in synaptic trafficking and demonstrated:
- Less than 50% expression upon quantitative RT-PCR in patients leukocytes, compared to control.
- Silencing and overexpression of Scamp5 in mouse β-TC3 cells resulted in increased and suppressed respectively secretion of large dense-core vesicles (LDCVs).
- Given conservation of some components involved in secretion of dense core granules (DCGs) in platelets and LDCVs in neuronal cells, study of patient platelets - where SCAMP5 was confirmed to be expressed - suggested an altered pattern of DCGs.
----------
SCAMP5 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.
----------
Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably with amber (# of unrelated individuals, 1 recurrent de novo variant and 1 regulatory effect, gene expressed in brain with a role in synaptic vesicle trafficking) or red rating (pending further evidence).
Sources: Literature
Intellectual disability v2.1098 FAM160B1 Konstantinos Varvagiannis gene: FAM160B1 was added
gene: FAM160B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FAM160B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM160B1 were set to 27431290; 31353455
Phenotypes for gene: FAM160B1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of the face
Penetrance for gene: FAM160B1 were set to Complete
Review for gene: FAM160B1 was set to AMBER
Added comment: Anazi et al. (2017 - PMID: 27431290) in a study of 337 subjects with ID, reported on a consanguineous family (15DG2696) with 3 affected sibs. The proband, a 7 y.o. boy had hypotonia, DD, mild ID (IQ of 69), some facial dysmorphic features as well as increased skin elasticity and joint hypermobility. Initial investigations included metabolic testing for OA and CDGs, FMR1 and aCGH. A 4 y.o. sister and a 3 y.o. brother of the proband had similar presentation of DD. Exome sequencing, autozygosity mapping and segregation studies suggested a FAM160B1 hmz missense SNV as the likely causal variant (NM_001135051.1:c.248T>C or p.Leu83Pro). There were no other candidate variants. As the encoded protein has a yet unknown function, with uncertain in silico 3D modeling, the authors speculated disruption of helices affecting fold/(ligand binding) function as the underlying effect of this variant.

Mavioğlu et al. (2019 - PMID: 31353455) reported on a 38 y.o. female with history of motor and language delay, severe ID, ataxia, behavioral abrnormalities as well as some dysmorphic features. This individual was born to consanguineous parents (2nd cousins). There was history of a deceased, similarly affected sib. Initial investigations included metabolic work-up (plasma AA, urinary OA) and karyotyping. SNP genotyping in the family (parents, affected sib, 3 unaffected sibs) and multipoint linkage analysis for AR inheritance, yielded a maximum LOD score of 2.15. Selection of homozygous regions unique to the patient (but not present in unaffected sibs) did not suggest any known ID gene. Exome sequencing of the proband, with analysis of the variants in candidate regions revealed a homozygous stopgain SNV (NM_020940.4:c.115G>T or p.Glu39*) as the best candidate variant (with few others not considered to be relevant). FAM160B1 has a pLI of 1, LoF variants in public databases have MAFs below 0.000034 with no recorded homozygotes. In silico predictions suggested a deleterious effect (CADD score of 40, etc). The previous report by Anazi and fulfilment of the ACMG criteria for its classification of this variant as pathogenic led to its consideration as causal of the patient's phenotype.

Study of the expression of the 2 isoforms of the gene (isoform1: NM_020940, 2:NM_001135051) revealed that the first is ubiquitously expressed and the second only in testes. [To my understanding the 2 isoforms seem to differ only in their last exon, the 2 reported variants affecting both isoforms - http://genome.ucsc.edu/cgi-bin/hgTracks?db=hg19&lastVirtModeType=default&lastVirtModeExtraState=&virtModeType=default&virtMode=0&nonVirtPosition=&position=chr10%3A116577123%2D116663023&hgsid=777553295_dPP9DgaheaF82gTRTfZO6XS5lEzA ]

The function of this gene remains unknown. Animal models/phenotypes are probably not available.

There is no associated phenotype in OMIM/G2P. SysID lists FAM160B1 as a candidate ID gene.
FAM160B1 is not commonly included in gene panels for ID offered by diagnostic laboratories.

As a result this gene can be considered for inclusion in the current panel probably with amber (2 families/variants, variable ID as a feature) or red rating pending further evidence (given the partial phenotypic overlap, unknown function of the gene, variants not further studied, no animal models).
Sources: Literature
Early onset or syndromic epilepsy v1.405 PCYT2 Konstantinos Varvagiannis gene: PCYT2 was added
gene: PCYT2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Cerebral atrophy; Cerebellar atrophy
Penetrance for gene: PCYT2 were set to Complete
Review for gene: PCYT2 was set to GREEN
Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations.

The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy.

Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below):
- P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu
- P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one.

Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID).

For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive.

All variants were absent from / had extremely low AF in public databases, with no homozygotes.

Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway.

In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability.

Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied:
- Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant.
- RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls.
- Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls.

The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping.

CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish.

Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088).

Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life.

PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.

As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating.

[Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc].
Sources: Literature
Intellectual disability v2.1098 PCYT2 Konstantinos Varvagiannis gene: PCYT2 was added
gene: PCYT2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Penetrance for gene: PCYT2 were set to Complete
Review for gene: PCYT2 was set to GREEN
Added comment: Vaz et al. (2019 - PMID: 31637422 - DDD study among the co-authors) report on 5 individuals - from 4 families - with biallelic PCYT2 mutations.

The phenotype corresponded to a complex hererditary paraplegia with global DD, regression (4/5), ID (mild in 3/5, severe in 2/5), spastic para-/tetraparesis, epilepsy (5/5 - variable onset 2-16 yrs - focal or tonic-clonic seizures) and progressive cerebral and cerebellar atrophy.

Exome sequencing in all revealed biallelic PCYT2 variants, confirmed with Sanger s. in probands and their parents (NM_001184917.2 - corresponding to the canonical transcript used as Ref below):
- P1 (Fam1) : 2 missense SNVs in trans configuration, c.730C>T or p.His244Tyr and c.920C>T or p.Pro307Leu
- P2 (Fam2 - consanguineous of White British origin), P3 (Fam3 - Consanguineous of Turkish origin), P4,5 (Fam4 - consanguineous, unspecified origin) : homozygosity for c.1129C>T or p.Arg377Ter) affecting the last exon of 8/12 transcripts, including the canonical one.

Individuals with the same genotype displayed variable degrees of ID (eg P3 - severe / P2, P4,5 - mild ID).

For sibs in Fam4, homozygosity for a missense SACS variant led to consideration of the respective disorder (AR spastic ataxia of Charlevoix-Saguenay) though the variant was predicted to be tolerated in silico and notably the MRI images not suggestive.

All variants were absent from / had extremely low AF in public databases, with no homozygotes.

Posphatidylethanolamine (PE) is a membrane lipid, particularly enriched in human brain (45% of phospholypid fraction). PE is synthesized either via the CDP-ethanolamine pathway or by decarboxylation of phosphatidylserine in mitochondria. PCYT2 encodes CTP:phosophoethanolamine cytidyltransferase (ET) which is an ubiquitously expressed rate-limiting enzyme for PE biosynthesis in the former pathway.

In silico, the 2 missense variants - localizing in the CTP catalytic domain 2 - were predicted to be damaging, as well as to affect protein stability.

Fibroblasts of 3 patients (P1, P2, P3) representing all variants were studied:
- Enzymatic activity was shown to be significantly reduced (though not absent) compared to controls. Abnormalities were noted upon Western Blot incl. absence in all 3 patients studied of one of the 2 bands normally found in controls (probably representing the longer isoform), reduced intensity in all 3 of another band probably corresponding to a shorter isoform, and presence of an additional band of intermediate molec. mass in patients with the truncating variant.
- RT-PCR on mRNA from patient fibroblasts did not reveal (significant) reduction compared to controls.
- Lipidomic profile of patient fibroblasts was compatible with the location of the block in the phospholipid biosynthesis pathway and different from controls.

The lipidomic profile had similarities with what has been reported for EPT1 deficiency, the enzyme directly downstream of ET. The SELENO1-related phenotype (/EPT1 deficiency) is also highly overlapping.

CRISPR-Cas9 was used to generate pcyt2 partial or complete knockout (ko) zebrafish, targeting either the final (ex13) or another exon (ex3) respectively. mRNA expression was shown to be moderately reduced in the first case and severely reduced/absent in the second, compared to wt. Similarly, complete-ko (ex3) led to significantly lower survival, with impaired though somewhat better survival of partial-ko (ex13) zebrafish.

Complete knockout of Pcyt2 in mice is embryonically lethal (PMID cited: 17325045) while heterozygous mice develop features of metabolic syndrome (PMID cited: 22764088).

Given lethality in knockout zebrafish / mice and the residual activity (15-20%) in patient fibroblasts, the variants reported were thought to be hypomorphic and complete loss of function possibly incompatible with life.

PCYT2 is not associated with any phenotype in OMIM/G2P/SysID and not commonly included in gene panels for ID.

As a result this gene could included in the ID / epilepsy panels with green (~/>3 indiv/fam/variants with the nonsense found in different populations, consistent phenotype, lipidomics, in silico/in vitro/in vivo evidence) or amber rating.

[Please consider inclusion in other possibly relevant panels eg. for metabolic disorders, etc].
Sources: Literature
Intellectual disability v2.1098 PDE6D Konstantinos Varvagiannis gene: PDE6D was added
gene: PDE6D was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: PDE6D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDE6D were set to 24166846; 30423442
Phenotypes for gene: PDE6D were set to ?Joubert syndrome 22 - MIM 615665
Penetrance for gene: PDE6D were set to Complete
Review for gene: PDE6D was set to AMBER
gene: PDE6D was marked as current diagnostic
Added comment: Thomas et al. (2014 - PMID: 24166846) reported on a consanguineous Pakistani family with 3 members presenting variable polydactyly, brain anomalies (incl. molar tooth sign), microphthalmia/coloboma with retinal disease, renal hypoplasia suggestive of Joubert syndrome.

Genotyping with a SNP array identified a unique 17-Mb region of homozygosity on chr2 with LOD score of 2.6. The region contained 208 genes, of which 15 present in ciliary gene databases. A homozygous splicing variant appeared to be the only relevant, PDE6D being a ciliary gene within this region [NM_002601.4:c.140-1G>A]. Status of all affected members, parents and 2 unaffected sibs was verified with Sanger sequencing.

PDE6D encodes a phosphodiesterase that binds to prenyl groups and has a critical role in ciliogenesis (Humbert et al. - PMID: 23150559 and OMIM).
Several lines of evidence provided support a role for PDE6D and the reported variants :
- Study of PDE6D expression during human embryogenesis suggests ubiquitous localization and highest levels in organs affected in ciliopathies (CNS, kidney tubules, respiratory tract epitherlial cells).
- RT-PCR of mRNA from control/patient fibroblasts and sequencing confirmed the splicing defect leading to an in-frame deletion of exon 3.
- Wt and mutant protein both localized in the basal body of primary cilia (patient/control fibroblasts). Cilia in both cases had normal morphology.
- Experiments in RPE cells confirmed that INPP5E (involved in Joubert/MORM syndrome) interacts (/is probably a cargo of) PDE6D, a process dependent on prenylation.
- Exon 3 deletion was confirmed to disrupt PDE6D binding to INPP5E.
- Analysis by immunofluoresence of INPP5E localization using control/patient fibroblasts and renal tissue showed absence of INPP5E from primary cilia in the case of patient cells (but not controls) suggesting that PDE6D is important for trafficking INPP5E to the cilium.
- Previous study in mice suggested altered photoreceptor physiology in Pde6d (-/-) animals, resulting in a slowly progressing rod/cone dystrophy. The effect was however limited to the eye. (PMID cited : 17496142 - Zhang et al., 2007).
- Morpholino knockdown of pde6d resulted in pericardial edema, eye abnormalities (microphthalmia and disorganized retinal cell layers) and kidney morphogenesis defects (distended, blocked pronephric openings and proximal tubule cysts). Edema was rescued upon coinjection of morpholino with wt (but not mutant) mRNA. Similarly coinjection led to complete or partial rescue of eye development in the case of wt and mutant mRNA respectively supporting pathogenicity and (partial) loss-of-function effect for the variant.
---------
Mégarbané et al. (2019 - PMID: 30423442) reported on an affected 6 month-old boy born to Lebanese first-cousin parents. Features included hypotonia, developmental delay, microcephaly, oculomotor apraxia, postaxial polydactyly of hands and feet and presence of a molar tooth sign upon brain MRI. Renal and retinal anomalies were absent (also given his age). Exome sequencing revealed homozygosity for a frameshift PDE6D variant [NM_002601.3:c.367_368insG or p.(Leu123Cysfs*13)]. Sanger sequencing confirmed presence of the variant in the proband and carrier status of the parents. The variant affected the penultimate exon (note : present in only this longest transcript) and was not predicted to trigger NMD but rather lead to elimination of a highly conserved PDZ-interaction domain.
---------
The phenotype associated with biallelic PDE6D variants in OMIM is ?Joubert syndrome 22 - MIM 615665 based only on the 1st report ('delayed psychomotor development' among the features). There is no relevant entry in G2P. PDE6D is listed as a Current primary (/confirmed) ID gene in SysID (the aforementioned PMIDs cited).

This gene is included in gene panels for ID offered by some diagnostic laboratories (eg. GeneDx).
---------
Overall PDE6D could be considered for inclusion in the ID panel probably with amber rating (2 families/variants, DD but outcome otherwise unknown - evidence for the the gene causing JS seems however sufficient).
Sources: Literature
Intellectual disability v2.1098 NTNG2 Konstantinos Varvagiannis gene: NTNG2 was added
gene: NTNG2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: NTNG2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NTNG2 were set to 31372774; 31668703
Phenotypes for gene: NTNG2 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Microcephaly; Seizures
Penetrance for gene: NTNG2 were set to Complete
Review for gene: NTNG2 was set to GREEN
Added comment: [1] Abu-Libdeh et al. (2019 - PMID: 31372774) reported 8 individuals from 4 unrelated consanguineous families of Arab Muslim origin, all homozygous for NM_032536.3:c.376dup - p.(Ser126PhefsTer241). Common features included hypotonia, failure to achieve milestones and developmental stagnation without regression during the first year (~9m) of life and severe ID. Minimal purposeful hand use (grasping and bringing objects to mouth), hand stereotypies and bruxism were also observed. Microcephaly and impaired growth were almost universal (with the exception of 2 having an OFC at ~10% percentile). Relevant previous investigations were normal in all and included MECP2, SMN1, aCGH, metabolic testing, etc. The variant was identified by exome in all, and Sanger confirmed with compatible segregation studies in parents and sibs. The variant was found within a shared haplotype of ~4.35 Mb, probably due to a founder effect.

[2] Dias et al. (2019 - PMID: 31668703) described 16 individuals from 7 unrelated families from Iran, Mexico, Turkey, Egypt and Bangladesh. Parents were known to be consanguineous or shown to be distantly related. All patients were homozygous for missense variants private to each family (7 variants) identified following exome sequencing. Shared features incl. hypotonia, GDD, severe to profound ID and behavioral anomalies incl. autistic features/stereotypies (most), screaming/laughing spells (most), bruxism. Microcephaly (5/14), growth below average/FTT and GI problems were also observed.

Epilepsy was reported in 5 individuals belonging to 4 different families in these 2 studies (5/24 overall / 4 variants).

Netrin-G2, the encoded protein, is bound to the plasma membrane by GPI-anchors. Netrins-G2 and G1 (another member of the Netrin-G subfamily) are enriched in presynaptic terminals. Interaction with their cognate Netrin-G ligand trans-synaptic partners / receptors (NGL2, NGL1 respectively) has been shown to promote axon outgrowth, induce and maintain excitatory synapse formation. Complementary and non-overlapping expression in the developping and mature CNS has been shown for Netrin-G2/1 in mice (several references provided by Abu-Libdeh / Dias).

Variant effect : The frameshift variant was not studied by Abu-Libdeh et al. Variants in the 2nd ref. were all missense, displayed no-specific localization and were suggested to affect protein stability and/or expression at the cell surface as 4/7 involved loss or addition of cystein residues (possibly creating unpaired cysteins) and 2 of the remaining 3 were predicted to affect the hydrophobic core. In line with this, overexpression of wt/variant constructs in HeLa cells demonstrated substantially decreased cell surface expression for all variants.

Mouse models/phenotypes : Dias et al. showed that siRNA-mediated Ntng2 knockdown in N2a cells led to significant reduction in neurite number and length. Studied previously, Ntng2 knockout mice display impaired learning, memory, visual and motor functioning (PMID cited : 26746425).

NTNG2 is not associated with any phenotype in OMIM/G2P. SysID lists it among the candidate ID genes, citing PMID: 29302074 (not here reviewed & NTNG2 not in the main text).

Overall this gene can be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, consistent phenotype in both reports, role of the gene, in silico and in vitro studies, animal model, etc) or amber.

[Please consider inclusion in other panels if relevant eg. ASD panel (many individuals having autistic / Rett-like features or epilepsy) or epilepsy (>3 individuals/families/variants although most families were also consanguineous)]
Sources: Literature
Intellectual disability v2.1098 AP1B1 Konstantinos Varvagiannis gene: AP1B1 was added
gene: AP1B1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: AP1B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP1B1 were set to 31630788; 31630791
Phenotypes for gene: AP1B1 were set to Failure to thrive; Abnormality of the skin; Hearing abnormality; Abnormality of copper homeostasis; Global developmental delay; Intellectual disability
Penetrance for gene: AP1B1 were set to Complete
Review for gene: AP1B1 was set to AMBER
Added comment: Boyden et al. (2019 - PMID: 31630788) and Alsaif et al (2019 - PMID: 31630791) report on the phenotype related to biallelic AP1B1 mutations.

Common features included failure to thrive, ichthyosis (with variable palmoplantar keratoderma/erythroderma/abnormal hair) and hearing loss. Each study focused on different additional features eg. thrombocytopenia or photophobia in all individuals reported by Boyden et al, while Alsaif et al. focused on abnormal copper metabolism (low plasma copper and ceruloplasmin) observed in all 3 affected individuals and enteropathy/hepatopathy observed in 2 sibs.

DD was observed in all 3 individuals (2 families) reported by Alsaif et al. and patient 424 reported by Boyden et al. ID was noted in all individuals of relevant age (2 from 2 families) in the study by Alsaif. Boyden commented that ID is not part of the phenotype. The adult (424) - despite his early DD - was noted to have normal intellect and had graduated college. The other patient (1325) was last followed up at 11 months (still DD was not reported).

AP1B1 encodes one of the large subunits (β1) of the adaptor protein complex 1. Each of the AP complexes is a heterotetramer composed of two large (one of γ, α, δ, ε and β1-β4 for AP-1 to AP-4 respectively), one medium (μ1-μ4) and one small (σ1-σ4) adaptin subunit. The complex is involved in vesicle-mediated transport.

Variants were confirmed in probands and carrier parents (NM_001127.3):
Boyden Pat424 (33y) : c.430T>C (p.Cys144Arg) in trans with c.2335delC (p.Leu779Serfs*26)
Boyden Pat1325 (11m) [consanguineous Ashkenazi Jewish family] : homozygosity for c.2374G>T (p.Glu792*)
Alsaif sibs P1,P2 (4y4m, 1y5m) [consanguineous - Pakistani origin] : homozygous for a chr22 75 kb deletion spanning only the promoter and ex1-2 of AP1B1
Alsaif P3 (4y6m) [consanguineous - Saudi origin] : homozygous for a c.38-1G>A

Variant / additional studies :
22q 75-kb deletion: PCR deletion mapping and Sanger delineated the breakpoints of the 22q12.2 del to chr22:29758984-29815476 (hg?). Complete absence of transcript upon RT-PCR (mRNA from fibrolasts).
Splicing variant (c.38-1G>A): RT-PCR confirmed replacement of the normal transcript by an aberrant harboring a 1 bp deletion (r.40del).
Stopgain variant (c.2374G>T): Western blot demonstrated loss of AP1B1 (and marked reduction also for AP1G1) in cultured keratinocytes of the homozygous patient.

Loss-of-function is the effect predicted by variants. Vesicular defects were observed in keratinocytes of an affected individual (homozygous for the nonsense variant). Rescue of these vesicular defects upon transduction with wt AP1B1 lentiviral construct confirmed the LoF effect. [Boyden et al.]

ATP7A and ATP7B, two copper transporters, have been shown to depend on AP-1 for their trafficking. Similar to MEDNIK syndrome, caused by mutations in AP1S1 and having an overlapping phenotype with AP1B1 (also including hypocupremia and hypoceruloplasminemia), fibroblasts from 2 affected individuals (from different families) demonstrated abnormal ATP7A trafficking. [Alsaif et al.]

Proteomic analysis of clathrin coated vesicles (2 ind from 2 fam) demonstrated that AP1B1 was the only AP1/AP2 CCV component consistently reduced in 2 individuals (from 2 families). [Alsaif et al.]

Boyden et al. provided evidence for abnormal differentiation and proliferation in skin from an affected individual. In addition E-cadherin and β-catenin were shown to be mislocalized in keratinocytes from this affected individual.

Loss of ap1b1 in zebrafish is not lethal but lead to auditory defects (/vestibular deficits). The inner ears appear to develop normally, although there is progressive degeneration of ear epithelia. There are no behavioral/neurological phenotypes listed for mouse models. [ http://www.informatics.jax.org/marker/MGI:1096368 ].

AP1B1 is not associated with any phenotype in OMIM/G2P/SysID.

Overall this gene could be considered for inclusion in the ID panel probably with amber rating.
Sources: Literature
Early onset or syndromic epilepsy v1.405 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
----
Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Intellectual disability v2.1098 FDFT1 Konstantinos Varvagiannis gene: FDFT1 was added
gene: FDFT1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: FDFT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDFT1 were set to 29909962
Phenotypes for gene: FDFT1 were set to Profound global developmental delay; Intellectual disability; Seizures; Abnormality of nervous system morphology; Cortical visual impairment; Abnormality of the skin; Abnormality of the face
Penetrance for gene: FDFT1 were set to Complete
Review for gene: FDFT1 was set to AMBER
Added comment: Biallelic pathogenic FDFT1 variants cause Squalene synthase deficiency (MIM 618156). 3 individuals from 2 families (and 3 variants) have been reported. DD, ID and seizures are part of the phenotype (3/3). The metabolic profile observed is specific and highly suggestive of disruption of the cholesterol biosynthesis pathway (at the specific level) while the clinical presentation is similar to other disorders of the pathway (SLO). The effect of 2 variants has been studied in detail (in one case mis-splicing demonstrated and in the other regulatory effect). Overall, this gene could be considered for inclusion in the ID/epilepsy panel with amber rating. As the gene is currently present only in the DDG2P panel, please consider adding it to relevant ones (eg. IEMs, undiagnosed metabolic disorders, etc). [Details provided below].
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Coman et al. (2018 - PMID: 29909962) reported on 3 relevant individuals from 2 unrelated families.

The phenotype consisted of seizures (3/3 - neonatal onset - generalized), profound DD (ID can be inferred from the description in the supplement), variable brain MRI abnormalities (white matter loss, hypoplastic CC), cortical visual impairment, dry skin with photosensitivity as well facial dysmorphic features. Male subjects presented genital anomalies (cryptorchidism/hypospadias).

FDFT1 encodes squalene synthase, the enzyme which catalyzes conversion of farnesyl-pyrophosphate to squalene - the first specific step in cholesterol biosynthesis.

A specific pattern of metabolites was observed in all, similar to a pattern previously observed in animal models/humans treated with squalene synthase inhibitor or upon loading with farnesol (in animals). Overall the pattern was suggestive of a cholesterol biosynthesis defect at the level of squalene synthase as suggested by increased total farnesol levels (farnesyl-pyrophosphate + free farnesol), reduced/normal squalene, low plasma cholesterol as well as other metabolites.

Clinical features also resembled those observed in Smith-Lemli-Opitz syndrome (another disorder of cholesterol biosynthesis).

WES was carried out in affected individuals and their parents and revealed for sibs of the first family, compound heterozygosity for a maternally inherited 120-kb deletion spanning exons 6-10 of FDFT1 and CTSB and a paternally inherited FDFT1 variant in intron 8 (TC deletion/AG insertion). Variant studies for the latter included:
- Minigene splice assay demonstrating retention of 22 bp in intron 8.
- Partial splicing defect with both nl and mis-spliced cDNA (patient fibroblasts)
- Reduced protein levels in lymphoblasts/fibroblasts from both sibs upon Western blot.
Contribution of the CTSB deletion was considered unlikely (carrier mother was unaffected).

As for the 2nd family, WES data allowed identification of a homozygous deep-intronic (although this is transcript-specific) 16-bp deletion in the proband. Parents were carriers. For the specific variant :
- cDNA studies failed to detect 3 (of 10) isoforms which are normally present in control fibroblasts. Eventual NMD (which would be predicted if the deletion resulted in splicing defect) was eliminated given the absent effect of cyclohexamide addition, thus suggesting a regulatory effect.
- Given a predicted promoter/enhancer effect of the deleted region, a luciferase assay performed, suggested that the sequence had promoter capacity, with the construct containing the 16-bp deletion showing reduced promoter activity.

Fdft1 knockout mice demonstrate embryonic lethality around mid-gestation while they exhibit severe growth retardation and defective neural tube closure.

In G2P FDFT1 is associated with 'Defect in Cholesterol Biosynthesis' (confidence:possible/biallelic/LoF). The gene belongs to the Current primary ID gene group of SysID. It is not commonly included in gene panels for ID offered by diagnostic laboratories.
Sources: Literature
Intellectual disability v2.1098 IQSEC1 Konstantinos Varvagiannis gene: IQSEC1 was added
gene: IQSEC1 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: IQSEC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IQSEC1 were set to 31607425
Phenotypes for gene: IQSEC1 were set to Central hypotonia; Global developmental delay; Intellectual disability; Behavioral abnormality; Short stature
Penetrance for gene: IQSEC1 were set to Complete
Review for gene: IQSEC1 was set to AMBER
Added comment: Ansar et al. (2019 - PMID: 31607425) reported on 5 individuals with biallelic IQSEC1 variants.

Common features included hypotonia, DD, speech impairment, severe ID, behavioral problems as well as short stature. Early-onset seizures were observed in 3 sibs (for whom there was also a paternal family history of seizures).

These subjects belonging to 2 consanguineous families from Pakistan and S. Arabia were found to harbor homozygous missense variants private to each family (Fam1: NM_001134382.2:c.1028C>T or p.Thr354Met following SNP genotyping of several members and exome of the proband | Fam2: c.962G>A or p.Arg321Gln following exome in 2 affected members). Sanger confirmation and study of parents (+/- sibs) were compatible.

The homozygous variant was the only candidate in the 1st family (also following exclusion of other causes of ID/short stature), and most likely/compatible with the patient's phenotype in the 2nd.

As the authors note, IQSEC1-3 encode guanine exchange factors (GEFs) for the ARF family of GTPases. IQSEC2 is a known XLID gene, while biallelic IQSEC3 mutations in ID have been recently reported (PMID: 31130284), all presenting phenotypic similarities (ID, short stature, speech defect).

Previous studies cited had shown that IQSEC1 & 2 are concentrated at the postsynaptic density of glutamatergic synapses in mammalian brain, playing a role in actin-dependent processes incl. AMPA receptor trafficing at synapses (all refs in article).

Drosophila model: The ortholog of IQSEC1, 2 and 3 is schizo and the phenotype associated with its loss is a growth cone guidance defect through dysregulation of the Slit-Robo pathway (all refs in article). The authors studied overexpression of either reference IQSEC1 cDNA or variant cDNAs in wt flies, the former only being toxic/lethal. Loss of schizo was also embryonically lethal but was partially rescued by expression of reference IQSEC1 cDNA. Expression of cDNA for the 2 variants did not rescue lethality. As a result LoF appears to be the underlying effect of both variants. The authors provided evidence that schizo is localized in glia and neurons at various stages of development and is important for proper axon guidance in both CNS and PNS. In Drosophila, schizo is also localized in photoreceptors and RNAi-mediated knockdown resulted in severely impaired sight (also observed in 1 patient).

Mouse model: Through generation of Iqsec1-floxed mice, it was demonstrated that targeted depletion of Iqsec1 in the cortex resulted in increased density/immature morphology of dendritic spines.

IQSEC1 is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in gene panels for ID.

As a result, this gene could be considered for inclusion in the ID panel as probably as amber (2 families/variants).
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.1 PIK3C2A Ivone Leong edited their review of gene: PIK3C2A: Changed rating: GREEN
Bilateral congenital or childhood onset cataracts v2.1 PIK3C2A Ivone Leong changed review comment from: PIK3C2A is associated with a relevant phenotype on OMIM but not on Gene2Phenotype. PMID: 31034465 describes 3 unrelated consanguineous families (Muslim-Arab Isreali, Tunisian and Syrian) with different homozygous variants in this gene. All affected members have similar features, which included "dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts". Therefore, this gene is appropriate for this panel and there is enough evidence for this gene to be promoted to Green status.
Sources: Literature; to: PIK3C2A is associated with a relevant phenotype on OMIM but not on Gene2Phenotype. PMID: 31034465 describes 3 unrelated consanguineous families (Muslim-Arab Isreali, Tunisian and Syrian) with different homozygous variants in this gene. All affected members have similar features, which included "dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts". Therefore, this gene is appropriate for this panel and there is enough evidence for this gene to be promoted to Green status.
Sources: Literature
Bilateral congenital or childhood onset cataracts v2.1 PIK3C2A Ivone Leong gene: PIK3C2A was added
gene: PIK3C2A was added to Cataracts. Sources: Literature
Mode of inheritance for gene: PIK3C2A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIK3C2A were set to 31034465
Phenotypes for gene: PIK3C2A were set to Oculoskeletodental syndrome, 618440
Review for gene: PIK3C2A was set to RED
Added comment: PIK3C2A is associated with a relevant phenotype on OMIM but not on Gene2Phenotype. PMID: 31034465 describes 3 unrelated consanguineous families (Muslim-Arab Isreali, Tunisian and Syrian) with different homozygous variants in this gene. All affected members have similar features, which included "dysmorphic facial features, short stature, skeletal and neurological abnormalities, and cataracts". Therefore, this gene is appropriate for this panel and there is enough evidence for this gene to be promoted to Green status.
Sources: Literature
Intellectual disability v2.1098 TAOK1 Rebecca Foulger Phenotypes for gene: TAOK1 were changed from to INTELLECTUAL DISABILITY; developmental delay
Intellectual disability v2.1097 TAOK1 Rebecca Foulger Publications for gene: TAOK1 were set to
Intellectual disability v2.1096 TAOK1 Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI to MONOALLELIC, to match Gene2Phenotype and PMID:31230721.
Intellectual disability v2.1096 TAOK1 Rebecca Foulger Mode of inheritance for gene: TAOK1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1095 TAOK1 Ellen McDonagh reviewed gene: TAOK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 31230721; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 FBN1 Eleanor Williams commented on gene: FBN1: PMID: 16596670 - Ades et al 2006 - report 2 patients with heterozygous FBN1 mutations (Patients 1 and 2) and a patient with a heterozygous FBN1 deletion (Patient 5). Patient 1 had Marfan syndrome with scaphocephaly, unusually rounded orbital rims and recession of the right orbital and frontal regions. Coronal sutures were indistinct. The anterior half of the sagittal suture was fused. Patient 2 had severe early onset Marfan sydnrome and plagiocephaly with coronal, lambdoid, and sagittal sutures. Patient 5 had marfanoid (MD) features, mental retardation (MR), and dolichocephaly.

PMID: 27884935 - Miller et al 2017 - report a case of a patient with craniosynostosis and a de novo splice variant affecting FBN1. c.8226+5G>A.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 MASP1 Eleanor Williams changed review comment from: PMID: 21258343 - Rooryck et al 2011 - report 1 patient with a homozygous MASP1variant ( c.1489 C>T, p.His497Tyr) that segregated with 3MC syndrome in the family. The patient's features included craniosynostosis.

PMID: 26789649 - Urquhart et al 2016 - report 2 patients with homozygous variants in MASP1 (c.760A>T,p.(Leu 254*) and c.547G>T, p(.Val 183Leu) ) who have plagiocephaly and turricephaly respectively, but they note that craniosynostosis was not observed.; to: PMID: 21258343 - Rooryck et al 2011 - report 1 patient with a homozygous MASP1variant ( c.1489 C>T, p.His497Tyr) that segregated with 3MC syndrome in the family. The patient's features included craniosynostosis.

PMID: 26789649 - Urquhart et al 2016 - report two 3MC syndrome patients with homozygous variants in MASP1 (c.760A>T,p.(Leu 254*) and c.547G>T, p(.Val 183Leu) ) who have plagiocephaly and turricephaly respectively, but they note that craniosynostosis was not observed.
Rare syndromic craniosynostosis or isolated multisuture synostosis v2.0 MASP1 Eleanor Williams commented on gene: MASP1: PMID: 21258343 - Rooryck et al 2011 - report 1 patient with a homozygous MASP1variant ( c.1489 C>T, p.His497Tyr) that segregated with 3MC syndrome in the family. The patient's features included craniosynostosis.

PMID: 26789649 - Urquhart et al 2016 - report 2 patients with homozygous variants in MASP1 (c.760A>T,p.(Leu 254*) and c.547G>T, p(.Val 183Leu) ) who have plagiocephaly and turricephaly respectively, but they note that craniosynostosis was not observed.
Intellectual disability v2.1095 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1095 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1095 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1095 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1095 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1095 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1095 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1095 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1095 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1094 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1094 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1094 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Intellectual disability v2.1094 TAOK1 Ellen Thomas Classified gene: TAOK1 as Green List (high evidence)
Intellectual disability v2.1094 TAOK1 Ellen Thomas Added comment: Comment on list classification: Recently reported DD gene
Intellectual disability v2.1094 TAOK1 Ellen Thomas Gene: taok1 has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v0.26 CNBP_CCTG Louise Daugherty changed review comment from: STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS. It should be noted that this STR is currently not offered as part of the 100K RD Skeletal muscle channelopathy panel as is currently difficult to report this STR using the WGS EH pipeline because of the complex locus (
Sources: Expert list; to: STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS. It should be noted that this STR is currently not offered as part of the 100K RD Skeletal muscle channelopathy panel as is currently difficult to report this STR using the WGS EH pipeline because of the complex locus
Sources: Expert list
Skeletal muscle channelopathy v0.26 CNBP_CCTG Louise Daugherty changed review comment from: STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS.
Sources: Expert list; to: STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS. It should be noted that this STR is currently not offered as part of the 100K RD Skeletal muscle channelopathy panel as is currently difficult to report this STR using the WGS EH pipeline because of the complex locus (
Sources: Expert list
Skeletal muscle channelopathy v0.26 DMPK_CTG Louise Daugherty Classified STR: DMPK_CTG as Green List (high evidence)
Skeletal muscle channelopathy v0.26 DMPK_CTG Louise Daugherty Str: dmpk_ctg has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v0.25 DMPK Louise Daugherty Classified gene: DMPK as Red List (low evidence)
Skeletal muscle channelopathy v0.25 DMPK Louise Daugherty Added comment: Comment on list classification: demoted to Red, this review is for the STR entity and not the gene entity.
Skeletal muscle channelopathy v0.25 DMPK Louise Daugherty Gene: dmpk has been classified as Red List (Low Evidence).
Skeletal muscle channelopathy v0.24 DMPK_CTG Louise Daugherty STR: DMPK_CTG was added
STR: DMPK_CTG was added to Myotonia congenita. Sources: Expert list
Mode of inheritance for STR: DMPK_CTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: DMPK_CTG were set to 7825566
Phenotypes for STR: DMPK_CTG were set to Myotonic dystrophy 1, 16090
Review for STR: DMPK_CTG was set to GREEN
Added comment: STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS.
Sources: Expert list
Skeletal muscle channelopathy v0.23 CNBP_CCTG Louise Daugherty Classified STR: CNBP_CCTG as Green List (high evidence)
Skeletal muscle channelopathy v0.23 CNBP_CCTG Louise Daugherty Str: cnbp_cctg has been classified as Green List (High Evidence).
Skeletal muscle channelopathy v0.22 CNBP_CCTG Louise Daugherty STR: CNBP_CCTG was added
STR: CNBP_CCTG was added to Myotonia congenita. Sources: Expert list
Mode of inheritance for STR: CNBP_CCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: CNBP_CCTG were set to 18807109
Phenotypes for STR: CNBP_CCTG were set to Myotonic dystrophy 2, 602668
Review for STR: CNBP_CCTG was set to GREEN
Added comment: STR added as part of the GMS. This STR is tested routinely using PCR-based methods in the NHS.
Sources: Expert list
Skeletal muscle channelopathy v0.21 CNBP Louise Daugherty Classified gene: CNBP as Red List (low evidence)
Skeletal muscle channelopathy v0.21 CNBP Louise Daugherty Added comment: Comment on list classification: demoted to Red, this review is for the STR entity and not the gene entity.
Skeletal muscle channelopathy v0.21 CNBP Louise Daugherty Gene: cnbp has been classified as Red List (Low Evidence).
Skeletal Muscle Channelopathies v1.21 SLC2A1 Louise Daugherty Classified gene: SLC2A1 as Green List (high evidence)
Skeletal Muscle Channelopathies v1.21 SLC2A1 Louise Daugherty Gene: slc2a1 has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.20 SLC2A1 Louise Daugherty gene: SLC2A1 was added
gene: SLC2A1 was added to Skeletal Muscle Channelopathies. Sources: Expert list
Mode of inheritance for gene: SLC2A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: SLC2A1 were set to 19630075; 26598494; 10980529
Phenotypes for gene: SLC2A1 were set to Epilepsy, idiopathic generalized, susceptibility to, 12, 614847; Can resemble skeletal muscle channelopathy; GLUT1 deficiency syndrome 1, infantile onset, severe, 606777 (recessive and dominant).; GLUT1 deficiency syndrome 2, childhood onset, 612126; myotonia; dystonia
Review for gene: SLC2A1 was set to GREEN
Added comment: added from review of the GMS myotonia congenita panel. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Sources: Expert list
Skeletal Muscle Channelopathies v1.19 ATP1A2 Louise Daugherty Classified gene: ATP1A2 as Green List (high evidence)
Skeletal Muscle Channelopathies v1.19 ATP1A2 Louise Daugherty Added comment: Comment on list classification: Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Skeletal Muscle Channelopathies v1.19 ATP1A2 Louise Daugherty Gene: atp1a2 has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.18 ATP1A2 Louise Daugherty gene: ATP1A2 was added
gene: ATP1A2 was added to Skeletal Muscle Channelopathies. Sources: Expert list
Mode of inheritance for gene: ATP1A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATP1A2 were set to 30423015; 15286158; 18056581
Phenotypes for gene: ATP1A2 were set to Migraine, familial hemiplegic, 2, 602481; Alternating hemiplegia of childhood 1, 104290; Hypokalaemic periodic paralysis
Review for gene: ATP1A2 was set to GREEN
Added comment: added from review of the GMS myotonia congenita panel. Appropriate phenotype, sufficient cases, and external review comment all support gene-disease association.
Sources: Expert list
Skeletal muscle channelopathy v0.20 ATP2A1 Louise Daugherty Publications for gene: ATP2A1 were set to 8841193; 30423015; 15286158; 18056581
Skeletal muscle channelopathy v0.19 ATP2A1 Louise Daugherty Publications for gene: ATP2A1 were set to 8841193; 30423015; 15286158,18056581
Skeletal muscle channelopathy v0.18 ATP2A1 Louise Daugherty Added comment: Comment on publications: added additional publications to support Green rating. NB: SERCA1 is the previous gene symbol for ATP1A2
Skeletal muscle channelopathy v0.18 ATP2A1 Louise Daugherty Publications for gene: ATP2A1 were set to 8841193
Skeletal Muscle Channelopathies v1.17 KCNJ5 Louise Daugherty commented on gene: KCNJ5
Skeletal Muscle Channelopathies v1.17 KCNQ2 Louise Daugherty Classified gene: KCNQ2 as Red List (low evidence)
Skeletal Muscle Channelopathies v1.17 KCNQ2 Louise Daugherty Added comment: Comment on list classification: Downgraded from Amber to Red. This gene was not submitted as part of the GMS on the Myotonia congenita panel, it is also noted by reviewer Fowzan Alkuraya that they do not think the evidence linking this gene to the intended phenotype for this panel i.e. muscle channelopathy is compelling
Skeletal Muscle Channelopathies v1.17 KCNQ2 Louise Daugherty Gene: kcnq2 has been classified as Red List (Low Evidence).
Skeletal Muscle Channelopathies v1.16 CACNB4 Louise Daugherty Classified gene: CACNB4 as Red List (low evidence)
Skeletal Muscle Channelopathies v1.16 CACNB4 Louise Daugherty Added comment: Comment on list classification: Downgraded from Amber to Red. This gene was not submitted as part of the GMS on the Myotonia congenita panel, it is also noted by reviewer Fowzan Alkuraya that they do not think the evidence linking this gene to the intended phenotype for this panel i.e. muscle channelopathy is compelling
Skeletal Muscle Channelopathies v1.16 CACNB4 Louise Daugherty Gene: cacnb4 has been classified as Red List (Low Evidence).
Skeletal Muscle Channelopathies v1.15 CACNA1A Louise Daugherty Classified gene: CACNA1A as Green List (high evidence)
Skeletal Muscle Channelopathies v1.15 CACNA1A Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Since the original review in 2017 there has been more evidence to support variants of this gene resulting in a phenotype suitable for inclusion
Skeletal Muscle Channelopathies v1.15 CACNA1A Louise Daugherty Gene: cacna1a has been classified as Green List (High Evidence).
Skeletal Muscle Channelopathies v1.14 CACNA1A Louise Daugherty Added comment: Comment on publications: added publications suggested by external reviwer on Myotonia congenita panel for GMS, new publication in particular new publication March 2018 https://www.ncbi.nlm.nih.gov/pubmed/?term=29442233 gives evidence to support variants of this gene resulting in a phenotype suitable for inclusion, there is also reference to a mouse model here : https://www.ncbi.nlm.nih.gov/pubmed/?term=28688851
Skeletal Muscle Channelopathies v1.14 CACNA1A Louise Daugherty Publications for gene: CACNA1A were set to
Skeletal Muscle Channelopathies v1.13 CACNA1A Louise Daugherty Mode of inheritance for gene: CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Unexplained young onset end-stage renal disease v0.56 ANOS1 Eleanor Williams changed review comment from: PMID:9719154 reports overt renal failure in one adult with a contiguous deletion involving KAL1/ANOS1, and evidence of impaired renal function in a second adult with a clinical diagnosis of Kallmann syndrome. Both had unilateral renal agenesis.

Note on MOI - PMID: 11297579 - Oliveira et al 2001 - report that "Genetically proven female carriers of KAL mutations in 3 families all had normal pubertal development, with regular menstrual cycles and normal olfaction". They also evaluated three families in which anosmic women gave birth to sons with KS, and none had any mutation in the coding sequence of the KAL gene.

Therefore I think the MOI should be X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not appear to present with the relevant phenotype.; to: PMID:9719154 Duke et al 1998 - reports overt renal failure in one adult with a contiguous deletion involving KAL1/ANOS1, and evidence of impaired renal function in a second adult with a clinical diagnosis of Kallmann syndrome. Both had unilateral renal agenesis.

PMID: 17603054 - Georgopoulos et al 2007 - report renal dysgenesis in 2 out of 16 male KS patients. One had two missense mutations in the KAL1 gene, the other had deletion of exons 5–10 of the KAL1 gene and a complete deletion of the steroid sulphatase (STS) gene which accounts for the X-linked ichthyosis seen in that patient.

PMID: 23533228 - Costa-Barbosa et al 2014 - report a cohort of 38 Kallman syndrome patients with rare variants in KAL1. 3/17 of them (where data was available) had renal agenesis.

PMID: 25597551 - Xu et al 2015 - report 2 Chinese brothers with KS and X-linked ichthyosis. The phenotypes of the patients were characterised by bilateral cryptorchidism, unilateral renal agenesis in one patient but normal kidney development in another. The two affected siblings had the same novel deletion at Xp22.3 including exons 9-14 of KAL1 gene and entire STS gene.

Note on MOI - PMID: 11297579 - Oliveira et al 2001 - report that "Genetically proven female carriers of KAL mutations in 3 families all had normal pubertal development, with regular menstrual cycles and normal olfaction". They also evaluated three families in which anosmic women gave birth to sons with KS, and none had any mutation in the coding sequence of the KAL gene.

Therefore I think the MOI should be X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not appear to present with the relevant phenotype.
Unexplained young onset end-stage renal disease v0.56 ANOS1 Eleanor Williams changed review comment from: Note on MOI - PMID: 11297579 - Oliveira et al 2001 - report that "Genetically proven female carriers of KAL mutations in 3 families all had normal pubertal development, with regular menstrual cycles and normal olfaction". They also evaluated three families in which anosmic women gave birth to sons with KS, and none had any mutation in the coding sequence of the KAL gene.

ANOS1 was previously known as KAL1.

Therefore I think the MOI should be X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not appear to present with the relevant phenotype.; to: PMID:9719154 reports overt renal failure in one adult with a contiguous deletion involving KAL1/ANOS1, and evidence of impaired renal function in a second adult with a clinical diagnosis of Kallmann syndrome. Both had unilateral renal agenesis.

Note on MOI - PMID: 11297579 - Oliveira et al 2001 - report that "Genetically proven female carriers of KAL mutations in 3 families all had normal pubertal development, with regular menstrual cycles and normal olfaction". They also evaluated three families in which anosmic women gave birth to sons with KS, and none had any mutation in the coding sequence of the KAL gene.

Therefore I think the MOI should be X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not appear to present with the relevant phenotype.
Unexplained young onset end-stage renal disease v0.56 APRT Eleanor Williams changed review comment from: Comment on list classification: Although there are enough cases with variants in this gene associated with a relevant phenotype, rating this gene as Amber just now until it is decided whether patients with nephrolithiaisis should have this panel applied or the Nephrocalcinosis or nephrolithiasis panel.; to: Comment on list classification: Although there are enough cases with variants in this gene associated with a relevant phenotype, this gene has been rated as amber on this panel since patients present with nephrolithiaisis and it is likely more appropriate for them to have the Nephrocalcinosis or nephrolithiasis panel applied. The gene is green on the Nephrocalcinosis or nephrolithiasis panel.
Unexplained young onset end-stage renal disease v0.56 APRT Eleanor Williams Classified gene: APRT as Amber List (moderate evidence)
Unexplained young onset end-stage renal disease v0.56 APRT Eleanor Williams Added comment: Comment on list classification: Although there are enough cases with variants in this gene associated with a relevant phenotype, rating this gene as Amber just now until it is decided whether patients with nephrolithiaisis should have this panel applied or the Nephrocalcinosis or nephrolithiasis panel.
Unexplained young onset end-stage renal disease v0.56 APRT Eleanor Williams Gene: aprt has been classified as Amber List (Moderate Evidence).
Unexplained young onset end-stage renal disease v0.55 APRT Eleanor Williams Phenotypes for gene: APRT were changed from nterstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis; Adenine phosphoribosyltransferase deficiency 614723 to interstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis; Adenine phosphoribosyltransferase deficiency 614723
Unexplained young onset end-stage renal disease v0.54 APRT Eleanor Williams gene: APRT was added
gene: APRT was added to Unexplained paediatric onset end-stage renal disease. Sources: Expert Review
Mode of inheritance for gene: APRT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APRT were set to 30355577; 30106368; 25307253; 22212387
Phenotypes for gene: APRT were set to nterstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis; Adenine phosphoribosyltransferase deficiency 614723
Review for gene: APRT was set to AMBER
Added comment: This gene was added to the 100,000 genomes project ' Unexplained kidney failure in young people' panel at the suggestion of external reviewer John Sayer.

Associated with Adenine phosphoribosyltransferase deficiency (#614723)(AR) in OMIM with renal failure and Urolithiasis listed as clinical features. APRT is green on the Nephrocalcinosis or nephrolithiasis panel (https://panelapp.genomicsengland.co.uk/panels/149/gene/APRT/). > 3 cases reported in OMIM where variants in APRT are associated with Adenine phosphoribosyltransferase deficiency and a renal phenotype.

Homozygous and compound heterozygous variants in APRT are associated with Adenine phosphoribosyltransferase deficiency and can lead to end-stage kidney disease if untreated. End-stage kidney disease can present under 50 years.
Sources: Expert Review
Unexplained young onset end-stage renal disease v0.53 FAN1 Eleanor Williams Classified gene: FAN1 as Green List (high evidence)
Unexplained young onset end-stage renal disease v0.53 FAN1 Eleanor Williams Added comment: Comment on list classification: Sufficient cases to rate green for association with a relevant disease and presentation can be in young adults.
Unexplained young onset end-stage renal disease v0.53 FAN1 Eleanor Williams Gene: fan1 has been classified as Green List (High Evidence).
Unexplained young onset end-stage renal disease v0.52 FAN1 Eleanor Williams gene: FAN1 was added
gene: FAN1 was added to Unexplained paediatric onset end-stage renal disease. Sources: Expert Review
Mode of inheritance for gene: FAN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAN1 were set to 22772369
Phenotypes for gene: FAN1 were set to interstitial nephritis; chronic kidney disease; Interstitial nephritis, karyomegalic 614817
Review for gene: FAN1 was set to GREEN
Added comment: This gene was added to the 100,000 genomes project ' Unexplained kidney failure in young people' panel at the suggestion of external reviewer John Sayer.

FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM. PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM). End-stage kidney failure ensued by a median age of 45 years in the 12 individuals with KIN and FAN1 mutations. Sufficient cases with likely disease causing mutations to rate this gene green.
Sources: Expert Review
Unexplained kidney failure in young people v1.82 FAN1 Eleanor Williams Phenotypes for gene: FAN1 were changed from interstitial nephritis; chronic kidney disease to interstitial nephritis; chronic kidney disease; Interstitial nephritis, karyomegalic 614817
Unexplained kidney failure in young people v1.81 FAN1 Eleanor Williams Classified gene: FAN1 as Green List (high evidence)
Unexplained kidney failure in young people v1.81 FAN1 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team, rating this gene green as relevant phenotype with onset in 20s-30s is appropriate for this panel.
Unexplained kidney failure in young people v1.81 FAN1 Eleanor Williams Gene: fan1 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.80 APRT Eleanor Williams commented on gene: APRT: After consultation with the Genomics England clinical team it has been decided to keep this gene amber on this panel. It is green on the Nephrocalcinosis or nephrolithiasis panel (https://panelapp.genomicsengland.co.uk/panels/149/) which is considered the more appropriate panel.
Pneumothorax - familial v2.16 COL3A1 Matthew Edwards changed review comment from: On CGGL Royal Brompton pneumothorax diagnostic panel. Pneumrpthorax is a minor diagnostic criteria in vEDS, therefore, although unlikely to be the presenting feature, COL3A1 appropriate for inclusion here.; to: On CGGL Royal Brompton pneumothorax diagnostic panel. Pneumothorax is a minor diagnostic criteria in vEDS, therefore, although unlikely to be the presenting feature, COL3A1 appropriate for inclusion here.
Nephrocalcinosis or nephrolithiasis v1.50 TRPM6 Eleanor Williams changed review comment from: Comment on list classification: Demoting this gene from green to red. A PubMed search didn't find publications listing nephrocalicinosis/nephrolithiasis in association with this gene. Hypermagnesuria no hypomagnesemia is included on the eligibility statement for this disease.; to: Comment on list classification: Demoting this gene from green to red. A PubMed search didn't find publications listing nephrocalicinosis/nephrolithiasis in association with this gene. Hypermagnesuria not hypomagnesemia is included on the eligibility statement for this disease.
Nephrocalcinosis or nephrolithiasis v1.50 HNF4A Eleanor Williams Phenotypes for gene: HNF4A were changed from to Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young, 616026
Nephrocalcinosis or nephrolithiasis v1.49 HNF4A Eleanor Williams Publications for gene: HNF4A were set to
Nephrocalcinosis or nephrolithiasis v1.48 SLC4A1 Eleanor Williams Phenotypes for gene: SLC4A1 were changed from distal renal tubular acidosis to distal renal tubular acidosis; Renal tubular acidosis, distal, AD, 179800; Renal tubular acidosis, distal, AR 611590
Pneumothorax - familial v2.16 FBN1 Louise Daugherty Phenotypes for gene: FBN1 were changed from Marfan syndrome to Marfan syndrome, 154700
Pneumothorax - familial v2.15 FBN1 Louise Daugherty Added comment: Comment on publications: added publication suggested by expert reviewer
Pneumothorax - familial v2.15 FBN1 Louise Daugherty Publications for gene: FBN1 were set to 12598898; 15161620; 11786720; 1864149; 2595640
Pneumothorax - familial v2.14 FLCN Louise Daugherty Phenotypes for gene: FLCN were changed from Primary Spontaneous Pneumothorax; OMIM 173600; Birt-Hogg-Dube Syndrome; OMIM 135150; Birt-Hogg-Dube syndrome; Spontaneous Pneumothorax; Birt-Hogg-Dube Syndrome to Primary Spontaneous Pneumothorax, 173600; Birt-Hogg-Dube Syndrome, 135150; Birt-Hogg-Dube syndrome; Spontaneous Pneumothorax; Birt-Hogg-Dube Syndrome
Pneumothorax - familial v2.13 FLCN Louise Daugherty Added comment: Comment on publications: added publication suggested by expert reviewer
Pneumothorax - familial v2.13 FLCN Louise Daugherty Publications for gene: FLCN were set to 21550484; 19483054; 15852235; 15805188; 15657874; 12204536; 26928018
Pneumothorax - familial v2.12 SERPINA1 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.12 SERPINA1 Louise Daugherty Phenotypes for gene: SERPINA1 were changed from Emphysema due to AAT deficiency; Emphysema-cirrhosis, due to AAT deficiency to Emphysema due to AAT deficiency; Emphysema-cirrhosis, due to AAT deficiency; Emphysema/cirrhosis due to AAT deficiency, 613490
Pneumothorax - familial v2.11 TGFB2 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.11 TGFB2 Louise Daugherty Phenotypes for gene: TGFB2 were changed from Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 4, 614816 to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 4, 614816
Pneumothorax - familial v2.10 TGFB2 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.10 TGFB2 Louise Daugherty Phenotypes for gene: TGFB2 were changed from Loeys-Dietz syndrome; Pulmonary emphysema to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 4, 614816
Pneumothorax - familial v2.9 TGFB3 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.9 TGFB3 Louise Daugherty Phenotypes for gene: TGFB3 were changed from Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 5, 615582 to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 5, 615582
Pneumothorax - familial v2.8 TGFB3 Louise Daugherty Phenotypes for gene: TGFB3 were changed from Loeys-Dietz syndrome; Pulmonary emphysema to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 5, 615582
Pneumothorax - familial v2.7 TGFB3 Louise Daugherty Added comment: Comment on publications: added publications suggested by expert reviewer
Pneumothorax - familial v2.7 TGFB3 Louise Daugherty Publications for gene: TGFB3 were set to 26493799; 15591413; 25006744; 23161884
Pneumothorax - familial v2.6 TGFBR1 Louise Daugherty Added comment: Comment on publications: added publication suggested by expert reviewer
Pneumothorax - familial v2.6 TGFBR1 Louise Daugherty Publications for gene: TGFBR1 were set to 26493799; 15591413; 25006744; 23161884
Pneumothorax - familial v2.5 TGFBR1 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.5 TGFBR1 Louise Daugherty Phenotypes for gene: TGFBR1 were changed from Loeys-Dietz syndrome; Pulmonary emphysema to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome 1, 609192
Pneumothorax - familial v2.4 TGFBR2 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.4 TGFBR2 Louise Daugherty Phenotypes for gene: TGFBR2 were changed from Loeys-Dietz syndrome; Pulmonary emphysema to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome type 2, 610168
Pneumothorax - familial v2.3 TSC1 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.3 TSC1 Louise Daugherty Phenotypes for gene: TSC1 were changed from Lymphangioleiomyomatosis (LAM); Tuberous sclerosis complex (TSC); Lymphangioleiomyomatosis to Lymphangioleiomyomatosis (LAM); Tuberous sclerosis complex (TSC); Lymphangioleiomyomatosis; Tuberous sclerosis 1, 191100
Pneumothorax - familial v2.2 TSC2 Louise Daugherty Phenotypes for gene: TSC2 were changed from Lymphangioleiomyomatosis (LAM); Tuberous sclerosis complex (TSC); Lymphangioleiomyomatosis to Lymphangioleiomyomatosis (LAM); Tuberous sclerosis complex (TSC); Lymphangioleiomyomatosis; Tuberous sclerosis 2, 613254
Pneumothorax - familial v2.1 SMAD3 Louise Daugherty Added comment: Comment on phenotypes: added phenotype suggested by expert reviewer
Pneumothorax - familial v2.1 SMAD3 Louise Daugherty Phenotypes for gene: SMAD3 were changed from Loeys-Dietz syndrome; Pulmonary emphysema to Loeys-Dietz syndrome; Pulmonary emphysema; Loeys-Dietz syndrome type 3, 613795
Early onset or syndromic epilepsy v1.405 GOT2 Rebecca Foulger commented on gene: GOT2
Early onset or syndromic epilepsy v1.405 HNRNPR Rebecca Foulger commented on gene: HNRNPR
Early onset or syndromic epilepsy v1.405 HLCS Rebecca Foulger Publications for gene: HLCS were set to
Early onset or syndromic epilepsy v1.404 HLCS Rebecca Foulger Phenotypes for gene: HLCS were changed from to Holocarboxylase synthetase deficiency, 253270
Early onset or syndromic epilepsy v1.403 PLA2G6 Rebecca Foulger Classified gene: PLA2G6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.403 PLA2G6 Rebecca Foulger Added comment: Comment on list classification: Although PLA2G6 is Green on the 'Inborn errors of metabolism' panel, have added to the Epilepsy panel as Amber as unclear if seizures are a consistent feature. Requires clinical review (and review of the MOI in PMID:27513994) before promotion to Green.
Early onset or syndromic epilepsy v1.403 PLA2G6 Rebecca Foulger Gene: pla2g6 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.402 PLA2G6 Rebecca Foulger Added comment: Comment on mode of inheritance: Selected 'BIALLELIC' inheritance to match the metabolism PanelApp panels (including Inborn errors of metabolism, V1.392), all OMIM disorders and both G2P disorders. However, PMID:27513994 report autosomal dominant inheritance for Familial cortical myoclonic tremor with epilepsy (FCMTE).
Early onset or syndromic epilepsy v1.402 PLA2G6 Rebecca Foulger Mode of inheritance for gene: PLA2G6 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:27513994 (Gao et al., 2016) report a family (41 members) which included 6 individuals affected with Familial cortical myoclonic tremor with epilepsy (FCMTE). All 6 individuals had tremors while 5 individuals had seizures. Genomic sequencing was performed on 3 affected and 2 unaffected individuals. A novel missense variant c.475C>T (p.A159T) in PLA2G6 with AD inheritance was identified in this family which segregated with the disease. Note that a variant in SNRNP200 gene also segregated with the disease but is within the untranslated region and the functional effect is unclear.
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:30772976. Ma et al., 2019 analyse a Chinese Han pedigree with seizures amongst the phenotype. Compound het variants in PLA2G6 were found (p.A80T and p.D331Y) (full English text not available).
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: PMID:30340910. Darling et al., 2019 investigated 16 patients from 13 families with PLA2G6-associated neurodegeneration (an autosomal recessive disorder). Epilepsy was observed in 8/16 patients (7 families, 2 patients had been previously reported, Table 1). All patients harboured missense, nonsense and frameshift variants in PLA2G6.
Early onset or syndromic epilepsy v1.401 PLA2G6 Rebecca Foulger gene: PLA2G6 was added
gene: PLA2G6 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: PLA2G6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLA2G6 were set to 30340910; 27513994; 30772976
Phenotypes for gene: PLA2G6 were set to PLA2G6-associated neurodegeneration (PLAN); Familial cortical myoclonic tremor with epilepsy (FCMTE); Infantile neuroaxonal dystrophy 1, 256600; Neurodegeneration with brain iron accumulation 2B, 610217
Added comment: Added to epilepsy panel based on a Green rating on the 'Inborn errors of metabolism panel'- seizures are a reported feature of MIM:256600 and MIM:610217.
Sources: Literature, Other
Pneumothorax - familial v2.0 SMAD3 Matthew Edwards edited their review of gene: SMAD3: Changed rating: AMBER
Pneumothorax - familial v2.0 SMAD3 Matthew Edwards reviewed gene: SMAD3: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: OMIM: 613795 Loeys-Dietz syndrome type 3; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Pneumothorax - familial v2.0 TSC2 Matthew Edwards reviewed gene: TSC2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: OMIM 613254 Tuberous sclerosis-2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Early onset or syndromic epilepsy v1.400 DNAJC5 Rebecca Foulger Classified gene: DNAJC5 as Green List (high evidence)
Early onset or syndromic epilepsy v1.400 DNAJC5 Rebecca Foulger Added comment: Comment on list classification: Added to panel as a Green gene as seizures are a symptom of the metabolic disorder, and sufficient epilepsy cases from literature.
Early onset or syndromic epilepsy v1.400 DNAJC5 Rebecca Foulger Gene: dnajc5 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.22 GAS2L2 Eleanor Williams Classified gene: GAS2L2 as Amber List (moderate evidence)
Primary ciliary disorders v1.22 GAS2L2 Eleanor Williams Added comment: Comment on list classification: Demoting to Amber for now as this gene currently has no Ensembl IDs in PanelApp. Will promote to green again when this issue is resolved.
Primary ciliary disorders v1.22 GAS2L2 Eleanor Williams Gene: gas2l2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:22235333: Velinov et al., 2012. The authors previously described the Parry family in the 1970s. All affected individuals from the family had a history of progressive seizure disorder. They identified a pLeu116del variant in DNAJC5 which segregated with the disease. 8 additional families were studied for this paper, with seizures amongst the phenotypes. In one affected individual, pLeu115Arg was identified (proband BD-319) who had seizures and gradual dementia beginning in the mid 30s.
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:29506599: Jarrett et al., 2018 report a family with Kufs disease in which the proband and 3/4 children presented with cognitive impariment, seizures and myoclonus. Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) variant in the DNAJC5 gene. EEG on the asymptomatic fourth child showed moderatley severe slowing. The proband's father was deceased but had a history of epileptic seizures.
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger commented on gene: DNAJC5: PMID:22978711: Cadieux-Dion et al., 2013. report a p.L116del variant in DNAJC5 in two distinct American families, and a p.L115R variant in an additional family. All individuals showed generalized tonic-clonic seizures.
Early onset or syndromic epilepsy v1.399 DNAJC5 Rebecca Foulger gene: DNAJC5 was added
gene: DNAJC5 was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: DNAJC5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DNAJC5 were set to 22978711; 29506599; 22235333
Phenotypes for gene: DNAJC5 were set to Ceroid lipofuscinosis, neuronal, 4, Parry type, 162350; autosomal dominant Kufs disease; generalized tonic–clonic seizures
Added comment: Added DNAJC5 to the Epilepsy panel based on a Green rating on the 'Inborn errors of metabolism' panel: seizures are listed as a symptom of MIM:162350 in OMIM.
Sources: Literature, Other
Pneumothorax - familial v2.0 TSC1 Matthew Edwards reviewed gene: TSC1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23729718, 19318672; Phenotypes: OMIM 606690 Lymphangioleiomyomatosis (LAM), 191100 Tuberous sclerosis-1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Pneumothorax - familial v2.0 TGFBR2 Matthew Edwards reviewed gene: TGFBR2: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: OMIM: 610168 Loeys-Dietz syndrome type 2; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Pneumothorax - familial v2.0 TGFBR1 Matthew Edwards reviewed gene: TGFBR1: Rating: GREEN; Mode of pathogenicity: None; Publications: 16799921; Phenotypes: OMIM: 609192 Loeys-Dietz syndrome 1; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Pneumothorax - familial v2.0 TGFB3 Matthew Edwards reviewed gene: TGFB3: Rating: GREEN; Mode of pathogenicity: None; Publications: 24577266, 25835445; Phenotypes: OMIM: 615582 Loeys-Dietz syndrome 5; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Pneumothorax - familial v2.0 TGFB2 Matthew Edwards changed review comment from: On CGGL Royal Brompton panel. Several pathogenic variants (including CNVs) reported in LDS, with extensive segregation. Pneumothorax can be a feature of LDS, potentially repsenting feature, therefore appropriate for this apenl as well as FTAAD panel.; to: On CGGL Royal Brompton panel. Several pathogenic variants (including CNVs) reported in LDS, with extensive segregation. Pneumothorax can be a feature of LDS, potentially repsenting feature, therefore appropriate for this panel as well as FTAAD panel.
Pneumothorax - familial v2.0 TGFB2 Matthew Edwards reviewed gene: TGFB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26493799; Phenotypes: OMIM 614816 Loeys-Dietz syndrome (LDS) 4; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Pneumothorax - familial v2.0 SERPINA1 Matthew Edwards reviewed gene: SERPINA1: Rating: GREEN; Mode of pathogenicity: None; Publications: 22215832, 18619132; Phenotypes: OMIM 613490 Emphysema/cirrhosis due to AAT deficiency; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Pneumothorax - familial v2.0 FLCN Matthew Edwards reviewed gene: FLCN: Rating: GREEN; Mode of pathogenicity: None; Publications: 15852235, 19483054, 12204536; Phenotypes: OMIM 173600 Pneumothorax, primary spontaneous, 135150 Birt-Hogg-Dube syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Pneumothorax - familial v2.0 FBN1 Matthew Edwards reviewed gene: FBN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 2595640, 12598898, 25765122; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Nephrocalcinosis or nephrolithiasis v1.47 CLCNKB Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM Autosomal recessive for Bartter syndrome, type 3 607364 and Digenic recessive for Bartter syndrome, type 4b, digenic 613090.
Nephrocalcinosis or nephrolithiasis v1.47 CLCNKB Eleanor Williams Mode of inheritance for gene: CLCNKB was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.46 CASR Eleanor Williams Added comment: Comment on mode of pathogenicity: Expert review states that Hypocalcemia can be caused by a mutation that inappropriately activates the receptor
Nephrocalcinosis or nephrolithiasis v1.46 CASR Eleanor Williams Mode of pathogenicity for gene: CASR was changed from to Other
Nephrocalcinosis or nephrolithiasis v1.45 BSND Eleanor Williams Added comment: Comment on mode of inheritance: AR in OMIM and Biallelic in Gene2Phenotype for Bartter syndrome, type 4a
Nephrocalcinosis or nephrolithiasis v1.45 BSND Eleanor Williams Mode of inheritance for gene: BSND was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.44 ATP6V1B1 Eleanor Williams Phenotypes for gene: ATP6V1B1 were changed from distal renal tubular acidosis to distal renal tubular acidosis; Renal tubular acidosis with deafness 267300
Nephrocalcinosis or nephrolithiasis v1.43 ATP6V0A4 Eleanor Williams commented on gene: ATP6V0A4
Nephrocalcinosis or nephrolithiasis v1.43 PHEX Eleanor Williams Classified gene: PHEX as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.43 PHEX Eleanor Williams Added comment: Comment on list classification: In light of expert review and consultation with the Genomics England clinical team it was decided to promote this gene from red to green. >3 cases reported with variants in this gene in patients with nephrocalicinosis.
Nephrocalcinosis or nephrolithiasis v1.43 PHEX Eleanor Williams Gene: phex has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.42 PHEX Eleanor Williams changed review comment from: Comment on mode of inheritance: Following XLD mode of inhertiance in OMIM, so changing to X-Linked: hemizyous mutation in males, monoallelic in females.; to: Comment on mode of inheritance: Following XLD mode of inhertiance in OMIM, so changing to X-Linked: hemizyous mutation in males, monoallelic in females. Monoallelic variants causing disease in females are reported e.g. PMID: 10439971 Filisetti et al 1999
Nephrocalcinosis or nephrolithiasis v1.42 PHEX Eleanor Williams Publications for gene: PHEX were set to
Nephrocalcinosis or nephrolithiasis v1.41 PHEX Eleanor Williams Phenotypes for gene: PHEX were changed from to Hypophosphatemic rickets, X-linked dominant 307800
Nephrocalcinosis or nephrolithiasis v1.40 FAM20A Eleanor Williams Classified gene: FAM20A as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.40 FAM20A Eleanor Williams Added comment: Comment on list classification: Upgrading from red to green. 3 independent cases where nephrocalcinosis is reported plus mouse knockout data showing a renal phenotype.
Nephrocalcinosis or nephrolithiasis v1.40 FAM20A Eleanor Williams Gene: fam20a has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.39 TRPM6 Eleanor Williams Classified gene: TRPM6 as Red List (low evidence)
Nephrocalcinosis or nephrolithiasis v1.39 TRPM6 Eleanor Williams Added comment: Comment on list classification: Demoting this gene from green to red. A PubMed search didn't find publications listing nephrocalicinosis/nephrolithiasis in association with this gene. Hypermagnesuria no hypomagnesemia is included on the eligibility statement for this disease.
Nephrocalcinosis or nephrolithiasis v1.39 TRPM6 Eleanor Williams Gene: trpm6 has been classified as Red List (Low Evidence).
Inherited pancreatic cancer v1.1 RABL3 Ivone Leong gene: RABL3 was added
gene: RABL3 was added to Inherited pancreatic cancer. Sources: Literature
Mode of inheritance for gene: RABL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RABL3 were set to 31406347
Phenotypes for gene: RABL3 were set to Hereditary pancreatic cancer
Review for gene: RABL3 was set to AMBER
Added comment: PMID: 31406347 describes a family with heterozygous variant in the RABL3 gene that causes a premature nonsense mutation. The family has multiple cases of pancreatic ductal adenocarcinoma. Sanger sequencing of the affected family showed significant co-segregation of the variant with cancer. Heterozygous knockdown of the rabl3 gene in zebrafish show increased susceptibility to cancer formation.
Sources: Literature
Silver Russell syndrome v1.9 PLAG1 Ivone Leong Classified gene: PLAG1 as Green List (high evidence)
Silver Russell syndrome v1.9 PLAG1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green. This gene is a Green gene on the Growth failure in early childhood panel (code 473, v1.3), which has been signed off by the GMS Endocrinology specialist group (31/07/2019).
Silver Russell syndrome v1.9 PLAG1 Ivone Leong Gene: plag1 has been classified as Green List (High Evidence).
Silver Russell syndrome v1.8 PLAG1 Ivone Leong Phenotypes for gene: PLAG1 were changed from to SRS; Silver-Russell syndrome
Silver Russell syndrome v1.7 PLAG1 Ivone Leong gene: PLAG1 was added
gene: PLAG1 was added to Silver Russell syndrome. Sources: Expert Review
Mode of inheritance for gene: PLAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PLAG1 were set to 28796236
Silver Russell syndrome v1.6 HMGA2 Ivone Leong Classified gene: HMGA2 as Green List (high evidence)
Silver Russell syndrome v1.6 HMGA2 Ivone Leong Gene: hmga2 has been classified as Green List (High Evidence).
Silver Russell syndrome v1.5 HMGA2 Ivone Leong gene: HMGA2 was added
gene: HMGA2 was added to Silver Russell syndrome. Sources: Expert Review
Mode of inheritance for gene: HMGA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: HMGA2 were set to 29655892
Phenotypes for gene: HMGA2 were set to SRS; Silver-Russell syndrome
Review for gene: HMGA2 was set to GREEN
Added comment: This is a Green gene on the Growth failure in early childhood panel (code 473, v1.3), which has been signed off by the GMS Endocrinology specialist group (31/07/2019).
Sources: Expert Review
Silver Russell syndrome v1.4 IGF2 Ivone Leong Classified gene: IGF2 as Green List (high evidence)
Silver Russell syndrome v1.4 IGF2 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green as this gene is a Green gene on the Growth failure in early childhood panel (code 473, v1.3), which has been signed off by the GMS Endocrinology specialist group (31/07/2019).
Silver Russell syndrome v1.4 IGF2 Ivone Leong Gene: igf2 has been classified as Green List (High Evidence).
Monogenic hearing loss v2.3 TMEM132E Eleanor Williams Tag watchlist tag was added to gene: TMEM132E.
Unexplained kidney failure in young people v1.80 FAN1 Eleanor Williams Classified gene: FAN1 as Amber List (moderate evidence)
Unexplained kidney failure in young people v1.80 FAN1 Eleanor Williams Added comment: Comment on list classification: Downgrading from green to amber while consulting with the Genomics England clinical team as to the suitability of this gene as the age of onset for renal disease is from 30 year old onwards.
Unexplained kidney failure in young people v1.80 FAN1 Eleanor Williams Gene: fan1 has been classified as Amber List (Moderate Evidence).
Unexplained kidney failure in young people v1.79 APRT Eleanor Williams Classified gene: APRT as Amber List (moderate evidence)
Unexplained kidney failure in young people v1.79 APRT Eleanor Williams Added comment: Comment on list classification: Downgrading from Green to Amber as presence of Nephrolithiasis is part of the exclusion criteria. Will consult with the Genomics England clinical team as to whether this gene should be included on this panel or not.
Unexplained kidney failure in young people v1.79 APRT Eleanor Williams Gene: aprt has been classified as Amber List (Moderate Evidence).
Unexplained kidney failure in young people v1.78 FAN1 Eleanor Williams changed review comment from: FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM.

PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM).

Sufficient cases with likely disease causing mutations to rate this gene green. ; to: FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM.

PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM). End-stage kidney failure ensued by a median age of 45 years in the 12 individuals with KIN and FAN1 mutations.

Sufficient cases with likely disease causing mutations to rate this gene green.
Primary ciliary disorders v1.21 GAS2L2 Eleanor Williams Classified gene: GAS2L2 as Green List (high evidence)
Primary ciliary disorders v1.21 GAS2L2 Eleanor Williams Added comment: Comment on list classification: After consultation with the Genomics England clinical team it was decided to change the rating of this gene from Amber to Green based on the additional green expert review.
Primary ciliary disorders v1.21 GAS2L2 Eleanor Williams Gene: gas2l2 has been classified as Green List (High Evidence).
Primary ciliary disorders v1.20 GAS2L2 Eleanor Williams Phenotypes for gene: GAS2L2 were changed from Primary ciliary dyskinesia to Primary ciliary dyskinesia; ?Ciliary dyskinesia, primary, 41 618449
Monogenic hearing loss v2.3 TMEM132E Eleanor Williams edited their review of gene: TMEM132E: Changed rating: AMBER
Monogenic hearing loss v2.3 TMEM132E Eleanor Williams gene: TMEM132E was added
gene: TMEM132E was added to Hearing loss. Sources: Literature
Mode of inheritance for gene: TMEM132E was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM132E were set to 25331638; 31656313
Phenotypes for gene: TMEM132E were set to Nonsyndromic Hearing Loss
Review for gene: TMEM132E was set to RED
Added comment: Two publications support the addition of this gene to the panel:

PMID: 25331638 - Li et al 2015 - report two siblings with prelingual, bilateral, severe to profound sensorineural hearing loss in a consanguineous Chinese family. Whole‐exome sequencing revealed a homozygous missense mutation c.1259G>A (rs139895222), p.Arg420Gln, in TMEM132E that cosegregates with deafness in the family. The parents and a brother were heterozygous. The 1259A allele was not found in 500 ethnically matched controls. Immunofluorescence staining of the Organ of Corti showed Tmem132e highly expressed in murine inner hair cells and knockdown of the tmem132e ortholog in zebrafish affected the mechanotransduction of hair cells. Wild‐type human TMEM132E mRNA, but not the mRNA carrying the c.1259G>A mutation rescued the Tmem132e knockdown phenotype.

PMID: 31656313 - Liaqat et al 2019 - a family of Pakistani origin with prelingual profound sensorineural hearing impairment displaying AR mode of inheritance was investigated via exome and Sanger sequencing. Compound heterozygous variants c.382G>T: p.(Ala128Ser) and c.2204C>T: p.(Pro735Leu) in TMEM132E were observed in affected but not in unaffected family members.
Sources: Literature
Unexplained kidney failure in young people v1.78 APRT Eleanor Williams Publications for gene: APRT were set to 30355577
Unexplained kidney failure in young people v1.77 APRT Eleanor Williams Classified gene: APRT as Green List (high evidence)
Unexplained kidney failure in young people v1.77 APRT Eleanor Williams Added comment: Comment on list classification: There are more than 3 cases where homozygous or compound heterozygous variants in APRT have been reported in patients with Adenine phosphoribosyltransferase deficiency. PMID: 30106368 and PMID: 25307253 report cases in which end-stage renal disease has been observed under the age of 50.
Unexplained kidney failure in young people v1.77 APRT Eleanor Williams Gene: aprt has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.76 APRT Eleanor Williams Phenotypes for gene: APRT were changed from interstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis to interstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis; Adenine phosphoribosyltransferase deficiency 614723
Unexplained kidney failure in young people v1.75 APRT Eleanor Williams commented on gene: APRT
Hereditary neuropathy v1.335 Louise Daugherty List of related panels changed from Charcot-Marie-Tooth disease to Charcot-Marie-Tooth disease; R78
Pneumothorax - familial v2.0 Louise Daugherty promoted panel to version 2.0
Pneumothorax - familial v1.19 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Pneumothorax - familial v1.18 SMAD3 Louise Daugherty commented on gene: SMAD3: October 2019: Gene flagged up for further discussion by Respiratory Test Group regarding the inclusion of genes associated with Loeys-Dietz syndrome and classical EDS. However, no additional feedback was received, so gene will not be upgraded to Green as inclusion on this panel remains unclear. COL5A1, SMAD2 and SMAD3 are rated Green on the R101 Ehlers Danlos syndromes panel https://panelapp.genomicsengland.co.uk/panels/53/
Pneumothorax - familial v1.18 SMAD2 Louise Daugherty commented on gene: SMAD2: October 2019: Gene flagged up for further discussion by Respiratory Test Group regarding the inclusion of genes associated with Loeys-Dietz syndrome and classical EDS. However, no additional feedback was received, so gene will not be upgraded to Green as inclusion on this panel remains unclear. COL5A1, SMAD2 and SMAD3 are rated Green on the R101 Ehlers Danlos syndromes panel https://panelapp.genomicsengland.co.uk/panels/53/
Pneumothorax - familial v1.18 COL5A1 Louise Daugherty commented on gene: COL5A1: October 2019: Gene flagged up for further discussion by Respiratory Test Group regarding the inclusion of genes associated with Loeys-Dietz syndrome and classical EDS. However, no additional feedback was received, so gene will not be upgraded to Green as inclusion on this panel remains unclear. COL5A1, SMAD2 and SMAD3 are rated Green on the R101 Ehlers Danlos syndromes panel https://panelapp.genomicsengland.co.uk/panels/53/
Hereditary spastic paraplegia, adult onset v1.1 L1CAM Louise Daugherty Added comment: Comment on mode of inheritance: Changed MOI due to upload of review MOI "X-LINKED recessive: hemizygous mutation in males, biallelic mutations in females" in inclusion of 'recessive' would result in an error with tiering, so has been corrected to 'X-LINKED: hemizygous mutation in males, biallelic mutations in females'
Hereditary spastic paraplegia, adult onset v1.1 L1CAM Louise Daugherty Mode of inheritance for gene: L1CAM was changed from X-LINKED recessive: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, biallelic mutations in females
DDG2P v1.148 CIC Rebecca Foulger changed review comment from: Original DDG2P rating: possible. DDG2P mode of pathogenicity: uncertain ; to: Original DDG2P rating for CAPICUA, DROSOPHILA, HOMOLOG OF: possible. DDG2P mode of pathogenicity: uncertain. Allelic requirement: monoallelic.
DDG2P v1.148 CIC Rebecca Foulger changed review comment from: Comment on mode of pathogenicity: Changed MOP to default LOF to match current Mutation consequence in Gene2Phenotype of 'Loss of Function'.; to: Comment on mode of pathogenicity: Changed MOP to default LOF to match Gene2Phenotype update: current Mutation consequence in Gene2Phenotype is 'Loss of Function'.
DDG2P v1.148 CIC Rebecca Foulger Added comment: Comment on mode of pathogenicity: Changed MOP to default LOF to match current Mutation consequence in Gene2Phenotype of 'Loss of Function'.
DDG2P v1.148 CIC Rebecca Foulger Mode of pathogenicity for gene: CIC was changed from Other - please provide details in the comments to None
DDG2P v1.147 CIC Rebecca Foulger Classified gene: CIC as Amber List (moderate evidence)
DDG2P v1.147 CIC Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following a change in G2P Disease confidence from possible to probable for 'CAPICUA, DROSOPHILA, HOMOLOG OF'.
DDG2P v1.147 CIC Rebecca Foulger Gene: cic has been classified as Amber List (Moderate Evidence).
DDG2P v1.146 FAM58A Rebecca Foulger commented on gene: FAM58A: The Gene2Phenotype allelic requirement for STAR SYNDROME has been updated to x-linked dominant, to match the recent update in PanelApp.
DDG2P v1.146 AMER1 Rebecca Foulger commented on gene: AMER1: The Gene2Phenotype allelic requirement for OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS has been updated to x-linked dominant, to match the recent update in PanelApp.
DDG2P v1.146 ACTL6B Rebecca Foulger Added comment: Comment on phenotypes: Removed 'Unspecified Neurodevelopmental Disorder' from phenotypes to match G2P update.
DDG2P v1.146 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Unspecified Neurodevelopmental Disorder; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE 618468; INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEVERE SPEECH AND AMBULATION DEFECTS 618470 to EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE 618468; INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEVERE SPEECH AND AMBULATION DEFECTS 618470
CAKUT v1.40 ANOS1 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the MOI to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This MOI has proposed by an expert reviewer and agrees with that found in OMIM. PMID: 15001591 - reports only male cases with ANOS1 variants, with female carriers, PMID: 11297579 - reports male cases and states that obligate female carriers in families with KAL mutations have no discernible phenotype.
CAKUT v1.40 ANOS1 Eleanor Williams Mode of inheritance for gene: ANOS1 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
Unexplained kidney failure in young people v1.75 ANOS1 Eleanor Williams changed review comment from: Comment on mode of inheritance: Updating the MOI to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This MOI has proposed by 2 reviewers and agrees with that found in OMIM. PMID: 15001591 - reports only male cases with ANOS1 variants, with female carriers, PMID: 11297579 - reports male cases and states that obligate female carriers in families with KAL mutations have no discernible phenotype.; to: Comment on mode of inheritance: Updating the MOI to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This MOI has proposed by 1reviewer and agrees with that found in OMIM. PMID: 15001591 - reports only male cases with ANOS1 variants, with female carriers, PMID: 11297579 - reports male cases and states that obligate female carriers in families with KAL mutations have no discernible phenotype.
Unexplained kidney failure in young people v1.75 ANOS1 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the MOI to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This MOI has proposed by 2 reviewers and agrees with that found in OMIM. PMID: 15001591 - reports only male cases with ANOS1 variants, with female carriers, PMID: 11297579 - reports male cases and states that obligate female carriers in families with KAL mutations have no discernible phenotype.
Unexplained kidney failure in young people v1.75 ANOS1 Eleanor Williams Mode of inheritance for gene: ANOS1 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
DDG2P v1.145 SLC35A2 Rebecca Foulger Phenotypes for gene: SLC35A2 were changed from CONGENITAL DISORDER OF GLYCOSYLATION to Epileptic Encephalopathy due to congenital disorder of glycosylation
DDG2P v1.144 SLC35A2 Rebecca Foulger Publications for gene: SLC35A2 were set to
Respiratory ciliopathies including non-CF bronchiectasis v1.0 FOXJ1 Hannah Mitchison gene: FOXJ1 was added
gene: FOXJ1 was added to Respiratory ciliopathies including non-CF bronchiectasis. Sources: Literature
Mode of inheritance for gene: FOXJ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: FOXJ1 were set to PMID: 31630787
Phenotypes for gene: FOXJ1 were set to Motile ciliopathy; situs inversus, hydrocephalus
Penetrance for gene: FOXJ1 were set to Complete
Mode of pathogenicity for gene: FOXJ1 was set to Other
Review for gene: FOXJ1 was set to AMBER
Added comment: Wallmeier et al 2019 report the first known cause of autosomal dominant 'PCD' - referred to here more as a motile ciliopathy, than strictly PCD, because there are reduced cilia numbers but no structural changes in the cilia axonemes which are typical for diagnosing PCD. The reported mutations are associated in this sole paper with haploinsufficiency. Wallmeier et al report FOXJ1 mutations in 6 unrelated patients - all were heterozygous, single de novo variants.
Sources: Literature
Respiratory ciliopathies including non-CF bronchiectasis v1.0 Louise Daugherty promoted panel to version 1.0
Respiratory ciliopathies including non-CF bronchiectasis v0.157 Louise Daugherty Panel types changed to GMS Rare Disease; GMS signed-off
Bleeding and platelet disorders v1.0 Louise Daugherty promoted panel to version 1.0
Bleeding and platelet disorders v0.79 Louise Daugherty Panel types changed to GMS Rare Disease; GMS signed-off
Hypogonadotropic hypogonadism v1.27 ANOS1 Eleanor Williams changed review comment from: Comment on mode of inheritance: Updating the mode of inheritance from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This gene is not in the pseudoautosomal region of the X chromosome.; to: Comment on mode of inheritance: Updating the mode of inheritance from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This gene is not in the pseudoautosomal region of the X chromosome. Mode of inhertiance in OMIM is XLR for Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) and several papers support this e.g. PMID: 15001591 - reports only male cases with ANOS1 variants, with female carriers, PMID: 11297579 - reports male cases and states that obligate female carriers in families with KAL mutations have no discernible phenotype.
Hypogonadotropic hypogonadism (GMS) v1.1 ANOS1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Hypogonadotropic hypogonadism (GMS) v1.1 ANOS1 Ivone Leong Mode of inheritance for gene: ANOS1 was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Likely inborn error of metabolism v1.392 DNM2 Catherine Snow Mode of inheritance for gene: DNM2 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.411 SETX Catherine Snow Classified gene: SETX as Green List (high evidence)
Undiagnosed metabolic disorders v1.411 SETX Catherine Snow Gene: setx has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.410 SETX Catherine Snow reviewed gene: SETX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyotrophic lateral sclerosis 4, juvenile, 602433, Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, 606002; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypogonadotropic hypogonadism v1.27 ANOS1 Eleanor Williams Added comment: Comment on mode of inheritance: Updating the mode of inheritance from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females. This gene is not in the pseudoautosomal region of the X chromosome.
Hypogonadotropic hypogonadism v1.27 ANOS1 Eleanor Williams Mode of inheritance for gene: ANOS1 was changed from BIALLELIC, autosomal or pseudoautosomal to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Likely inborn error of metabolism v1.391 SETX Catherine Snow Classified gene: SETX as Green List (high evidence)
Likely inborn error of metabolism v1.391 SETX Catherine Snow Gene: setx has been classified as Green List (High Evidence).
Cytopenia - NOT Fanconi anaemia v0.136 VWF Louise Daugherty Source Expert Review Red was added to VWF.
Cytopenia - NOT Fanconi anaemia v0.136 VPS13B Louise Daugherty Source Expert Review Red was added to VPS13B.
Cytopenia - NOT Fanconi anaemia v0.136 TUBB1 Louise Daugherty Source Expert Review Amber was added to TUBB1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 TCN2 Louise Daugherty Source Expert Review Amber was added to TCN2.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 STK4 Louise Daugherty Source Expert Review Red was added to STK4.
Cytopenia - NOT Fanconi anaemia v0.136 STIM1 Louise Daugherty Source Expert Review Amber was added to STIM1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 SRC Louise Daugherty Source Expert Review Green was added to SRC.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Cytopenia - NOT Fanconi anaemia v0.136 SLFN14 Louise Daugherty Source Expert Review Amber was added to SLFN14.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 RUNX1 Louise Daugherty Source Expert Review Amber was added to RUNX1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 RNU4ATAC Louise Daugherty Source Expert Review Red was added to RNU4ATAC.
Cytopenia - NOT Fanconi anaemia v0.136 RBM8A Louise Daugherty Source Expert Review Red was added to RBM8A.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v0.136 PTPN11 Louise Daugherty Source Expert Review Red was added to PTPN11.
Cytopenia - NOT Fanconi anaemia v0.136 PSMB8 Louise Daugherty Source Expert Review Red was added to PSMB8.
Cytopenia - NOT Fanconi anaemia v0.136 NBEAL2 Louise Daugherty Source Expert Review Amber was added to NBEAL2.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 MYH9 Louise Daugherty Source Expert Review Amber was added to MYH9.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 MTHFD1 Louise Daugherty Source Expert Review Red was added to MTHFD1.
Cytopenia - NOT Fanconi anaemia v0.136 MSN Louise Daugherty Source Expert Review Red was added to MSN.
Cytopenia - NOT Fanconi anaemia v0.136 MPIG6B Louise Daugherty Source Expert Review Red was added to MPIG6B.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v0.136 LYST Louise Daugherty Source Expert Review Red was added to LYST.
Cytopenia - NOT Fanconi anaemia v0.136 LAMTOR2 Louise Daugherty Source Expert Review Red was added to LAMTOR2.
Cytopenia - NOT Fanconi anaemia v0.136 KDSR Louise Daugherty Source Expert Review Red was added to KDSR.
Cytopenia - NOT Fanconi anaemia v0.136 ITGB3 Louise Daugherty Source Expert Review Red was added to ITGB3.
Cytopenia - NOT Fanconi anaemia v0.136 ITGA2B Louise Daugherty Source Expert Review Red was added to ITGA2B.
Cytopenia - NOT Fanconi anaemia v0.136 HTRA2 Louise Daugherty Source Expert Review Red was added to HTRA2.
Cytopenia - NOT Fanconi anaemia v0.136 HOXA11 Louise Daugherty Source Expert Review Red was added to HOXA11.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Cytopenia - NOT Fanconi anaemia v0.136 GP9 Louise Daugherty Source Expert Review Amber was added to GP9.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 GP1BB Louise Daugherty Source Expert Review Amber was added to GP1BB.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 GP1BA Louise Daugherty Source Expert Review Amber was added to GP1BA.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 GNE Louise Daugherty Source Expert Review Red was added to GNE.
Cytopenia - NOT Fanconi anaemia v0.136 GINS1 Louise Daugherty Source Expert Review Red was added to GINS1.
Cytopenia - NOT Fanconi anaemia v0.136 FLNA Louise Daugherty Source Expert Review Red was added to FLNA.
Cytopenia - NOT Fanconi anaemia v0.136 FLI1 Louise Daugherty Source Expert Review Amber was added to FLI1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 DIAPH1 Louise Daugherty Source Expert Review Red was added to DIAPH1.
Cytopenia - NOT Fanconi anaemia v0.136 CLPB Louise Daugherty Source Expert Review Red was added to CLPB.
Cytopenia - NOT Fanconi anaemia v0.136 CDC42 Louise Daugherty Source Expert Review Red was added to CDC42.
Cytopenia - NOT Fanconi anaemia v0.136 CD40LG Louise Daugherty Source Expert Review Red was added to CD40LG.
Cytopenia - NOT Fanconi anaemia v0.136 CD40 Louise Daugherty Source Expert Review Red was added to CD40.
Cytopenia - NOT Fanconi anaemia v0.136 ARPC1B Louise Daugherty Source Expert Review Red was added to ARPC1B.
Cytopenia - NOT Fanconi anaemia v0.136 AP3B1 Louise Daugherty Source Expert Review Amber was added to AP3B1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 ADAMTS13 Louise Daugherty Source Expert Review Amber was added to ADAMTS13.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 ACTN1 Louise Daugherty Source Expert Review Amber was added to ACTN1.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 ACTB Louise Daugherty Source Expert Review Red was added to ACTB.
Cytopenia - NOT Fanconi anaemia v0.136 ABCG8 Louise Daugherty Source Expert Review Amber was added to ABCG8.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.136 ABCG5 Louise Daugherty Source Expert Review Amber was added to ABCG5.
Rating Changed from Red List (low evidence) to Amber List (moderate evidence)
Cytopenia - NOT Fanconi anaemia v0.135 WAS Louise Daugherty edited their review of gene: WAS: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Wiskott-Aldrich syndrome, can present as neonatal thrombocytopenia; North West GLH: no comment submitted; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 VWF Louise Daugherty reviewed gene: VWF: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 VPS13B Louise Daugherty reviewed gene: VPS13B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 TUBB1 Louise Daugherty commented on gene: TUBB1: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there was only enough evidence to rate this gene Amber. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Macrothrombocytopenia, beta-tubulin 1 related; North West GLH: Not isolated thrombocytopenia; Yorkshire and North East GLH: no comment submitted;London South GLH: no comment submitted.
Cytopenia - NOT Fanconi anaemia v0.135 THPO Louise Daugherty edited their review of gene: THPO: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH:Thrombocytopenia progressing to trilineage bone marrow failure; North West GLH: no comment submitted; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 TCN2 Louise Daugherty reviewed gene: TCN2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 STK4 Louise Daugherty reviewed gene: STK4: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 STIM1 Louise Daugherty commented on gene: STIM1: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there was only enough evidence to rate this gene Amber. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Stormorken syndrome (York platelet syndrome); North West GLH: Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH: no commetn submitted; London South GLH: no comment submitted.
Cytopenia - NOT Fanconi anaemia v0.135 SRC Louise Daugherty reviewed gene: SRC: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 SMARCAL1 Louise Daugherty edited their review of gene: SMARCAL1: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agree to rate this gene Red on this panel. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Multisystem disorder, skeletal defects seem to be consistently present, has not been associated with a cytopenia as presenting symptom; North West GLH:Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH:no comment submitted; London South GLH: no comment submitted; Changed rating: RED
Cytopenia - NOT Fanconi anaemia v0.135 SLFN14 Louise Daugherty reviewed gene: SLFN14: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 SLC37A4 Louise Daugherty edited their review of gene: SLC37A4: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agree to rate this gene Red on this panel. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Glycogen storage disorders - other syndromic features (eg hypoglycaemia and splenomegaly) unlikely to present as neutropenia; North West GLH: Syndromic features, neutropenia, not isolated Thrombocytopenia; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: RED
Cytopenia - NOT Fanconi anaemia v0.135 RUNX1 Louise Daugherty commented on gene: RUNX1: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there was only enough evidence to rate this gene Amber. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Familial platelet disorder with predisposition to AML, typically presents with mild to moderate thrombocytopenia (normal sized platelets); North West GLH: Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.
Cytopenia - NOT Fanconi anaemia v0.135 RNU4ATAC Louise Daugherty reviewed gene: RNU4ATAC: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 RBM8A Louise Daugherty edited their review of gene: RBM8A: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agree to rate this gene Red on this panel. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Thrombocytopenia-absent radius syndrome (TAR); Thrombocytopenia is variable but skeletal abnormalities are always present so I would class red; however already agreed as Amber in July Update October: RBM8A is green on R90 (bleeding & platelet disorders panel), so its covered. Considering this, Id favour Red on R91 for consistency with other syndromic thrombocytopenia associated genes that weve considered for this panel; North West GLH: Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH: no comment submitted ;London South GLH: no comment submitted.; Changed rating: RED
Cytopenia - NOT Fanconi anaemia v0.135 PTPN11 Louise Daugherty reviewed gene: PTPN11: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 PSMB8 Louise Daugherty reviewed gene: PSMB8: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 NBEAL2 Louise Daugherty commented on gene: NBEAL2: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there was only enough evidence to rate this gene Amber. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Gray platelet syndrome; associated with low platelet count; North West GLH: Not isolated thrombocytopenia; Yorkshire and North East GLH:no comment submitted; London South GLH: no comment submitted.
Cytopenia - NOT Fanconi anaemia v0.135 MYH9 Louise Daugherty commented on gene: MYH9: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there was only enough evidence to rate this gene Amber. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: May-Hegglin and other MYH9 disorders (macrothrombocytopenia plus other syndromic features); North West GLH: Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.
Cytopenia - NOT Fanconi anaemia v0.135 MTHFD1 Louise Daugherty reviewed gene: MTHFD1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 MSN Louise Daugherty reviewed gene: MSN: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 MPL Louise Daugherty edited their review of gene: MPL: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Congenital amegakaryocytic thrombocytopenia (CAMT) presents with isolated thrombocytopenia in infancy and developing into a pancytopenia in later childhood); North West GLH: no comment submitted; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 MPIG6B Louise Daugherty edited their review of gene: MPIG6B: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agree to rate this gene Red on this panel. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Typically Thrombocytopenia, anemia and myelofibrosis (myelofibrosis is a distinct phenotype that is not targeted by this panel) - but one case of child presenting with pancytopenia; North West GLH: Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: RED
Cytopenia - NOT Fanconi anaemia v0.135 MECOM Louise Daugherty edited their review of gene: MECOM: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Clinical spectrum ranged from isolated radioulnar synostosis with no or mild hematological involvement to severe bone marrow failure without obvious skeletal abnormality. Germeshausen 2018;North West GLH: no comment submitted; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 LYST Louise Daugherty reviewed gene: LYST: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 LAMTOR2 Louise Daugherty reviewed gene: LAMTOR2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 KDSR Louise Daugherty reviewed gene: KDSR: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ITGB3 Louise Daugherty reviewed gene: ITGB3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ITGA2B Louise Daugherty reviewed gene: ITGA2B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 HTRA2 Louise Daugherty reviewed gene: HTRA2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 HOXA11 Louise Daugherty edited their review of gene: HOXA11: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agree to rate this gene Red on this panel. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Amegakaryocytic thrombocytopenia with radioulnar synostosis; so far has always been described in combination with obvious skeletal defect; North West GLH: Syndromic, not isolated thrombocytopenia; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.; Changed rating: RED
Cytopenia - NOT Fanconi anaemia v0.135 GP9 Louise Daugherty reviewed gene: GP9: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 GP1BB Louise Daugherty reviewed gene: GP1BB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 GP1BA Louise Daugherty commented on gene: GP1BA: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there was only enough evidence to rate this gene Amber. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Mild macrothrombocytopenia; North West GLH: Platelet type VWD, mild thrombocytopenia; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted.
Cytopenia - NOT Fanconi anaemia v0.135 GNE Louise Daugherty reviewed gene: GNE: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 GINS1 Louise Daugherty reviewed gene: GINS1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 GFI1 Louise Daugherty edited their review of gene: GFI1: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Platelet type bleeding disorder 17; Severe congenital neutropenia 2; North West GLH: no comment submitted; Yorkshire and North East GLH: only 2 changes on HGMD neutropenia; London South GLH: no comment submitted. ; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 GATA1 Louise Daugherty edited their review of gene: GATA1: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: X-linked thrombocytopenia with dyserythropoiesis; North West GLH: no comment submitted; Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted. ; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 FYB1 Louise Daugherty edited their review of gene: FYB1: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Thrombocytopenia 3; North West GLH: no comment submitted; Yorkshire and North East GLH: Rare (2cases); London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 FLNA Louise Daugherty reviewed gene: FLNA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 FLI1 Louise Daugherty reviewed gene: FLI1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ETV6 Louise Daugherty edited their review of gene: ETV6: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Thrombocytopenia and susceptibility to cancer; North West GLH: no comment submitted; Yorkshire and North East GLH:mainly somatic AML and some thrombocytopenia; London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 DIAPH1 Louise Daugherty reviewed gene: DIAPH1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 CYCS Louise Daugherty edited their review of gene: CYCS: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Autosomal dominant thrombocytopenia 4; North West GLH: no comment submitted; Yorkshire and North East GLH: rare (4 cases); London South GLH: no comment submitted.; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 CLPB Louise Daugherty reviewed gene: CLPB: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 CDC42 Louise Daugherty reviewed gene: CDC42: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 CD40LG Louise Daugherty reviewed gene: CD40LG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 CD40 Louise Daugherty reviewed gene: CD40: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ARPC1B Louise Daugherty reviewed gene: ARPC1B: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 AP3B1 Louise Daugherty reviewed gene: AP3B1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ANKRD26 Louise Daugherty edited their review of gene: ANKRD26: Added comment: Gene reviewed due to Haematology Specialist Test Group considering the inclusion of relevant neutropenia thrombocytopenia genes. The Specialist Test Group 21st October 2019 (consisting of 4 centres: WWMGLH, NWGLH, YNEGLH, LSGLH) all agreed that there is enough evidence to rate this gene Green. Additional comments from Haematology Specialist Test Group (Copy of Extra genes R91_consensus_v2.xlsx) 21st October 2019. Wessex and West Midlands GLH: Autosomal dominant thrombocytopenia 2; North West GLH: TTP and Upshaw-Schulman syndrome (recessive TTP); Yorkshire and North East GLH: no comment submitted; London South GLH: no comment submitted. ; Changed rating: GREEN
Cytopenia - NOT Fanconi anaemia v0.135 ADAMTS13 Louise Daugherty reviewed gene: ADAMTS13: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ACTN1 Louise Daugherty reviewed gene: ACTN1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ACTB Louise Daugherty reviewed gene: ACTB: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ABCG8 Louise Daugherty reviewed gene: ABCG8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.135 ABCG5 Louise Daugherty reviewed gene: ABCG5: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Cytopenia - NOT Fanconi anaemia v0.134 WAS Louise Daugherty Source Expert review Green was added to WAS.
Cytopenia - NOT Fanconi anaemia v0.134 VWF Louise Daugherty Source Expert review Red was added to VWF.
Cytopenia - NOT Fanconi anaemia v0.134 VPS13B Louise Daugherty Source Expert review Red was added to VPS13B.
Cytopenia - NOT Fanconi anaemia v0.134 TUBB1 Louise Daugherty Source Expert review Amber was added to TUBB1.
Cytopenia - NOT Fanconi anaemia v0.134 THPO Louise Daugherty Source Expert review Green was added to THPO.
Cytopenia - NOT Fanconi anaemia v0.134 TCN2 Louise Daugherty Source Expert review Amber was added to TCN2.
Cytopenia - NOT Fanconi anaemia v0.134 STK4 Louise Daugherty Source Expert review Red was added to STK4.
Cytopenia - NOT Fanconi anaemia v0.134 STIM1 Louise Daugherty Source Expert review Amber was added to STIM1.
Cytopenia - NOT Fanconi anaemia v0.134 SRC Louise Daugherty Source Expert review Green was added to SRC.
Cytopenia - NOT Fanconi anaemia v0.134 SMARCAL1 Louise Daugherty Source Expert review Red was added to SMARCAL1.
Cytopenia - NOT Fanconi anaemia v0.134 SLFN14 Louise Daugherty Source Expert review Amber was added to SLFN14.
Cytopenia - NOT Fanconi anaemia v0.134 SLC37A4 Louise Daugherty Source Expert review Red was added to SLC37A4.
Cytopenia - NOT Fanconi anaemia v0.134 RUNX1 Louise Daugherty Source Expert review Amber was added to RUNX1.
Cytopenia - NOT Fanconi anaemia v0.134 RNU4ATAC Louise Daugherty Source Expert review Red was added to RNU4ATAC.
Cytopenia - NOT Fanconi anaemia v0.134 RBM8A Louise Daugherty Source Expert review Red was added to RBM8A.
Cytopenia - NOT Fanconi anaemia v0.134 PTPN11 Louise Daugherty Source Expert review Red was added to PTPN11.
Cytopenia - NOT Fanconi anaemia v0.134 PSMB8 Louise Daugherty Source Expert review Red was added to PSMB8.
Cytopenia - NOT Fanconi anaemia v0.134 NBEAL2 Louise Daugherty Source Expert review Amber was added to NBEAL2.
Cytopenia - NOT Fanconi anaemia v0.134 MYH9 Louise Daugherty Source Expert review Amber was added to MYH9.
Cytopenia - NOT Fanconi anaemia v0.134 MTHFD1 Louise Daugherty Source Expert review Red was added to MTHFD1.
Cytopenia - NOT Fanconi anaemia v0.134 MSN Louise Daugherty Source Expert review Red was added to MSN.
Cytopenia - NOT Fanconi anaemia v0.134 MPL Louise Daugherty Source Expert review Green was added to MPL.
Cytopenia - NOT Fanconi anaemia v0.134 MPIG6B Louise Daugherty Source Expert review Red was added to MPIG6B.
Cytopenia - NOT Fanconi anaemia v0.134 MECOM Louise Daugherty Source Expert review Green was added to MECOM.
Cytopenia - NOT Fanconi anaemia v0.134 LYST Louise Daugherty Source Expert review Red was added to LYST.
Cytopenia - NOT Fanconi anaemia v0.134 LAMTOR2 Louise Daugherty Source Expert review Red was added to LAMTOR2.
Cytopenia - NOT Fanconi anaemia v0.134 KDSR Louise Daugherty Source Expert review Red was added to KDSR.
Cytopenia - NOT Fanconi anaemia v0.134 ITGB3 Louise Daugherty Source Expert review Red was added to ITGB3.
Cytopenia - NOT Fanconi anaemia v0.134 ITGA2B Louise Daugherty Source Expert review Red was added to ITGA2B.
Cytopenia - NOT Fanconi anaemia v0.134 HTRA2 Louise Daugherty Source Expert review Red was added to HTRA2.
Cytopenia - NOT Fanconi anaemia v0.134 HOXA11 Louise Daugherty Source Expert review Red was added to HOXA11.
Cytopenia - NOT Fanconi anaemia v0.134 GP9 Louise Daugherty Source Expert review Amber was added to GP9.
Cytopenia - NOT Fanconi anaemia v0.134 GP1BB Louise Daugherty Source Expert review Amber was added to GP1BB.
Cytopenia - NOT Fanconi anaemia v0.134 GP1BA Louise Daugherty Source Expert review Amber was added to GP1BA.
Cytopenia - NOT Fanconi anaemia v0.134 GNE Louise Daugherty Source Expert review Red was added to GNE.
Cytopenia - NOT Fanconi anaemia v0.134 GINS1 Louise Daugherty Source Expert review Red was added to GINS1.
Cytopenia - NOT Fanconi anaemia v0.134 GFI1 Louise Daugherty Source Expert review Green was added to GFI1.
Cytopenia - NOT Fanconi anaemia v0.134 GATA1 Louise Daugherty Source Expert review Green was added to GATA1.
Cytopenia - NOT Fanconi anaemia v0.134 FYB1 Louise Daugherty Source Expert review Green was added to FYB1.
Cytopenia - NOT Fanconi anaemia v0.134 FLNA Louise Daugherty Source Expert review Red was added to FLNA.
Cytopenia - NOT Fanconi anaemia v0.134 FLI1 Louise Daugherty Source Expert review Amber was added to FLI1.
Cytopenia - NOT Fanconi anaemia v0.134 ETV6 Louise Daugherty Source Expert review Green was added to ETV6.
Cytopenia - NOT Fanconi anaemia v0.134 DIAPH1 Louise Daugherty Source Expert review Red was added to DIAPH1.
Cytopenia - NOT Fanconi anaemia v0.134 CYCS Louise Daugherty Source Expert review Green was added to CYCS.
Cytopenia - NOT Fanconi anaemia v0.134 CLPB Louise Daugherty Source Expert review Red was added to CLPB.
Cytopenia - NOT Fanconi anaemia v0.134 CDC42 Louise Daugherty Source Expert review Red was added to CDC42.
Cytopenia - NOT Fanconi anaemia v0.134 CD40LG Louise Daugherty Source Expert review Red was added to CD40LG.
Cytopenia - NOT Fanconi anaemia v0.134 CD40 Louise Daugherty Source Expert review Red was added to CD40.
Cytopenia - NOT Fanconi anaemia v0.134 ARPC1B Louise Daugherty Source Expert review Red was added to ARPC1B.
Cytopenia - NOT Fanconi anaemia v0.134 AP3B1 Louise Daugherty Source Expert review Amber was added to AP3B1.
Cytopenia - NOT Fanconi anaemia v0.134 ANKRD26 Louise Daugherty Source Expert review Green was added to ANKRD26.
Cytopenia - NOT Fanconi anaemia v0.134 ADAMTS13 Louise Daugherty Source Expert review Amber was added to ADAMTS13.
Cytopenia - NOT Fanconi anaemia v0.134 ACTN1 Louise Daugherty Source Expert review Amber was added to ACTN1.
Cytopenia - NOT Fanconi anaemia v0.134 ACTB Louise Daugherty Source Expert review Red was added to ACTB.
Cytopenia - NOT Fanconi anaemia v0.134 ABCG8 Louise Daugherty Source Expert review Amber was added to ABCG8.
Cytopenia - NOT Fanconi anaemia v0.134 ABCG5 Louise Daugherty Source Expert review Amber was added to ABCG5.
Cytopenia - NOT Fanconi anaemia v0.133 VWF Louise Daugherty Mode of inheritance for gene VWF was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes von Willebrand disease, types 2A, 2B, 2M, and 2N, 613554; von Willibrand disease, type 3, 277480; von Willebrand disease, type 1, 193400 for gene: VWF
Cytopenia - NOT Fanconi anaemia v0.133 VPS13B Louise Daugherty Mode of inheritance for gene VPS13B was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Cohen syndrome, 216550 for gene: VPS13B
Cytopenia - NOT Fanconi anaemia v0.133 TCN2 Louise Daugherty Mode of inheritance for gene TCN2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Transcobalamin II deficiency, 275350 for gene: TCN2
Cytopenia - NOT Fanconi anaemia v0.133 STK4 Louise Daugherty Mode of inheritance for gene STK4 was changed from to Unknown
Added phenotypes T-cell immunodeficiency, recurrent infections, autoimmunity, and cardiac malformations, 614868 for gene: STK4
Cytopenia - NOT Fanconi anaemia v0.133 SRC Louise Daugherty Mode of inheritance for gene SRC was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes ?Thrombocytopenia 6, 616937 for gene: SRC
Cytopenia - NOT Fanconi anaemia v0.133 SLFN14 Louise Daugherty Mode of inheritance for gene SLFN14 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Bleeding disorder, platelet-type, 20, 616913 for gene: SLFN14
Cytopenia - NOT Fanconi anaemia v0.133 RNU4ATAC Louise Daugherty Mode of inheritance for gene RNU4ATAC was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Roifman syndrome, 616651; Microcephalic osteodysplastic primordial dwarfism, type I, 210710 for gene: RNU4ATAC
Cytopenia - NOT Fanconi anaemia v0.133 PTPN11 Louise Daugherty Mode of inheritance for gene PTPN11 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Noonan syndrome 1, 163950 for gene: PTPN11
Cytopenia - NOT Fanconi anaemia v0.133 PSMB8 Louise Daugherty Mode of inheritance for gene PSMB8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Proteasome-associated autoinflammatory syndrome 1 and digenic forms, 256040 for gene: PSMB8
Cytopenia - NOT Fanconi anaemia v0.133 MTHFD1 Louise Daugherty Mode of inheritance for gene MTHFD1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, 617780 for gene: MTHFD1
Cytopenia - NOT Fanconi anaemia v0.133 MSN Louise Daugherty Mode of inheritance for gene MSN was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Added phenotypes Immunodeficiency 50, 300988 for gene: MSN
Cytopenia - NOT Fanconi anaemia v0.133 LYST Louise Daugherty Mode of inheritance for gene LYST was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Chediak-Higashi syndrome, 214500 for gene: LYST
Cytopenia - NOT Fanconi anaemia v0.133 LAMTOR2 Louise Daugherty Mode of inheritance for gene LAMTOR2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Immunodeficiency due to defect in MAPBP-interacting protein, 610798 for gene: LAMTOR2
Cytopenia - NOT Fanconi anaemia v0.133 KDSR Louise Daugherty Mode of inheritance for gene KDSR was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Erythrokeratodermia variabilis et progressiva 4, 617526 for gene: KDSR
Cytopenia - NOT Fanconi anaemia v0.133 ITGB3 Louise Daugherty Mode of inheritance for gene ITGB3 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Glanzmann thrombasthenia, 273800 for gene: ITGB3
Cytopenia - NOT Fanconi anaemia v0.133 ITGA2B Louise Daugherty Mode of inheritance for gene ITGA2B was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Glanzmann thrombasthenia, 273800 for gene: ITGA2B
Cytopenia - NOT Fanconi anaemia v0.133 HTRA2 Louise Daugherty Mode of inheritance for gene HTRA2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes 3-methylglutaconic aciduria, type VIII, 617248 for gene: HTRA2
Cytopenia - NOT Fanconi anaemia v0.133 GP9 Louise Daugherty Mode of inheritance for gene GP9 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Bernard-Soulier syndrome (includes macrothrombocytopenia); Bernard-Soulier syndrome, type C, 231200 for gene: GP9
Cytopenia - NOT Fanconi anaemia v0.133 GP1BB Louise Daugherty Mode of inheritance for gene GP1BB was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Bernard-Soulier syndrome, type B, 231200; Mild macrothrombocytopenia for gene: GP1BB
Cytopenia - NOT Fanconi anaemia v0.133 GNE Louise Daugherty Mode of inheritance for gene GNE was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Nonaka myopathy, 605820 for gene: GNE
Cytopenia - NOT Fanconi anaemia v0.133 GINS1 Louise Daugherty Mode of inheritance for gene GINS1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Immunodeficiency 55, 617827 for gene: GINS1
Cytopenia - NOT Fanconi anaemia v0.133 FLNA Louise Daugherty Mode of inheritance for gene FLNA was changed from to Unknown
Cytopenia - NOT Fanconi anaemia v0.133 FLI1 Louise Daugherty Mode of inheritance for gene FLI1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Bleeding disorder, platelet-type, 21, 617443 for gene: FLI1
Cytopenia - NOT Fanconi anaemia v0.133 DIAPH1 Louise Daugherty Mode of inheritance for gene DIAPH1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Macrothrombocytopenia and hearing loss; Deafness, autosomal dominant 1, 124900 for gene: DIAPH1
Cytopenia - NOT Fanconi anaemia v0.133 CLPB Louise Daugherty Mode of inheritance for gene CLPB was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271 for gene: CLPB
Cytopenia - NOT Fanconi anaemia v0.133 CDC42 Louise Daugherty Mode of inheritance for gene CDC42 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Takenouchi-Kosaki syndrome, 616737 for gene: CDC42
Cytopenia - NOT Fanconi anaemia v0.133 CD40LG Louise Daugherty Mode of inheritance for gene CD40LG was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Added phenotypes Immunodeficiency, X-linked, with hyper-IgM, 308230 for gene: CD40LG
Cytopenia - NOT Fanconi anaemia v0.133 CD40 Louise Daugherty Mode of inheritance for gene CD40 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Immunodeficiency with hyper-IgM, type 3, 606843 for gene: CD40
Cytopenia - NOT Fanconi anaemia v0.133 ARPC1B Louise Daugherty Mode of inheritance for gene ARPC1B was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718 for gene: ARPC1B
Cytopenia - NOT Fanconi anaemia v0.133 AP3B1 Louise Daugherty Mode of inheritance for gene AP3B1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Hermansky-Pudlak syndrome 2, 608233 for gene: AP3B1
Cytopenia - NOT Fanconi anaemia v0.133 ADAMTS13 Louise Daugherty Mode of inheritance for gene ADAMTS13 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Thrombotic thrombocytopenic purpura, familial, 274150 for gene: ADAMTS13
Cytopenia - NOT Fanconi anaemia v0.133 ACTN1 Louise Daugherty Mode of inheritance for gene ACTN1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Bleeding disorder, platelet-type, 15, 615193; Macrothrombocytopenia for gene: ACTN1
Cytopenia - NOT Fanconi anaemia v0.133 ACTB Louise Daugherty Mode of inheritance for gene ACTB was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Baraitser-Winter syndrome 1 with macrothrombocytopenia; Baraitser-Winter syndrome 1, 243310 for gene: ACTB
Cytopenia - NOT Fanconi anaemia v0.133 ABCG8 Louise Daugherty Mode of inheritance for gene ABCG8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Sitosterolemia with macrothrombocytopenia; Sitosterolemia, 210250 for gene: ABCG8
Cytopenia - NOT Fanconi anaemia v0.133 ABCG5 Louise Daugherty Mode of inheritance for gene ABCG5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Sitosterolemia with macrothrombocytopenia; Sitosterolemia, 210250 for gene: ABCG5
Cytopenia - NOT Fanconi anaemia v0.132 VWF Louise Daugherty gene: VWF was added
gene: VWF was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: VWF was set to
Cytopenia - NOT Fanconi anaemia v0.132 VPS13B Louise Daugherty gene: VPS13B was added
gene: VPS13B was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: VPS13B was set to
Cytopenia - NOT Fanconi anaemia v0.132 TUBB1 Louise Daugherty Source Wessex and West Midlands GLH was added to TUBB1.
Source Yorkshire and North East GLH was added to TUBB1.
Source North West GLH was added to TUBB1.
Cytopenia - NOT Fanconi anaemia v0.132 THPO Louise Daugherty Source Wessex and West Midlands GLH was added to THPO.
Cytopenia - NOT Fanconi anaemia v0.132 TCN2 Louise Daugherty gene: TCN2 was added
gene: TCN2 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: TCN2 was set to
Cytopenia - NOT Fanconi anaemia v0.132 STK4 Louise Daugherty gene: STK4 was added
gene: STK4 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: STK4 was set to
Cytopenia - NOT Fanconi anaemia v0.132 STIM1 Louise Daugherty Source Wessex and West Midlands GLH was added to STIM1.
Source Yorkshire and North East GLH was added to STIM1.
Source North West GLH was added to STIM1.
Cytopenia - NOT Fanconi anaemia v0.132 SRC Louise Daugherty gene: SRC was added
gene: SRC was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: SRC was set to
Cytopenia - NOT Fanconi anaemia v0.132 SMARCAL1 Louise Daugherty Source Wessex and West Midlands GLH was added to SMARCAL1.
Source Yorkshire and North East GLH was added to SMARCAL1.
Source North West GLH was added to SMARCAL1.
Cytopenia - NOT Fanconi anaemia v0.132 SLFN14 Louise Daugherty gene: SLFN14 was added
gene: SLFN14 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: SLFN14 was set to
Cytopenia - NOT Fanconi anaemia v0.132 SLC37A4 Louise Daugherty Source Wessex and West Midlands GLH was added to SLC37A4.
Source Yorkshire and North East GLH was added to SLC37A4.
Source North West GLH was added to SLC37A4.
Cytopenia - NOT Fanconi anaemia v0.132 RUNX1 Louise Daugherty Source Wessex and West Midlands GLH was added to RUNX1.
Source Yorkshire and North East GLH was added to RUNX1.
Source North West GLH was added to RUNX1.
Cytopenia - NOT Fanconi anaemia v0.132 RNU4ATAC Louise Daugherty gene: RNU4ATAC was added
gene: RNU4ATAC was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: RNU4ATAC was set to
Cytopenia - NOT Fanconi anaemia v0.132 RBM8A Louise Daugherty Source Wessex and West Midlands GLH was added to RBM8A.
Cytopenia - NOT Fanconi anaemia v0.132 PTPN11 Louise Daugherty gene: PTPN11 was added
gene: PTPN11 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: PTPN11 was set to
Cytopenia - NOT Fanconi anaemia v0.132 PSMB8 Louise Daugherty gene: PSMB8 was added
gene: PSMB8 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: PSMB8 was set to
Cytopenia - NOT Fanconi anaemia v0.132 NBEAL2 Louise Daugherty Source Wessex and West Midlands GLH was added to NBEAL2.
Source Yorkshire and North East GLH was added to NBEAL2.
Source North West GLH was added to NBEAL2.
Cytopenia - NOT Fanconi anaemia v0.132 MYH9 Louise Daugherty Source Wessex and West Midlands GLH was added to MYH9.
Source Yorkshire and North East GLH was added to MYH9.
Source North West GLH was added to MYH9.
Cytopenia - NOT Fanconi anaemia v0.132 MTHFD1 Louise Daugherty gene: MTHFD1 was added
gene: MTHFD1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: MTHFD1 was set to
Cytopenia - NOT Fanconi anaemia v0.132 MSN Louise Daugherty gene: MSN was added
gene: MSN was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: MSN was set to
Cytopenia - NOT Fanconi anaemia v0.132 MPL Louise Daugherty Source Wessex and West Midlands GLH was added to MPL.
Cytopenia - NOT Fanconi anaemia v0.132 MPIG6B Louise Daugherty Source Yorkshire and North East GLH was added to MPIG6B.
Cytopenia - NOT Fanconi anaemia v0.132 MECOM Louise Daugherty Source Wessex and West Midlands GLH was added to MECOM.
Cytopenia - NOT Fanconi anaemia v0.132 LYST Louise Daugherty gene: LYST was added
gene: LYST was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: LYST was set to
Cytopenia - NOT Fanconi anaemia v0.132 LAMTOR2 Louise Daugherty gene: LAMTOR2 was added
gene: LAMTOR2 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: LAMTOR2 was set to
Cytopenia - NOT Fanconi anaemia v0.132 KDSR Louise Daugherty gene: KDSR was added
gene: KDSR was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: KDSR was set to
Cytopenia - NOT Fanconi anaemia v0.132 ITGB3 Louise Daugherty gene: ITGB3 was added
gene: ITGB3 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ITGB3 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ITGA2B Louise Daugherty gene: ITGA2B was added
gene: ITGA2B was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ITGA2B was set to
Cytopenia - NOT Fanconi anaemia v0.132 HTRA2 Louise Daugherty gene: HTRA2 was added
gene: HTRA2 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: HTRA2 was set to
Cytopenia - NOT Fanconi anaemia v0.132 HOXA11 Louise Daugherty Source Wessex and West Midlands GLH was added to HOXA11.
Source North West GLH was added to HOXA11.
Cytopenia - NOT Fanconi anaemia v0.132 GP9 Louise Daugherty gene: GP9 was added
gene: GP9 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: GP9 was set to
Cytopenia - NOT Fanconi anaemia v0.132 GP1BB Louise Daugherty gene: GP1BB was added
gene: GP1BB was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: GP1BB was set to
Cytopenia - NOT Fanconi anaemia v0.132 GP1BA Louise Daugherty Source Wessex and West Midlands GLH was added to GP1BA.
Source Yorkshire and North East GLH was added to GP1BA.
Source North West GLH was added to GP1BA.
Cytopenia - NOT Fanconi anaemia v0.132 GNE Louise Daugherty gene: GNE was added
gene: GNE was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: GNE was set to
Cytopenia - NOT Fanconi anaemia v0.132 GINS1 Louise Daugherty gene: GINS1 was added
gene: GINS1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: GINS1 was set to
Cytopenia - NOT Fanconi anaemia v0.132 FYB1 Louise Daugherty Source Wessex and West Midlands GLH was added to FYB1.
Cytopenia - NOT Fanconi anaemia v0.132 FLNA Louise Daugherty gene: FLNA was added
gene: FLNA was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: FLNA was set to
Cytopenia - NOT Fanconi anaemia v0.132 FLI1 Louise Daugherty gene: FLI1 was added
gene: FLI1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: FLI1 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ETV6 Louise Daugherty Source Wessex and West Midlands GLH was added to ETV6.
Source North West GLH was added to ETV6.
Cytopenia - NOT Fanconi anaemia v0.132 DIAPH1 Louise Daugherty gene: DIAPH1 was added
gene: DIAPH1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: DIAPH1 was set to
Cytopenia - NOT Fanconi anaemia v0.132 CYCS Louise Daugherty Source Wessex and West Midlands GLH was added to CYCS.
Source North West GLH was added to CYCS.
Cytopenia - NOT Fanconi anaemia v0.132 CLPB Louise Daugherty gene: CLPB was added
gene: CLPB was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: CLPB was set to
Cytopenia - NOT Fanconi anaemia v0.132 CDC42 Louise Daugherty gene: CDC42 was added
gene: CDC42 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: CDC42 was set to
Cytopenia - NOT Fanconi anaemia v0.132 CD40LG Louise Daugherty gene: CD40LG was added
gene: CD40LG was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: CD40LG was set to
Cytopenia - NOT Fanconi anaemia v0.132 CD40 Louise Daugherty gene: CD40 was added
gene: CD40 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: CD40 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ARPC1B Louise Daugherty gene: ARPC1B was added
gene: ARPC1B was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ARPC1B was set to
Cytopenia - NOT Fanconi anaemia v0.132 AP3B1 Louise Daugherty gene: AP3B1 was added
gene: AP3B1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: AP3B1 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ANKRD26 Louise Daugherty Source Wessex and West Midlands GLH was added to ANKRD26.
Source North West GLH was added to ANKRD26.
Cytopenia - NOT Fanconi anaemia v0.132 ADAMTS13 Louise Daugherty gene: ADAMTS13 was added
gene: ADAMTS13 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ADAMTS13 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ACTN1 Louise Daugherty gene: ACTN1 was added
gene: ACTN1 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ACTN1 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ACTB Louise Daugherty gene: ACTB was added
gene: ACTB was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ACTB was set to
Cytopenia - NOT Fanconi anaemia v0.132 ABCG8 Louise Daugherty gene: ABCG8 was added
gene: ABCG8 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ABCG8 was set to
Cytopenia - NOT Fanconi anaemia v0.132 ABCG5 Louise Daugherty gene: ABCG5 was added
gene: ABCG5 was added to Cytopenia - NOT Fanconi anaemia. Sources: Wessex and West Midlands GLH,Yorkshire and North East GLH,London South GLH,North West GLH,NHS GMS
Mode of inheritance for gene: ABCG5 was set to
Cytopenia - NOT Fanconi anaemia v0.131 TUBB1 Louise Daugherty Phenotypes for gene: TUBB1 were changed from 613112 Macrothrombocytopenia to Macrothrombocytopenia, 613112
Cytopenia - NOT Fanconi anaemia v0.130 STIM1 Louise Daugherty Phenotypes for gene: STIM1 were changed from 185070 Stormorken syndrome to Stormorken syndrome, 185070
Cytopenia - NOT Fanconi anaemia v0.129 SMARCAL1 Louise Daugherty Phenotypes for gene: SMARCAL1 were changed from 242900 Schimke immunoosseous dysplasia to Schimke immunoosseous dysplasia, 242900
Cytopenia - NOT Fanconi anaemia v0.128 SLC37A4 Louise Daugherty Phenotypes for gene: SLC37A4 were changed from 232220 Glycogen storage disease Ib to Glycogen storage disease Ib, 232220
Cytopenia - NOT Fanconi anaemia v0.127 RUNX1 Louise Daugherty Phenotypes for gene: RUNX1 were changed from 601399 Platelet disorder, familial, with associated myeloid malignancy to Platelet disorder, familial, with associated myeloid malignancy, 601399
Cytopenia - NOT Fanconi anaemia v0.126 NBEAL2 Louise Daugherty Phenotypes for gene: NBEAL2 were changed from 139090 Gray platelet syndrome to Gray platelet syndrome, 139090
Cytopenia - NOT Fanconi anaemia v0.125 MYH9 Louise Daugherty Phenotypes for gene: MYH9 were changed from 155100 Macrothrombocytopenia to Macrothrombocytopenia, 155100
Cytopenia - NOT Fanconi anaemia v0.124 HOXA11 Louise Daugherty Phenotypes for gene: HOXA11 were changed from 605432 Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 to Radioulnar synostosis with amegakaryocytic thrombocytopenia 1, 605432
Cytopenia - NOT Fanconi anaemia v0.123 GP1BA Louise Daugherty Phenotypes for gene: GP1BA were changed from 231200 Bernard-Soulier syndrome, type A1 to Bernard-Soulier syndrome, type A1, 231200; Mild macrothrombocytopenia; Platelet type VWD, mild thrombocytopenia
Cytopenia - NOT Fanconi anaemia v0.122 CYCS Louise Daugherty Phenotypes for gene: CYCS were changed from 612004 Thrombocytopenia 4; Thrombocytopenia to Thrombocytopenia 4, 612004; Thrombocytopenia
Cytopenia - NOT Fanconi anaemia v0.121 ANKRD26 Louise Daugherty Phenotypes for gene: ANKRD26 were changed from 188000 Thrombocytopenia 2 to Thrombocytopenia 2, 188000
Polycystic liver disease v0.8 STN1 Ivone Leong changed review comment from: Comment when marking as ready: After discussion with Anna de Burca (Genomics England) and Bill Griffiths (Cambridge University Hospitals), it was decided that RTEL1 will remain as an amber gene.; to: Comment when marking as ready: After discussion with Anna de Burca (Genomics England) and Bill Griffiths (Cambridge University Hospitals), it was decided that STN1 will remain as an amber gene.
Polycystic liver disease v0.8 TERC Ivone Leong changed review comment from: Comment when marking as ready: After discussion with Anna de Burca (Genomics England) and Bill Griffiths (Cambridge University Hospitals), it was decided that RTEL1 will remain as an amber gene.; to: Comment when marking as ready: After discussion with Anna de Burca (Genomics England) and Bill Griffiths (Cambridge University Hospitals), it was decided that TERC will remain as an amber gene.
Polycystic liver disease v0.8 TERT Ivone Leong changed review comment from: Comment when marking as ready: After discussion with Anna de Burca (Genomics England) and Bill Griffiths (Cambridge University Hospitals), it was decided that RTEL1 will remain as an amber gene.; to: Comment when marking as ready: After discussion with Anna de Burca (Genomics England) and Bill Griffiths (Cambridge University Hospitals), it was decided that TERT will remain as an amber gene.
Likely inborn error of metabolism v1.390 SETX Catherine Snow reviewed gene: SETX: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyotrophic lateral sclerosis 4, juvenile, 602433, Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, 606002; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.410 SKIV2L Catherine Snow Classified gene: SKIV2L as Green List (high evidence)
Undiagnosed metabolic disorders v1.410 SKIV2L Catherine Snow Gene: skiv2l has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.409 SKIV2L Catherine Snow reviewed gene: SKIV2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 22444670, 30397475; Phenotypes: Trichohepatoenteric syndrome 2, 614602; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.390 SKIV2L Catherine Snow Classified gene: SKIV2L as Green List (high evidence)
Likely inborn error of metabolism v1.390 SKIV2L Catherine Snow Gene: skiv2l has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.389 SKIV2L Catherine Snow reviewed gene: SKIV2L: Rating: GREEN; Mode of pathogenicity: None; Publications: 22444670, 30397475; Phenotypes: Trichohepatoenteric syndrome 2, 614602; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.409 SLC12A3 Catherine Snow Classified gene: SLC12A3 as Green List (high evidence)
Undiagnosed metabolic disorders v1.409 SLC12A3 Catherine Snow Gene: slc12a3 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.408 SLC12A3 Catherine Snow reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22009145; Phenotypes: Gitelman syndrome, 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.389 SLC12A3 Catherine Snow Classified gene: SLC12A3 as Green List (high evidence)
Likely inborn error of metabolism v1.389 SLC12A3 Catherine Snow Gene: slc12a3 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.388 SLC12A3 Catherine Snow Classified gene: SLC12A3 as Green List (high evidence)
Likely inborn error of metabolism v1.388 SLC12A3 Catherine Snow Gene: slc12a3 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.387 SLC12A3 Catherine Snow reviewed gene: SLC12A3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22009145; Phenotypes: Gitelman syndrome, 263800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.408 SLC18A2 Catherine Snow Classified gene: SLC18A2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.408 SLC18A2 Catherine Snow Gene: slc18a2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.407 SLC18A2 Catherine Snow reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31240161, 23363473, 26497564, 28716265; Phenotypes: ?Parkinsonism-dystonia, infantile, 2, 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.387 SLC18A2 Catherine Snow Classified gene: SLC18A2 as Green List (high evidence)
Likely inborn error of metabolism v1.387 SLC18A2 Catherine Snow Gene: slc18a2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.387 SLC18A2 Catherine Snow Classified gene: SLC18A2 as Green List (high evidence)
Likely inborn error of metabolism v1.387 SLC18A2 Catherine Snow Gene: slc18a2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.386 SLC18A2 Catherine Snow reviewed gene: SLC18A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 31240161, 23363473, 26497564, 28716265; Phenotypes: ?Parkinsonism-dystonia, infantile, 2, 618049; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.407 SLC35A2 Catherine Snow Classified gene: SLC35A2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.407 SLC35A2 Catherine Snow Gene: slc35a2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.386 SLC35A2 Catherine Snow Classified gene: SLC35A2 as Green List (high evidence)
Likely inborn error of metabolism v1.386 SLC35A2 Catherine Snow Gene: slc35a2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.386 SLC35A2 Catherine Snow Classified gene: SLC35A2 as Green List (high evidence)
Likely inborn error of metabolism v1.386 SLC35A2 Catherine Snow Gene: slc35a2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.406 SLC35A2 Catherine Snow reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30746764; Phenotypes: Congenital disorder of glycosylation, type IIm, 300896; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Likely inborn error of metabolism v1.385 SLC35A2 Catherine Snow reviewed gene: SLC35A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 30746764; Phenotypes: Congenital disorder of glycosylation, type IIm, 300896; Mode of inheritance: None
Undiagnosed metabolic disorders v1.406 SLC3A1 Catherine Snow Classified gene: SLC3A1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.406 SLC3A1 Catherine Snow Gene: slc3a1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.405 SLC3A1 Catherine Snow reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v1.385 SLC3A1 Catherine Snow Classified gene: SLC3A1 as Green List (high evidence)
Likely inborn error of metabolism v1.385 SLC3A1 Catherine Snow Gene: slc3a1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.384 SLC3A1 Catherine Snow reviewed gene: SLC3A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v1.384 SLC6A3 Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. SLC7A9 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. SLC6A3 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.405 SLC6A3 Catherine Snow Phenotypes for gene: SLC6A3 were changed from Dopamine transporter deficiency syndrome (Other disorders of neurotransmitter metabolism) ; Early onset dystonia; Intellectual disability; Parkinson Disease and Complex Parkinsonism to Parkinsonism-dystonia, infantile, 1, 613135; Dopamine transporter deficiency syndrome (Other disorders of neurotransmitter metabolism); Early onset dystonia; Intellectual disability; Parkinson Disease and Complex Parkinsonism
Undiagnosed metabolic disorders v1.404 SLC6A3 Catherine Snow Publications for gene: SLC6A3 were set to 27604308
Undiagnosed metabolic disorders v1.403 SLC6A3 Catherine Snow Classified gene: SLC6A3 as Green List (high evidence)
Undiagnosed metabolic disorders v1.403 SLC6A3 Catherine Snow Added comment: Comment on list classification: ted from Amber to Green. SLC6A3 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.403 SLC6A3 Catherine Snow Gene: slc6a3 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.384 SLC6A3 Catherine Snow Classified gene: SLC6A3 as Green List (high evidence)
Likely inborn error of metabolism v1.384 SLC6A3 Catherine Snow Gene: slc6a3 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.383 SLC6A3 Catherine Snow edited their review of gene: SLC6A3: Changed publications: 21112253; Changed phenotypes: Parkinsonism-dystonia, infantile, 1, 613135
Likely inborn error of metabolism v1.383 SLC6A3 Catherine Snow reviewed gene: SLC6A3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.383 RNASET2 Ivone Leong reviewed gene: RNASET2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v1.383 SDHC Ivone Leong changed review comment from: his gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

This gene is present as an Amber gene on the Mitochondrial disorder with complex II deficiency (v 1.0) and Possible mitochondrial disorder - nuclear genes (v 1.12). Both GMS panels have been signed off by the GMS Metabolic Consensus Specialist Test Group. Therefore, this gene will remain Amber until further evidence is available.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

This gene is present as an Amber gene on the Mitochondrial disorder with complex II deficiency (v 1.0) and Possible mitochondrial disorder - nuclear genes (v 1.12). Both GMS panels have been signed off by the GMS Metabolic Consensus Specialist Test Group. Therefore, this gene will remain Amber until further evidence is available.
Undiagnosed metabolic disorders v1.402 RBP4 Ivone Leong Classified gene: RBP4 as Green List (high evidence)
Undiagnosed metabolic disorders v1.402 RBP4 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. RBP4 is associated with retinoid metabolism on OMIM, but not on Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.402 RBP4 Ivone Leong Gene: rbp4 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.383 RBP4 Ivone Leong Classified gene: RBP4 as Green List (high evidence)
Likely inborn error of metabolism v1.383 RBP4 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. RBP4 is associated with retinoid metabolism on OMIM, but not on Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Likely inborn error of metabolism v1.383 RBP4 Ivone Leong Gene: rbp4 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.38 PHEX Eleanor Williams Added comment: Comment on mode of inheritance: Following XLD mode of inhertiance in OMIM, so changing to X-Linked: hemizyous mutation in males, monoallelic in females.
Nephrocalcinosis or nephrolithiasis v1.38 PHEX Eleanor Williams Mode of inheritance for gene: PHEX was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Nephrocalcinosis or nephrolithiasis v1.37 SLC7A9 Eleanor Williams Phenotypes for gene: SLC7A9 were changed from Cystinuria to Cystinuria 220100
Nephrocalcinosis or nephrolithiasis v1.36 SLC3A1 Eleanor Williams Phenotypes for gene: SLC3A1 were changed from Cystinuria to Cystinuria 220100
Nephrocalcinosis or nephrolithiasis v1.35 SLC22A12 Eleanor Williams changed review comment from: Comment on mode of inheritance: The evidence for biallelic inheritance is stronger so setting to this for now.; to: Comment on mode of inheritance: The evidence for biallelic inheritance is stronger so setting to this for now. AR in OMIM.
Nephrocalcinosis or nephrolithiasis v1.35 CLCN5 Eleanor Williams changed review comment from: Comment on Mode of Inheritance - PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate. However, in OMIM the mode of inheritance for Hypophosphatemic rickets, Nephrolithiasis, type I and Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis) is XLR so keeping as Xlinked (biallelic in females) just now.; to: Comment on Mode of Inheritance - PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate. However, in OMIM the mode of inheritance for Dents disease, Hypophosphatemic rickets, Nephrolithiasis, type I and Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis is XLR so keeping as Xlinked (biallelic in females) just now.
Nephrocalcinosis or nephrolithiasis v1.35 SLC2A9 Eleanor Williams Phenotypes for gene: SLC2A9 were changed from to Hypouricemia, renal, 2, 612076
Nephrocalcinosis or nephrolithiasis v1.34 SLC2A9 Eleanor Williams Publications for gene: SLC2A9 were set to
Nephrocalcinosis or nephrolithiasis v1.33 SLC2A9 Eleanor Williams Classified gene: SLC2A9 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.33 SLC2A9 Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. 3 unrelated cases with Hypouricemia, renal, with Nephrolithiasis in some family members.
Nephrocalcinosis or nephrolithiasis v1.33 SLC2A9 Eleanor Williams Gene: slc2a9 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.32 SLC2A9 Eleanor Williams Added comment: Comment on mode of inheritance: Both monoallelic and biallelic for Hypouricemia, renal. However, the reported cases with nephrolithiasis are homozygous.
Nephrocalcinosis or nephrolithiasis v1.32 SLC2A9 Eleanor Williams Mode of inheritance for gene: SLC2A9 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.31 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.

PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned. ; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

Cases with nepthrolithiasis:
PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygous insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

Cases with no report of nepthrolithiasis:
PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.

PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.31 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned. ; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.

PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.31 SLC22A12 Eleanor Williams Classified gene: SLC22A12 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.31 SLC22A12 Eleanor Williams Added comment: Comment on list classification: Promoting from red to green. Sufficient number of cases with biallelic or compound heterozygous variants in this gene and a relevant phenotype reported. A few heterozygous cases also reported but the evidence is not so strong (asymptomatic family members with the same variant, only the SLC22A12 gene looked at).
Nephrocalcinosis or nephrolithiasis v1.31 SLC22A12 Eleanor Williams Gene: slc22a12 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.30 SLC22A12 Eleanor Williams Phenotypes for gene: SLC22A12 were changed from to Hypouricemia, renal, 220150
Nephrocalcinosis or nephrolithiasis v1.29 SLC22A12 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal #220150 (AR) in OMIM with Uric acid nephrolithiasis listed as a clinical feature.

PMID: 29486147 - Claverie-Martin et al 2018 - report patients from 6 unrelated Spanish families with Renal hypouricemia and variants in SLC22A12. Nephrolithiasis was reported in one Roma patient with compound heterozygous variants in this gene.

PMID: 29958533 - Vidanapathirana et al 2018 - report a 9 year old Sri Lankan boy with renal hypouricemia who presented with nephrolithiasis and haematuria. He was found to have a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. The genotype c.[1400C > T] was found in the proband, his sister and father (both asymptomatic).

PMID: 18492088 - Ichida et al 2008 - identified SLC22A12 mutations in 66 of 71 Japanese patients with hypouricemia. A total of 13 mutations, including 3 novel mutations, were identified. Urolithiasis occurred in 5 of the patients with variants in SLC22A12. 4 were homozygous or compound heterozygous, one was heterozygous. One variant G774A/W258X was the most common variant and is thought to be a founder mutation.

PMID: 15912381 - Cheong et al 2005 - studied the SLC22A12 gene in five Korean patients with idiopathic renal hypouricemia, 1 patient with a R90H substitution had uric acid urolithiasis. The variant was heterozygous.; to: Associated with Hypouricemia, renal #220150 (AR) in OMIM with Uric acid nephrolithiasis listed as a clinical feature.

PMID: 29486147 - Claverie-Martin et al 2018 - report patients from 6 unrelated Spanish families with Renal hypouricemia and variants in SLC22A12. Nephrolithiasis was reported in one Roma patient with compound heterozygous variants in this gene (L415_G417del, T467M).

PMID: 29958533 - Vidanapathirana et al 2018 - report a 9 year old Sri Lankan boy with renal hypouricemia who presented with nephrolithiasis and haematuria. He was found to have a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. The genotype c.[1400C > T] was found in the proband, his sister and father (both asymptomatic).

PMID: 18492088 - Ichida et al 2008 - identified SLC22A12 mutations in 66 of 71 Japanese patients with hypouricemia. A total of 13 mutations, including 3 novel mutations, were identified. Urolithiasis occurred in 5 of the patients with variants in SLC22A12. 4 were homozygous or compound heterozygous, one was heterozygous. One variant G774A/W258X was the most common variant and is thought to be a founder mutation.

PMID: 15912381 - Cheong et al 2005 - studied the SLC22A12 gene in five Korean patients with idiopathic renal hypouricemia, 1 patient with a R90H substitution had uric acid urolithiasis. The variant was heterozygous.
Nephrocalcinosis or nephrolithiasis v1.29 SLC22A12 Eleanor Williams Publications for gene: SLC22A12 were set to
Nephrocalcinosis or nephrolithiasis v1.28 SLC22A12 Eleanor Williams Added comment: Comment on mode of inheritance: The evidence for biallelic inheritance is stronger so setting to this for now.
Nephrocalcinosis or nephrolithiasis v1.28 SLC22A12 Eleanor Williams Mode of inheritance for gene: SLC22A12 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.203 KIZ Ivone Leong Classified gene: KIZ as Green List (high evidence)
Retinal disorders v1.203 KIZ Ivone Leong Added comment: Comment on list classification: Promoted from red to green based on evidence provided by Mohammed Abdallah (Divsion of Human Genetics, university of Cape Town). The gene was previously classified as non-coding because of problems with Ensembl grch37 release; however, that has been fixed now and it is an actual gene.
Retinal disorders v1.203 KIZ Ivone Leong Gene: kiz has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.27 PHEX Eleanor Williams commented on gene: PHEX: Personal communication from Detlef Bockenhauer. They see nephrocalcinosis in ~50% patients. It clearly is also related to treatment, but probably an intrinsic part of the disease.
Nephrocalcinosis or nephrolithiasis v1.27 HPRT1 Eleanor Williams Classified gene: HPRT1 as Green List (high evidence)
Nephrocalcinosis or nephrolithiasis v1.27 HPRT1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to green. > 3 unrelated cases with variants in this gene and Lesch-Nyhan syndrome with nephrocalcinosis as a feature are reported. Numerous variants are reported. Two publications.
Nephrocalcinosis or nephrolithiasis v1.27 HPRT1 Eleanor Williams Gene: hprt1 has been classified as Green List (High Evidence).
Nephrocalcinosis or nephrolithiasis v1.26 HPRT1 Eleanor Williams Phenotypes for gene: HPRT1 were changed from to Lesch-Nyhan syndrome, 300322
Nephrocalcinosis or nephrolithiasis v1.25 HPRT1 Eleanor Williams Publications for gene: HPRT1 were set to
Nephrocalcinosis or nephrolithiasis v1.24 HNF4A Eleanor Williams Classified gene: HNF4A as Amber List (moderate evidence)
Nephrocalcinosis or nephrolithiasis v1.24 HNF4A Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber. Only one paper (PMID: 24285859) reporting variants in this gene associated with Fanconi syndrome and nephrocalcinosis and all patients have the same variant. Another paper reports that individuals with that variant have congenital hyperinsulinism and Fanconi syndrome but no nephrocalcinosis, however they are younger than the previously reported patients. Rating amber for now until another report confirms the association.
Nephrocalcinosis or nephrolithiasis v1.24 HNF4A Eleanor Williams Gene: hnf4a has been classified as Amber List (Moderate Evidence).
Nephrocalcinosis or nephrolithiasis v1.23 FGF23 Eleanor Williams commented on gene: FGF23: Leaving this gene red as no published evidence to date to associate variants in this gene with Nephrocalcinosis or nephrolithiasis. However, it is a likely contender so added the watchlist tag.
Nephrocalcinosis or nephrolithiasis v1.23 FGF23 Eleanor Williams Tag watchlist tag was added to gene: FGF23.
Nephrocalcinosis or nephrolithiasis v1.23 STRADA Eleanor Williams commented on gene: STRADA: Despite red rating from reviewer, there is some published evidence that nephrocalcinosis is reported in patients with Polyhydramnios, so keeping green rating for now.
Nephrocalcinosis or nephrolithiasis v1.23 CLCN5 Eleanor Williams commented on gene: CLCN5
Unexplained young onset end-stage renal disease v0.51 CLCN5 Eleanor Williams Mode of inheritance for gene: CLCN5 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
Nephrocalcinosis or nephrolithiasis v1.23 ZNF365 Detlef Bockenhauer reviewed gene: ZNF365: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 VDR Detlef Bockenhauer reviewed gene: VDR: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 TRPM6 Detlef Bockenhauer reviewed gene: TRPM6: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 STRADA Detlef Bockenhauer reviewed gene: STRADA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC9A3 Detlef Bockenhauer reviewed gene: SLC9A3: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC6A20 Detlef Bockenhauer reviewed gene: SLC6A20: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC6A19 Detlef Bockenhauer reviewed gene: SLC6A19: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC36A2 Detlef Bockenhauer reviewed gene: SLC36A2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 GNA11 Detlef Bockenhauer reviewed gene: GNA11: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 CLCNKA Detlef Bockenhauer reviewed gene: CLCNKA: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 AP2S1 Detlef Bockenhauer reviewed gene: AP2S1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 AGK Detlef Bockenhauer reviewed gene: AGK: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 ADCY10 Detlef Bockenhauer reviewed gene: ADCY10: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 HNF4A Detlef Bockenhauer reviewed gene: HNF4A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC2A9 Detlef Bockenhauer reviewed gene: SLC2A9: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 SLC22A12 Detlef Bockenhauer reviewed gene: SLC22A12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.23 PHEX Detlef Bockenhauer reviewed gene: PHEX: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 HPRT1 Detlef Bockenhauer reviewed gene: HPRT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 FGF23 Detlef Bockenhauer reviewed gene: FGF23: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Nephrocalcinosis or nephrolithiasis v1.23 FAM20A Detlef Bockenhauer reviewed gene: FAM20A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Hereditary ataxia and cerebellar anomalies, childhood onset v3.392 Louise Daugherty Changed child panels to: Inborn errors of metabolism; Congenital disorders of glycosylation; Ataxia and cerebellar anomalies - narrow panel; Neurological ciliopathies
Undiagnosed metabolic disorders v1.401 SLC6A8 Catherine Snow Classified gene: SLC6A8 as Green List (high evidence)
Undiagnosed metabolic disorders v1.401 SLC6A8 Catherine Snow Gene: slc6a8 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.400 SLC6A8 Catherine Snow reviewed gene: SLC6A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21660517; Phenotypes: Cerebral creatine deficiency syndrome 1, 300352; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Likely inborn error of metabolism v1.382 SLC6A8 Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Comment on list classification: Promoted from Amber to Green. SLC6A8 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Promoted from Amber to Green. SLC6A8 is associated with an appropriate phenotype on OMIM. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Likely inborn error of metabolism v1.382 SLC6A8 Catherine Snow Classified gene: SLC6A8 as Green List (high evidence)
Likely inborn error of metabolism v1.382 SLC6A8 Catherine Snow Gene: slc6a8 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.381 SLC6A8 Catherine Snow reviewed gene: SLC6A8: Rating: GREEN; Mode of pathogenicity: None; Publications: 21660517; Phenotypes: Cerebral creatine deficiency syndrome 1, 300352; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Structural eye disease v0.95 RARA Ivone Leong gene: RARA was added
gene: RARA was added to Structural eye disease. Sources: Expert list
Mode of inheritance for gene: RARA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RARA were set to 31343737
Phenotypes for gene: RARA were set to Coloboma
Review for gene: RARA was set to RED
Added comment: Gene added on behalf of Nicola Ragge (Birmingham Women's and Children's NHS Foundation Hospital Trust).

There is currently only 1 reported case of a de novo variant in RARA in a patient with symptoms overlapping those described in RARB patients (coloboma, muscular hypotonia, dilated pulmonary artery, ectopic kidney). Therefore, this gene has been given a Red rating until further evidence is available.
Sources: Expert list
Undiagnosed metabolic disorders v1.400 SLC7A9 Catherine Snow Classified gene: SLC7A9 as Green List (high evidence)
Undiagnosed metabolic disorders v1.400 SLC7A9 Catherine Snow Gene: slc7a9 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.399 SLC7A9 Catherine Snow reviewed gene: SLC7A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Likely inborn error of metabolism v1.381 SLC7A9 Catherine Snow Classified gene: SLC7A9 as Green List (high evidence)
Likely inborn error of metabolism v1.381 SLC7A9 Catherine Snow Gene: slc7a9 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.380 SLC7A9 Catherine Snow Publications for gene: SLC7A9 were set to 27604308; 24816252
Likely inborn error of metabolism v1.379 SLC7A9 Catherine Snow reviewed gene: SLC7A9: Rating: GREEN; Mode of pathogenicity: None; Publications: 12239244; Phenotypes: Cystinuria, 220100; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v1.136 RASGRP1 Louise Daugherty Phenotypes for gene: RASGRP1 were changed from Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency; Immunodeficiency 64, 618534 to Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Diseases of Immune Dysregulation; EBV-induced lymphoma; Immunodeficiency; Immunodeficiency 64, 618534; Immunodeficiency; immunde dysregulation; EBV-induced lymphoma
Primary immunodeficiency or monogenic inflammatory bowel disease v1.135 POMP Louise Daugherty Phenotypes for gene: POMP were changed from CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Proteasome-associated autoinflammatory syndrome 2, 618048 to CANDLE syndrome (Autoinflammation, lipodystrophy, and dermatosis syndrome); Proteasome-associated autoinflammatory syndrome 2, 618048; combined immunodeficiency with autoinflammation
Primary immunodeficiency or monogenic inflammatory bowel disease v1.134 POMP Louise Daugherty Publications for gene: POMP were set to 26524591
Primary immunodeficiency or monogenic inflammatory bowel disease v1.133 POMP Louise Daugherty Mode of inheritance for gene: POMP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary spastic paraplegia v1.207 PCYT2 Louise Daugherty Classified gene: PCYT2 as Green List (high evidence)
Hereditary spastic paraplegia v1.207 PCYT2 Louise Daugherty Added comment: Comment on list classification: New gene for HSP. There are more than 3 unrelated cases to support the HSP phenotype caused by homozygous mutation in the gene encoding phosphoethanolamine cytidylyltransferase
Hereditary spastic paraplegia v1.207 PCYT2 Louise Daugherty Gene: pcyt2 has been classified as Green List (High Evidence).
Hereditary spastic paraplegia v1.206 PCYT2 Louise Daugherty gene: PCYT2 was added
gene: PCYT2 was added to Hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Complex hereditary spastic paraplegia
Review for gene: PCYT2 was set to GREEN
Added comment: New publication (2019) : Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia: Vaz, Frédéric M et.al., PMID: 31637422. Identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy.

CTP:phosphoethanolamine cytidylyltransferase (ET) is encoded by the PCYT2 gene. Using patient fibroblasts they demonstrated that the variants were hypomorphic, resulting in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR- Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency.

The data establishes that PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirmed that etherlipid homeostasis is important for the development and function of the brain.
Sources: Literature
Structural eye disease v0.94 NAA10 Ivone Leong Classified gene: NAA10 as Green List (high evidence)
Structural eye disease v0.94 NAA10 Ivone Leong Added comment: Comment on list classification: Promoted to Green based on expert review.
Structural eye disease v0.94 NAA10 Ivone Leong Gene: naa10 has been classified as Green List (High Evidence).
Retinal disorders v1.202 KIZ Ivone Leong Phenotypes for gene: KIZ were changed from Retinitis pigmentosa 69 to Retinitis pigmentosa 69, 615780; HP:0000556; HP:0000510
Retinal disorders v1.201 KIZ Ivone Leong Mode of inheritance for gene: KIZ was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.200 KIZ Ivone Leong Publications for gene: KIZ were set to
Dystonia, chorea or related movement disorder, adult onset v0.128 GLB1 Louise Daugherty Classified gene: GLB1 as Amber List (moderate evidence)
Dystonia, chorea or related movement disorder, adult onset v0.128 GLB1 Louise Daugherty Added comment: Comment on list classification: Rated Amber until further review/agreement with the Neurology Test Group. To be reviewed before panel sign off
Dystonia, chorea or related movement disorder, adult onset v0.128 GLB1 Louise Daugherty Gene: glb1 has been classified as Amber List (Moderate Evidence).
Dystonia, chorea or related movement disorder, adult onset v0.127 GLB1 Louise Daugherty Added comment: Comment on publications: added publications to support gene-phenotype
Dystonia, chorea or related movement disorder, adult onset v0.127 GLB1 Louise Daugherty Publications for gene: GLB1 were set to
Dystonia, chorea or related movement disorder, adult onset v0.126 GLB1 Louise Daugherty gene: GLB1 was added
gene: GLB1 was added to Adult onset movement disorder. Sources: Expert Review
Mode of inheritance for gene: GLB1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GLB1 were set to GM1-gangliosidosis, type III, 230650
Review for gene: GLB1 was set to GREEN
Added comment: New Green gene suggested by Dr Julia Rankin, Consultant in Clinical Genetics (Royal Devon and Exeter NHS Foundation Trust). Adults with GM1 gangliosidosis can present with dystonia and parkinsonism.
Sources: Expert Review
Early onset or syndromic epilepsy v1.398 CLN6 Rebecca Foulger commented on gene: CLN6: PMID:30561534. Berkovic et al., 2019 report phenotypes of patients with CLN6 pathogenic variants from 13 unrelated families (homozygous in 4 families and compound het in 9 families). The typical presentation was progressive myoclonus epilepsy with debilitating myoclonic seizures and relatively infrequent tonic-clonic seizures.
Early onset or syndromic epilepsy v1.398 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341; 31029456; 31216804
Intellectual disability v2.1093 SIX3 Rebecca Foulger Phenotypes for gene: SIX3 were changed from Holoprosencephaly-2, 157170Schizensephaly, 269160; HOLOPROSENCEPHALY to Holoprosencephaly-2, 157170; Schizensephaly, 269160; HOLOPROSENCEPHALY
Early onset or syndromic epilepsy v1.397 SETD5 Rebecca Foulger Phenotypes for gene: SETD5 were changed from Mental retardation, autosomal dominant 23 to Mental retardation, autosomal dominant 23, 615761
Early onset or syndromic epilepsy v1.396 SETD5 Rebecca Foulger Publications for gene: SETD5 were set to
Early onset or syndromic epilepsy v1.395 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341; 31029456
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger changed review comment from: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not avaialble).; to: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not available).
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger commented on gene: CLN6: PMID:31216804. Zhang et al. 2019 identify the pathogenic gene variants and clinical phenotype features of 26 children with progressive myoclonic epilepsy. 1 patient had a variant in CLN6 (full English text not avaialble).
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger commented on gene: CLN6: Additional case in PMID:31029456 (Matsumoto et al., 2019) of Japanese boy with a homozygous C.794_976del variant p. (Ser265del) in CLN6. Symptoms include focal seizures.
Early onset or syndromic epilepsy v1.394 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to 21549341
Early onset or syndromic epilepsy v1.393 SGSH Rebecca Foulger Classified gene: SGSH as Green List (high evidence)
Early onset or syndromic epilepsy v1.393 SGSH Rebecca Foulger Added comment: Comment on list classification: Added SGSH to the panel with a Green rating: Green on the 'Inborn errors of metabolism' panel, and seizures are part of the MPS IIIA phenotype. Sufficient cases from the literature for inclusion on the panel.
Early onset or syndromic epilepsy v1.393 SGSH Rebecca Foulger Gene: sgsh has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.392 SGSH Rebecca Foulger commented on gene: SGSH: PMID: 30593151 (Li et al., 2018) report an 8 year old female with developmental regression and seizures amongst her symptoms. She was diagnosed with autosomal recessive (AR) MPS IIIA with compound het variants in SGSH (c.1298G>A p.Arg433Gln and c.630 G>T p.Trp210Cys), inherited from each parent. The pathogenicity of c.630G>T has not been reported yet. c.1298G>A has been associated with MPS-IIIA previously.
Early onset or syndromic epilepsy v1.392 SGSH Rebecca Foulger commented on gene: SGSH: PMID:21061399: Valstar et al. 2010 retrospectively reviewed the clinical features of 92 patients with MPS IIIA, including 32 living and 60 deceased individuals. There was wide phenotypic variability but Epilepsy was reported in 53/80 patients with a median seizure age of 11 years (range, 1-43 years). Patients with a severe MPS IIIA phenotype developed epilepsy at a significantly earlier age compared to patients suffering from a more attenuated form of the disease.
Early onset or syndromic epilepsy v1.392 SGSH Rebecca Foulger gene: SGSH was added
gene: SGSH was added to Genetic epilepsy syndromes. Sources: Literature,Other
Mode of inheritance for gene: SGSH was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGSH were set to 21061399; 30593151
Phenotypes for gene: SGSH were set to Mucopolysaccharidosis type IIIA (Sanfilippo A), 252900; seizures
Review for gene: SGSH was set to GREEN
Added comment: Added SGSH to the panel based on Green rating on the 'Inborn errors of metabolism' panel: seizures are a part of the Mucopolysaccharidosis phenotype.
Sources: Literature, Other
Intellectual disability v2.1092 SVBP Alistair Pagnamenta reviewed gene: SVBP: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 31363758, 30607023; Phenotypes: brain abnormalities, microcephaly, intellectual disability, delayed gross motor development, spasticity, delayed speech development; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.17 SLC2A1 Louise Daugherty Publications for gene SLC2A1 were changed from to 19630075; 26598494; 10980529
Skeletal muscle channelopathy v0.17 SLC1A3 Louise Daugherty Publications for gene SLC1A3 were changed from to 19139306
Skeletal muscle channelopathy v0.17 SCN4A Louise Daugherty Publications for gene SCN4A were changed from to 18166706; 15534250; 19118277; 26700687
Skeletal muscle channelopathy v0.17 RYR1 Louise Daugherty Publications for gene RYR1 were changed from to 12136074; 16163667; 20839240
Skeletal muscle channelopathy v0.17 PYGM Louise Daugherty Publications for gene PYGM were changed from to 21880526
Skeletal muscle channelopathy v0.17 MT-ATP8 Louise Daugherty Publications for gene MT-ATP8 were changed from to 24153443
Skeletal muscle channelopathy v0.17 MT-ATP6 Louise Daugherty Publications for gene MT-ATP6 were changed from to 24153443
Skeletal muscle channelopathy v0.17 KCNJ2 Louise Daugherty Publications for gene KCNJ2 were changed from to 16217063; 12796536
Skeletal muscle channelopathy v0.17 KCNA1 Louise Daugherty Publications for gene KCNA1 were changed from to 19770477; 17575281
Skeletal muscle channelopathy v0.17 DMPK Louise Daugherty Publications for gene DMPK were changed from to 7825566
Skeletal muscle channelopathy v0.17 CNBP Louise Daugherty Publications for gene CNBP were changed from to 18807109
Skeletal muscle channelopathy v0.17 CLCN1 Louise Daugherty Publications for gene CLCN1 were changed from to 17932099
Skeletal muscle channelopathy v0.17 CACNA1S Louise Daugherty Publications for gene CACNA1S were changed from to 28012042; 19118277
Skeletal muscle channelopathy v0.17 CACNA1A Louise Daugherty Publications for gene CACNA1A were changed from to 29442233; 8734765; 17575281
Skeletal muscle channelopathy v0.17 ATP2A1 Louise Daugherty Publications for gene ATP2A1 were changed from to 8841193
Skeletal muscle channelopathy v0.17 ATP1A2 Louise Daugherty Publications for gene ATP1A2 were changed from to 30423015; 15286158; 18056581
Skeletal muscle channelopathy v0.17 ADCY5 Louise Daugherty Publications for gene ADCY5 were changed from to 24700542
Skeletal muscle channelopathy v0.16 SLC1A3 Louise Daugherty Source NHS GMS was added to SLC1A3.
Skeletal muscle channelopathy v0.16 RYR1 Louise Daugherty Source NHS GMS was added to RYR1.
Skeletal muscle channelopathy v0.16 PYGM Louise Daugherty Source NHS GMS was added to PYGM.
Skeletal muscle channelopathy v0.16 MT-ATP8 Louise Daugherty Source NHS GMS was added to MT-ATP8.
Skeletal muscle channelopathy v0.16 MT-ATP6 Louise Daugherty Source NHS GMS was added to MT-ATP6.
Skeletal muscle channelopathy v0.16 KCNA1 Louise Daugherty Source NHS GMS was added to KCNA1.
Skeletal muscle channelopathy v0.16 DMPK Louise Daugherty Source NHS GMS was added to DMPK.
Skeletal muscle channelopathy v0.16 CNBP Louise Daugherty Source NHS GMS was added to CNBP.
Skeletal muscle channelopathy v0.16 ATP2A1 Louise Daugherty Source NHS GMS was added to ATP2A1.
Skeletal muscle channelopathy v0.16 ADCY5 Louise Daugherty Source NHS GMS was added to ADCY5.
Skeletal muscle channelopathy v0.15 SLC2A1 James Polke edited their review of gene: SLC2A1: Changed publications: Gardiner et al 2015 Brain 138, 3567-3580 PMID: 26598494. Wang et al 2000 Hum Mut 16, 224-31 PMID: 10980529. Schneider et al 2009 Mov Disord 24, 1684-8 PMID: 19630075. Suls et al 2009 Ann Neurol 66, 415-9; Changed phenotypes: Can resemble skeletal muscle channelopathy, GLUT1 deficiency syndrome 2, childhood onset, 612126, Epilepsy, idiopathic generalized, susceptibility to, 12, 614847, GLUT1 deficiency syndrome 1, infantile onset, severe, 606777 (recessive and dominant). ; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 SLC1A3 James Polke reviewed gene: SLC1A3: Rating: GREEN; Mode of pathogenicity: ; Publications: de Vries et al 2009 Arch Neurol 66. 97-101 PMID: 19139306; Phenotypes: Episodic ataxia, type 6, 612656; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Skeletal muscle channelopathy v0.15 SCN4A James Polke edited their review of gene: SCN4A: Changed publications: Miller et al 2004 Neurology 9, 1647-55 PMID: 15534250. Matthews et al 2009 Neurology 72, 1544-7 PMID:19118277. Matthews et al 2008 Neurology 70, 50-3 PMID: 18166706. Zaharieva et al 2016 Brain 139, 674-91 PMID: 26700687; Changed phenotypes: Dominant: Hyperkalemic periodic paralysis (170500), Hypokalemic periodic paralysis, type 2 (613345), Paramyotonia congenita (168300). Recessive: Congenital myopathy. ; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 RYR1 James Polke reviewed gene: RYR1: Rating: GREEN; Mode of pathogenicity: ; Publications: Jungbluth et al 2002 Neurology 59, 284-7 PMID: 12136074, Wilmhurst et al 2010 Ann Neurol 68, 717-26 PMID: 20839240, Monnier et al 2005 Hum Mutat 26, 413-25 PMID: 16163667; Phenotypes: Central core disease , 11700 (Dominant & recessive), Minicore myopathy with external ophthalmoplegia, 255320 (recessive), Malignant hyperthermia susceptibility 1, 145600 (Dominant); Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 PYGM James Polke reviewed gene: PYGM: Rating: GREEN; Mode of pathogenicity: ; Publications: Wu et al 2011 Mol Genet Metab 104, 587-91 PMID: 21880526; Phenotypes: McArdle disease, 232600; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 MT-ATP8 James Polke reviewed gene: MT-ATP8: Rating: GREEN; Mode of pathogenicity: ; Publications: Aure et al 2013 Neurology 81, 1810-8 PMID:24153443; Phenotypes: Can resemble skeletal muscle channelopathy; Mode of inheritance: MITOCHONDRIAL; Current diagnostic: yes
Skeletal muscle channelopathy v0.15 MT-ATP6 James Polke reviewed gene: MT-ATP6: Rating: GREEN; Mode of pathogenicity: ; Publications: Aure et al 2013 Neurology 81, 1810-8 PMID:24153443; Phenotypes: Can resemble skeletal muscle channelopathy; Mode of inheritance: MITOCHONDRIAL; Current diagnostic: yes
Skeletal muscle channelopathy v0.15 KCNJ2 James Polke edited their review of gene: KCNJ2: Changed publications: Davies et al 2005 Neurology 11, 1083-9 PMID: 16217063. Donaldson et al 2003 Neurology 10, 1811-6 PMID: 12796536; Changed phenotypes: Andersen syndrome, 170390; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v0.15 KCNA1 James Polke reviewed gene: KCNA1: Rating: GREEN; Mode of pathogenicity: ; Publications: Rajakulendran et al 2009 Neurology 73, 993-5 PMID: 19770477. Jen et al 2007 Brain 130, 2484-93 PMID: 17575281; Phenotypes: Episodic ataxia type 1/myokymia syndrome, 160120; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Skeletal muscle channelopathy v0.15 DMPK James Polke reviewed gene: DMPK: Rating: GREEN; Mode of pathogenicity: ; Publications: Wong et al 1995 Am J Hum Genet 56, 114-122 PMID: 7825566; Phenotypes: Myotonic dystrophy 1, 160900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v0.15 CNBP James Polke reviewed gene: CNBP: Rating: GREEN; Mode of pathogenicity: ; Publications: Suominen et al 2008 J Neurol 255, 1731-6 PMID: 18807109; Phenotypes: Myotonic dystrophy 2, 602668; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v0.15 CLCN1 James Polke edited their review of gene: CLCN1: Changed publications: Fialho et al 2007 Brain 130, 3265-74 PMID: 17932099; Changed phenotypes: Myotonia congenita, dominant, 160800, Myotonia congenita, recessive, 255700; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 CACNA1S James Polke edited their review of gene: CACNA1S: Changed publications: Matthews et al 2009 Neurology 72, 1544-7 PMID:19118277. Schartner et al 2017 Acta Neuropathol 133, 517-533 PMID: 28012042; Changed phenotypes: Hypokalaemic periodic paralysis, type I, 170400 (Dominant), Congenital myopathy (Dominant & recessive); Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 CACNA1A James Polke edited their review of gene: CACNA1A: Changed publications: Park et al 2018 Acta Neurologica Belgica 118, 137-139 PMID: 29442233. Jen et al 2007 Brain 130, 2484-93 PMID: 17575281. Terwindt et al 1996 Cephalalgia 16, 153-5 PMID: 8734765; Changed phenotypes: Episodic ataxia 2 with periodic paralysis, Episodic ataxia, type 2, 108500, Migraine, familial hemiplegic, 1, 141500, Epileptic encephalopathy, early infantile, 42, 617106; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v0.15 ATP2A1 James Polke reviewed gene: ATP2A1: Rating: GREEN; Mode of pathogenicity: ; Publications: Odermatt et al 1996 Nat Genet 14, 191-4 PMID: 8841193; Phenotypes: Brody myopathy, 601003; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal muscle channelopathy v0.15 ATP1A2 James Polke edited their review of gene: ATP1A2: Changed publications: Castaneda et al 2018 Brain 141, 3308-3318 PMID: 30423015. Bassi et al 2004 J Med Genet 41, 621-8 PMID: 15286158. de Vries et al 2007 Neurology 69, 2170-6 PMID: 18056581; Changed phenotypes: Hypokalaemic periodic paralysis, Alternating hemiplegia of childhood 1, 104290, Migraine, familial hemiplegic, 2, 602481 ; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v0.15 ADCY5 James Polke reviewed gene: ADCY5: Rating: RED; Mode of pathogenicity: ; Publications: Chen et al 2014 Ann Neurol 75, 542-9 PMID: 24700542; Phenotypes: Dyskinesia, familial, with facial myokymia, 606703; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Skeletal muscle channelopathy v0.14 SLC2A1 Louise Daugherty Mode of inheritance for gene SLC2A1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Epilepsy, idiopathic generalized, susceptibility to, 12, 614847; Can resemble skeletal muscle channelopathy; GLUT1 deficiency syndrome 1, infantile onset, severe, 606777 (recessive and dominant).; GLUT1 deficiency syndrome 2, childhood onset, 612126 for gene: SLC2A1
Skeletal muscle channelopathy v0.14 SLC1A3 Louise Daugherty Mode of inheritance for gene SLC1A3 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Episodic ataxia, type 6, 612656 for gene: SLC1A3
Skeletal muscle channelopathy v0.14 SCN4A Louise Daugherty Mode of inheritance for gene SCN4A was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Hypokalemic periodic paralysis, type 2 (613345); Dominant: Hyperkalemic periodic paralysis (170500); Paramyotonia congenita (168300). Recessive: Congenital myopathy. for gene: SCN4A
Skeletal muscle channelopathy v0.14 RYR1 Louise Daugherty Mode of inheritance for gene RYR1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Central core disease , 11700 (Dominant & recessive); Minicore myopathy with external ophthalmoplegia, 255320 (recessive); Malignant hyperthermia susceptibility 1, 145600 (Dominant) for gene: RYR1
Skeletal muscle channelopathy v0.14 PYGM Louise Daugherty Mode of inheritance for gene PYGM was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes McArdle disease, 232600 for gene: PYGM
Skeletal muscle channelopathy v0.14 MT-ATP8 Louise Daugherty Added phenotypes Can resemble skeletal muscle channelopathy for gene: MT-ATP8
Skeletal muscle channelopathy v0.14 MT-ATP6 Louise Daugherty Added phenotypes Can resemble skeletal muscle channelopathy for gene: MT-ATP6
Skeletal muscle channelopathy v0.14 KCNJ2 Louise Daugherty Mode of inheritance for gene KCNJ2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Andersen syndrome, 170390 for gene: KCNJ2
Skeletal muscle channelopathy v0.14 KCNA1 Louise Daugherty Mode of inheritance for gene KCNA1 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Episodic ataxia type 1/myokymia syndrome, 160120 for gene: KCNA1
Skeletal muscle channelopathy v0.14 DMPK Louise Daugherty Mode of inheritance for gene DMPK was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Myotonic dystrophy 1, 160900 for gene: DMPK
Skeletal muscle channelopathy v0.14 CNBP Louise Daugherty Mode of inheritance for gene CNBP was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Myotonic dystrophy 2, 602668 for gene: CNBP
Skeletal muscle channelopathy v0.14 CLCN1 Louise Daugherty Mode of inheritance for gene CLCN1 was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Myotonia congenita, dominant, 160800; Myotonia congenita, recessive, 255700 for gene: CLCN1
Skeletal muscle channelopathy v0.14 CACNA1S Louise Daugherty Mode of inheritance for gene CACNA1S was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Added phenotypes Congenital myopathy (Dominant & recessive); Hypokalaemic periodic paralysis, type I, 170400 (Dominant) for gene: CACNA1S
Skeletal muscle channelopathy v0.14 CACNA1A Louise Daugherty Mode of inheritance for gene CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Episodic ataxia 2 with periodic paralysis; Epileptic encephalopathy, early infantile, 42, 617106; Migraine, familial hemiplegic, 1, 141500; Episodic ataxia, type 2, 108500 for gene: CACNA1A
Skeletal muscle channelopathy v0.14 ATP2A1 Louise Daugherty Mode of inheritance for gene ATP2A1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Added phenotypes Brody myopathy, 601003 for gene: ATP2A1
Skeletal muscle channelopathy v0.14 ATP1A2 Louise Daugherty Mode of inheritance for gene ATP1A2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Migraine, familial hemiplegic, 2, 602481; Alternating hemiplegia of childhood 1, 104290; Hypokalaemic periodic paralysis for gene: ATP1A2
Skeletal muscle channelopathy v0.14 ADCY5 Louise Daugherty Mode of inheritance for gene ADCY5 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Added phenotypes Dyskinesia, familial, with facial myokymia, 606703 for gene: ADCY5
Skeletal muscle channelopathy v0.13 SLC1A3 Louise Daugherty Source Expert Review Green was added to SLC1A3.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 RYR1 Louise Daugherty Source Expert Review Green was added to RYR1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 PYGM Louise Daugherty Source Expert Review Green was added to PYGM.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 MT-ATP8 Louise Daugherty Source Expert Review Green was added to MT-ATP8.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 MT-ATP6 Louise Daugherty Source Expert Review Green was added to MT-ATP6.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 KCNA1 Louise Daugherty Source Expert Review Green was added to KCNA1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 DMPK Louise Daugherty Source Expert Review Green was added to DMPK.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 CNBP Louise Daugherty Source Expert Review Green was added to CNBP.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 ATP2A1 Louise Daugherty Source Expert Review Green was added to ATP2A1.
Rating Changed from Red List (low evidence) to Green List (high evidence)
Skeletal muscle channelopathy v0.13 ADCY5 Louise Daugherty Source Expert Review Red was added to ADCY5.
Skeletal muscle channelopathy v0.12 SLC1A3 Louise Daugherty gene: SLC1A3 was added
gene: SLC1A3 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: SLC1A3 was set to
Skeletal muscle channelopathy v0.12 RYR1 Louise Daugherty gene: RYR1 was added
gene: RYR1 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: RYR1 was set to
Skeletal muscle channelopathy v0.12 PYGM Louise Daugherty gene: PYGM was added
gene: PYGM was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: PYGM was set to
Skeletal muscle channelopathy v0.12 MT-ATP8 Louise Daugherty gene: MT-ATP8 was added
gene: MT-ATP8 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene gene: MT-ATP8 was set to MITOCHONDRIAL
Skeletal muscle channelopathy v0.12 MT-ATP6 Louise Daugherty gene: MT-ATP6 was added
gene: MT-ATP6 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene gene: MT-ATP6 was set to MITOCHONDRIAL
Skeletal muscle channelopathy v0.12 KCNA1 Louise Daugherty gene: KCNA1 was added
gene: KCNA1 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: KCNA1 was set to
Skeletal muscle channelopathy v0.12 DMPK Louise Daugherty gene: DMPK was added
gene: DMPK was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: DMPK was set to
Skeletal muscle channelopathy v0.12 CNBP Louise Daugherty gene: CNBP was added
gene: CNBP was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: CNBP was set to
Skeletal muscle channelopathy v0.12 ATP2A1 Louise Daugherty gene: ATP2A1 was added
gene: ATP2A1 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: ATP2A1 was set to
Skeletal muscle channelopathy v0.12 ADCY5 Louise Daugherty gene: ADCY5 was added
gene: ADCY5 was added to Myotonia congenita. Sources: London North GLH
Mode of inheritance for gene: ADCY5 was set to
Unexplained kidney failure in young people v1.74 APRT John Sayer gene: APRT was added
gene: APRT was added to Unexplained kidney failure in young people. Sources: Expert list
Mode of inheritance for gene: APRT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APRT were set to 30355577
Phenotypes for gene: APRT were set to interstitial nephritis; chronic kidney disease; end stage renal disease; nephrolithiaisis
Penetrance for gene: APRT were set to Complete
Review for gene: APRT was set to GREEN
Added comment: Sources: Expert list
Cystic kidney disease v2.0 SEC61A1 John Sayer edited their review of gene: SEC61A1: Changed phenotypes: interstitial nephritis, chronic kidney disease, cystic kidney disease, anaemia, glomerulocystic kidney disease
Cystic kidney disease v2.0 SEC61A1 John Sayer gene: SEC61A1 was added
gene: SEC61A1 was added to Cystic kidney disease. Sources: Expert Review
Mode of inheritance for gene: SEC61A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SEC61A1 were set to 31488840; 27392076
Phenotypes for gene: SEC61A1 were set to interstitial nephritis; chronic kidney disease; cystic kidney disease
Review for gene: SEC61A1 was set to GREEN
Added comment: Sources: Expert Review
Cystic kidney disease v2.0 ALG9 John Sayer gene: ALG9 was added
gene: ALG9 was added to Cystic kidney disease. Sources: Expert Review
Mode of inheritance for gene: ALG9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALG9 were set to 31395617
Phenotypes for gene: ALG9 were set to cystic liver disease; cystic kidney disease
Penetrance for gene: ALG9 were set to Complete
Review for gene: ALG9 was set to GREEN
Added comment: Sources: Expert Review
Cystic kidney disease v2.0 ALG8 John Sayer gene: ALG8 was added
gene: ALG8 was added to Cystic kidney disease. Sources: Expert Review
Mode of inheritance for gene: ALG8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALG8 were set to 30135240
Phenotypes for gene: ALG8 were set to cystic liver disease; cystic kidney disease
Penetrance for gene: ALG8 were set to Complete
Review for gene: ALG8 was set to GREEN
Added comment: Sources: Expert Review
Intellectual disability v2.1092 NKAP Catherine Snow Phenotypes for gene: NKAP were changed from to Global developmental delay; Intellectual disability
Intellectual disability v2.1091 NKAP Catherine Snow Classified gene: NKAP as Green List (high evidence)
Intellectual disability v2.1091 NKAP Catherine Snow Added comment: Comment on list classification: NKAP reviewed by Konstantinos Varvagiannis following publication by Fiordaliso et al. (PMID:31587868) who identified 10 males from 8 unrelated families with missense mutations in NKAP (on Xq24) Hypotonia and tall stature with Marfanoid habitus was predominant phenotype. One variant (NM_024528:c.988G>A / p.Arg333Gln) was seen in 4 families and although origin was not provided for all families this variant was seen in brothers with parents from Slovakia and an individual with parents from Japan.
NKAP is not currently in OMIM or Gene2Phenotype.
Rating NKAP as Green as consistent phenotype observed, >3 unrelated individuals and some functional work in Zebrafish.
Intellectual disability v2.1091 NKAP Catherine Snow Gene: nkap has been classified as Green List (High Evidence).
Intellectual disability v2.1090 NKAP Catherine Snow Tag missense tag was added to gene: NKAP.
Intellectual disability v2.1090 METTL5 Rebecca Foulger Classified gene: METTL5 as Amber List (moderate evidence)
Intellectual disability v2.1090 METTL5 Rebecca Foulger Added comment: Comment on list classification: METTL5 was added to the panel and rated Green by Konstantinos Varvagiannis. There are just sufficient (3) cases from the literature (siblings in PMID:29302074 plus 2 families in PMID:31564433), and animal models (mice and zebrafish) exhibit microcephaly similar to the human phenotype. However, the Gly61Asp variant found in the PMID:29302074 siblings is currently classed as VUS and PMID:31564433 failed to demonstrate a functional impact for this variant on the encoded protein.

METTL5 has been recently added (October 2019) to DD-G2P with a probable rating for 'Autosomal-Recessive Intellectual Disability and Microcephaly'. METTL5 is not yet associated with a disorder in OMIM. Given the uncertainty of the functional significance of the Gly61Asp variant, on balance an Amber rating is appropriate at this time, pending further cases or functional evidence.
Intellectual disability v2.1090 METTL5 Rebecca Foulger Gene: mettl5 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1089 METTL5 Rebecca Foulger Publications for gene: METTL5 were set to 29302074; http://doi.org/10.1016/j.ajhg.2019.09.007; https://imgc2019.sciencesconf.org/data/abstract_book_complete.pdf
Skeletal muscle channelopathy v0.11 Louise Daugherty List of related panels changed from to R76
Intellectual disability v2.1088 METTL5 Rebecca Foulger Phenotypes for gene: METTL5 were changed from Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality to Autosomal-Recessive Intellectual Disability and Microcephaly; Delayed speech and language development; Intellectual disability; Microcephaly; Behavioral abnormality
Intellectual disability v2.1088 NKAP Catherine Snow Publications for gene: NKAP were set to 26358559; 26350204
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Classified gene: TRAPPC6B as Green List (high evidence)
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on Aug 2019 review by Konstantinos Varvagiannis. Konstantinos notes an additional 2019 paper (Nair et al) who report a Lebanese patient with global DD and ID, who is homozygous for a nonsense variant in TRAPPC6B (p.Leu8*). The unaffected mother was a heterozygous carrier. In contrast to previous cases, the patient did not show any seizures, but the authors note he was only 3.5 years old at the time of writing, and will be monitored for seizure events. ID/DD is a consistent phenotype across cases. This takes the number of cases to 3 (with the 3 families in Marin-Valencia forming 1 case), with 3 separate variants. Therefore Green rating is appropriate.
Intellectual disability v2.1087 TRAPPC6B Rebecca Foulger Gene: trappc6b has been classified as Green List (High Evidence).
Intellectual disability v2.1086 CSDE1 Catherine Snow Classified gene: CSDE1 as Green List (high evidence)
Intellectual disability v2.1086 CSDE1 Catherine Snow Added comment: Comment on list classification: CSDE1 identified by Konstantinos Varvagiannis based on a publication by Guo et al. (PMID: 31579823) This is the first time CSDE1 has been associated with any diseases therefore it not currently in OMIM or Gene2Phenotype. However consistent phenotype of DD/ID and autism seen among all individuals with variants. With functional work on both mice and Drosophila.
Intellectual disability v2.1086 CSDE1 Catherine Snow Gene: csde1 has been classified as Green List (High Evidence).
Intellectual disability v2.1085 CSDE1 Catherine Snow Publications for gene: CSDE1 were set to http://doi.org/10.1126/sciadv.aax2166
Intellectual disability v2.1084 SMG9 Catherine Snow Publications for gene: SMG9 were set to 27018474; 30914295
Intellectual disability v2.1083 SMG9 Catherine Snow edited their review of gene: SMG9: Added comment: Maintaining Amber rating as although another individual with a variant has been identified in PMID: 31390136 there are still only full details of serve developmental delays for 2 unrelated families due to the young age of death of one reported individual in 27018474; Changed publications: 31390136
Intellectual disability v2.1083 PMPCB Catherine Snow changed review comment from: PMPCB identified by Konstantinos Varvagiannis following publication by Vögtle et al. (2018 - PMID: 29576218) who reported on by Vögtle et al. (2018 - PMID: 29576218) who identified 5 individuals from 4 unrelated families (in one case consanguineous) who have biallelic pathogenic PMPCB variants.
PMPCB is in OMIM and Gene2Phenotype with relevant phenotype. Individuals reported have stagnation in their development before onset of symptoms. PMPCB is Green on relevant Mitochondrial disorders panel (Version 2.1). As phenotype of DD is relevant to ID panel PMPCB is classified as Green.; to: PMPCB identified by Konstantinos Varvagiannis following publication by Vögtle et al. (2018 - PMID: 29576218) who identified 5 individuals from 4 unrelated families (in one case consanguineous) who have biallelic pathogenic PMPCB variants.
PMPCB is in OMIM and Gene2Phenotype with relevant phenotype. Individuals reported have stagnation in their development before onset of symptoms including, delayed psychomotor development and ID. PMPCB is Green on relevant Mitochondrial disorders panel (Version 2.1). As phenotype of DD is relevant to ID panel PMPCB is classified as Green.
Intellectual disability v2.1083 PMPCB Catherine Snow Publications for gene: PMPCB were set to
Intellectual disability v2.1083 PMPCB Catherine Snow Classified gene: PMPCB as Green List (high evidence)
Intellectual disability v2.1083 PMPCB Catherine Snow Gene: pmpcb has been classified as Green List (High Evidence).
Intellectual disability v2.1082 PMPCB Catherine Snow reviewed gene: PMPCB: Rating: GREEN; Mode of pathogenicity: None; Publications: 29576218; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained kidney failure in young people v1.74 FAN1 Eleanor Williams Classified gene: FAN1 as Green List (high evidence)
Unexplained kidney failure in young people v1.74 FAN1 Eleanor Williams Added comment: Comment on list classification: More than 3 cases reported with plausible disease causing variants. Not found in small set on controls (96 individuals). Some functional data.
Unexplained kidney failure in young people v1.74 FAN1 Eleanor Williams Gene: fan1 has been classified as Green List (High Evidence).
Unexplained kidney failure in young people v1.73 FAN1 Eleanor Williams changed review comment from: FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM.

PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM).

Sufficient cases with likely disease causing mutations to rate this gene green. ; to: FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM.

PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM).

Sufficient cases with likely disease causing mutations to rate this gene green.
Early onset or syndromic epilepsy v1.391 Rebecca Foulger Panel types changed to Rare Disease 100K; GMS Rare Disease
Unexplained kidney failure in young people v1.73 FAN1 Eleanor Williams changed review comment from: FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM.

PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM).

Sufficient cases with likely disease causing mutations to rate this gene green.; to: FAN1 associated with Interstitial nephritis, karyomegalic #614817 (AR) in OMIM.

PMID: 22772369 - Zhou et al 2012 - 9 unrelated families with karyomegalic interstitial nephritis which can result in Chronic kidney disease. They identified 12 different homozygous or compound heterozygous mutations in the FAN1 gene. Eight of the 12 mutations resulted in a truncated protein. (Summary from OMIM).

Sufficient cases with likely disease causing mutations to rate this gene green.
Unexplained kidney failure in young people v1.73 FAN1 Eleanor Williams commented on gene: FAN1
Intellectual disability v2.1082 PCDH12 Catherine Snow Phenotypes for gene: PCDH12 were changed from intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities to intellectual disability; microcephaly; epilepsy; perithalamic hyperechogenicity; periventricular hyperechogenicity; midbrain abnormalities; hypothalamic abnormalities; Microcephaly, seizures, spasticity, and brain calcification, 251280
Intellectual disability v2.1081 PCDH12 Catherine Snow Classified gene: PCDH12 as Green List (high evidence)
Intellectual disability v2.1081 PCDH12 Catherine Snow Added comment: Comment on list classification: Following review by Konstantinos Varvagiannis on PCDH12, highlighted that here is now a sufficient number of published variants from unrelated families to classify PCDH12 as Green with ID reported in all.
Intellectual disability v2.1081 PCDH12 Catherine Snow Gene: pcdh12 has been classified as Green List (High Evidence).
Intellectual disability v2.1081 PCDH12 Catherine Snow Publications for gene: PCDH12 were set to 27164683
Intellectual disability v2.1080 CDH2 Catherine Snow Classified gene: CDH2 as Amber List (moderate evidence)
Intellectual disability v2.1080 CDH2 Catherine Snow Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1079 CDH2 Catherine Snow reviewed gene: CDH2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early onset or syndromic epilepsy v1.389 Rebecca Foulger List of related panels changed from Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus to Epilepsy Plus; Epilepsy plus other features; Genetic Epilepsy Syndromes; Epileptic encephalopathy; Familial Focal Epilepsies; Familial Genetic Generalised Epilepsies; Genetic Epilepsies with Febrile Seizures Plus (GEFS+); Genetic Epilepsies with Febrile Seizures Plus; Early onset or syndromic epilepsy
Unexplained young onset end-stage renal disease v0.50 UMOD Eleanor Williams commented on gene: UMOD: Red review was for the gene on another panel.
Unexplained young onset end-stage renal disease v0.50 TTC21B Eleanor Williams Added comment: Comment on mode of inheritance: In OMIM both AR and AD are listed for Nephronophthisis 12.
Unexplained young onset end-stage renal disease v0.50 TTC21B Eleanor Williams Mode of inheritance for gene: TTC21B was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.388 APC2 Catherine Snow reviewed gene: APC2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.49 RET Eleanor Williams commented on gene: RET: Note on MOI - keeping BOTH mono and biallelic because Gene2Phenotype has Renal agenesis as biallalic. All other renal related conditions are monoallelic.
Intellectual disability v2.1079 APC2 Catherine Snow Classified gene: APC2 as Green List (high evidence)
Intellectual disability v2.1079 APC2 Catherine Snow Gene: apc2 has been classified as Green List (High Evidence).
Intellectual disability v2.1078 APC2 Catherine Snow Classified gene: APC2 as No list
Intellectual disability v2.1078 APC2 Catherine Snow Added comment: Comment on list classification: APC2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. APC2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore APC2 can be classified as Green
Intellectual disability v2.1078 APC2 Catherine Snow Gene: apc2 has been removed from the panel.
Early onset or syndromic epilepsy v1.388 BSCL2 Rebecca Foulger Phenotypes for gene: BSCL2 were changed from Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685 to Intractable epilepsy and neurological regression; Encephalopathy, progressive, with or without lipodystrophy 615924; Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Silver spastic paraplegia syndrome 270685
Early onset or syndromic epilepsy v1.387 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077; 30767895; 23564749
Early onset or syndromic epilepsy v1.386 BSCL2 Rebecca Foulger Added comment: Comment on mode of inheritance: PMID:31369919 (Fernandez-Marmiesse et al., 2019) report 2 siblings with profound refractory epilepsy and neurological regression. A de novo Met189Lys variant in BSCL2 was detected that was absent in the parents and unaffected sibling. This is the first evidence of an association between a heterozygous BSCL2 variant and EIEE, and supports an AD+AR Mode of inheritance.
Early onset or syndromic epilepsy v1.386 BSCL2 Rebecca Foulger Mode of inheritance for gene: BSCL2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.385 BSCL2 Rebecca Foulger Publications for gene: BSCL2 were set to 24896178; 26503795; 23564749; 15181077; 30767895
Early onset or syndromic epilepsy v1.384 CYP27A1 Rebecca Foulger Publications for gene: CYP27A1 were set to 18227423; 22336472; 24442603; 29484516
Early onset or syndromic epilepsy v1.383 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added EXT2 to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Early onset or syndromic epilepsy v1.383 EMX2 Rebecca Foulger Classified gene: EMX2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.383 EMX2 Rebecca Foulger Gene: emx2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.382 EMX2 Rebecca Foulger Classified gene: EMX2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.382 EMX2 Rebecca Foulger Added comment: Comment on list classification: Demoted EMX2 from Green to Amber based on the Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy, and the post-Webex review by Helen Lord. The Schizencephaly phenotype is more appropriate for the ID/Cortical malformations panel, and EMX2 has now been added as a Green gene to 'Malformations of cortical development' (#96) panel.
Early onset or syndromic epilepsy v1.382 EMX2 Rebecca Foulger Gene: emx2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow changed review comment from: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green; to: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. All individuals reported to have seizures, although age of onset varied from 2 months to 12 years. There are sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green.
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow Classified gene: TDP2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow Added comment: Comment on list classification: TDP2 is in OMIM with a relevant clinical features but not in Gene2Phenotype. TDP2 was identified by Konstantinos Varvagiannis who reviewed all variants. Sufficient number of individuals from unrelated families reported upon in the literature and three different variants identified. Therefore TDP2 can be classified as Green
Early onset or syndromic epilepsy v1.381 TDP2 Catherine Snow Gene: tdp2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.380 TDP2 Catherine Snow Mode of inheritance for gene: TDP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.379 TANC2 Rebecca Foulger Classified gene: TANC2 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.379 TANC2 Rebecca Foulger Added comment: Comment on list classification: Set rating of TANC2 to Amber. Not yet associated with a disorder in OMIM or Gene2Phenotype. One 2019 paper linking TANC2 with epilepsy in 11/20 cases: sufficient unrelated cases in PMID:31616000 but the pathogenicity of the variants has not been confirmed.
Early onset or syndromic epilepsy v1.379 TANC2 Rebecca Foulger Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.378 TANC2 Rebecca Foulger gene: TANC2 was added
gene: TANC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TANC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TANC2 were set to 31616000
Phenotypes for gene: TANC2 were set to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Seizures; Epilepsy
Added comment: Added TANC2 to panel following curation of TANC2 on the Intellectual disability panel. PMID:31616000 (Guo et al, 2019) report 11/20 individuals with a TANC2 variant who had a formal diagnosis of epilepsy (n=9) or who suffered recurrent seizures (n=2).
Sources: Literature
Intellectual disability v2.1077 TDP2 Catherine Snow Classified gene: TDP2 as Green List (high evidence)
Intellectual disability v2.1077 TDP2 Catherine Snow Gene: tdp2 has been classified as Green List (High Evidence).
Intellectual disability v2.1076 TDP2 Catherine Snow commented on gene: TDP2
Intellectual disability v2.1076 TANC2 Rebecca Foulger edited their review of gene: TANC2: Changed rating: AMBER
Intellectual disability v2.1076 TANC2 Rebecca Foulger changed review comment from: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.; to: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Not yet associated with a disorder in Gene2Phenotype or OMIM. Currently only 1 paper, therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability v2.1076 TANC2 Rebecca Foulger Classified gene: TANC2 as Amber List (moderate evidence)
Intellectual disability v2.1076 TANC2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on PMID:31616000 2019 article suggested by Andrea Haworth. Sufficient unrelated cases (19/20) with an ID/DD phenotype but the pathogenicity of the variants has not yet been verified. Therefore Amber with 'watchlist' tag is appropriate pending functional studies.
Intellectual disability v2.1076 TANC2 Rebecca Foulger Gene: tanc2 has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1075 TANC2 Rebecca Foulger commented on gene: TANC2: Summary of PMID:31616000 (PMC:6794285) suggested by Andrea Haworth reviewer: Guo et al assembled phenotypic data for 19 probands and 1 affected sibling with TANC2 variants. Variants include 16 LGD (likely gene-disruptive) variants and three intragenic microdeletions. Phenotypes included ASD, ID, speech-language delay and childhood motor delay:
- 15/20 individuals had ASD/autism features (7 with a formal diagnosis).
- 19/20 individuals had some form of ID (17 with a formal diagnosis of borderline to severe ID, and 2 with learning difficulties without a formal diagnosis).
- 18/20 showed speech-language delay.
- 13/19 individuals had childhood motor delay.
- 11/20 individuals had a formal diagnosis of epilepsy (9) or suffered recurrent seizures (2).
Intellectual disability v2.1075 TANC2 Rebecca Foulger Phenotypes for gene: TANC2 were changed from to NDD syndrome; Neurodevelopmental Disorder; Intellectual disability; Childhood speech delay; Childhood motor delay
Intellectual disability v2.1074 TANC2 Rebecca Foulger Added comment: Comment on mode of inheritance: Set MOI as MONOALLELIC based on PMID:31616000 (Figure 2).
Intellectual disability v2.1074 TANC2 Rebecca Foulger Mode of inheritance for gene: TANC2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1073 TDP2 Catherine Snow Mode of inheritance for gene: TDP2 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1072 TANC2 Rebecca Foulger Publications for gene: TANC2 were set to 26350204
Fetal anomalies v0.346 AMER1 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from Monoallelic to X-linked dominant to match other PanelApp panels. Although the Gene2Phenotype inheritance is currently listed as monoallelic, AMER1 is an X-linked gene.
Fetal anomalies v0.346 AMER1 Rebecca Foulger Mode of inheritance for gene: AMER1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v1.143 AMER1 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from Monoallelic to X-linked dominant to match other PanelApp panels. Although the Gene2Phenotype inheritance is currently listed as monoallelic, AMER1 is an X-linked gene.
DDG2P v1.143 AMER1 Rebecca Foulger Mode of inheritance for gene: AMER1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v1.142 AMER1 Rebecca Foulger changed review comment from: Original DDG2P rating: both DD and IF. ; to: Original DDG2P rating: both DD and IF for OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS. Allelic requirement: monoallelic. Mutation consequence: loss of function.
Fetal anomalies v0.345 FAM58A Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from MONOALLELIC to X-linked dominant. Although monoallelic inheritance is currently listed in DDG2P for STAR SYNDROME, FAM58A (CCNQ) is an X-linked gene.
Fetal anomalies v0.345 FAM58A Rebecca Foulger Mode of inheritance for gene: FAM58A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v1.142 FAM58A Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from MONOALLELIC to X-linked dominant. Although monoallelic inheritance is currently listed in DDG2P for STAR SYNDROME, FAM58A is an X-linked gene.
DDG2P v1.142 FAM58A Rebecca Foulger Mode of inheritance for gene: FAM58A was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v1.141 FAM58A Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. Gene symbol used in Original DD-G2P gene list is CCNQ.; to: Original DDG2P rating: confirmed for STAR SYNDROME. Gene symbol used in Original DD-G2P gene list is CCNQ. DDG2P allelic requirement: monoallelic. Mutation consequence: loss of function.
Likely inborn error of metabolism v1.379 UQCRC2 Catherine Snow Classified gene: UQCRC2 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.379 UQCRC2 Catherine Snow Added comment: Comment on list classification: Promoted from Red to Amber due to two unrelated cases/families - though this is for the same missense variant.
Likely inborn error of metabolism v1.379 UQCRC2 Catherine Snow Gene: uqcrc2 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.378 UQCRC2 Catherine Snow Publications for gene: UQCRC2 were set to
Intellectual disability v2.1071 PIGP Rebecca Foulger Classified gene: PIGP as Amber List (moderate evidence)
Intellectual disability v2.1071 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and Amber rating on the Genetic epilepsy syndromes panel. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Intellectual disability v2.1071 PIGP Rebecca Foulger Gene: pigp has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1070 PMPCA Rebecca Foulger Classified gene: PMPCA as Amber List (moderate evidence)
Intellectual disability v2.1070 PMPCA Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Amber. PMPCA was added and rated Green by Konstantinos Varvagiannis. Although there are sufficient (3) literature cases overall, the phenotype is variable across cases: 3 families with a possible Founder variant in PMID:25808372, no ID reported in PMID:26657514, 1 family in PMID:27148589 and 1 individual in PMID:30617178. Therefore rated Amber awaiting further cases.
Intellectual disability v2.1070 PMPCA Rebecca Foulger Gene: pmpca has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1069 PMPCA Rebecca Foulger commented on gene: PMPCA
Intellectual disability v2.1069 CA5A Rebecca Foulger commented on gene: CA5A
Intellectual disability v2.1069 CA5A Rebecca Foulger Mode of inheritance for gene: CA5A was changed from to BIALLELIC, autosomal or pseudoautosomal
Intellectual disability v2.1068 CA5A Rebecca Foulger Phenotypes for gene: CA5A were changed from to Hyperammonemia due to carbonic anhydrase VA deficiency, 615751
Intellectual disability v2.1067 CA5A Rebecca Foulger Publications for gene: CA5A were set to
Unexplained young onset end-stage renal disease v0.49 OCRL Eleanor Williams commented on gene: OCRL: Red review refers to the gene on another panel.
Unexplained young onset end-stage renal disease v0.49 OCRL Eleanor Williams changed review comment from: Comment on mode of inheritance: Taking suggested MOI from GMS list for Proteinuiric renal disease; to: Comment on mode of inheritance: Taking suggested MOI from GMS list for Proteinuiric renal disease but note OMIM has XLR as the MOI.
Unexplained young onset end-stage renal disease v0.49 OCRL Eleanor Williams Added comment: Comment on mode of inheritance: Taking suggested MOI from GMS list for Proteinuiric renal disease
Unexplained young onset end-stage renal disease v0.49 OCRL Eleanor Williams Mode of inheritance for gene: OCRL was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Intellectual disability v2.1066 TANC2 Andrea Haworth commented on gene: TANC2
Undiagnosed metabolic disorders v1.399 NNT Catherine Snow Classified gene: NNT as Green List (high evidence)
Undiagnosed metabolic disorders v1.399 NNT Catherine Snow Gene: nnt has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.398 NNT Catherine Snow gene: NNT was added
gene: NNT was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: NNT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NNT were set to 27129361; 28546232
Phenotypes for gene: NNT were set to Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736
Review for gene: NNT was set to GREEN
Added comment: Relevant phenotype in OMIM but not in Gene2Phenotype. Sufficient cases in OMIM to classify NNT as Green
Sources: Expert Review
Likely inborn error of metabolism v1.377 NNT Catherine Snow Publications for gene: NNT were set to
Unexplained young onset end-stage renal disease v0.48 MUC1 Eleanor Williams Mode of pathogenicity for gene: MUC1 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
Unexplained young onset end-stage renal disease v0.47 MUC1 Eleanor Williams Publications for gene: MUC1 were set to 25738250; 24670410; 23396133; 27157321
Unexplained young onset end-stage renal disease v0.46 MUC1 Eleanor Williams commented on gene: MUC1: Numerous reports of variants within VNTR associated with mutant protein and single report of 2bp deletion outside VNTR with equivalent effect on protein (PMID: 29156055). Note: variants within VNTR are unlikely to be detected by NGS.
Unexplained young onset end-stage renal disease v0.46 COL4A4 Eleanor Williams Added comment: Comment on mode of inheritance: Changing to BOTH monoallelic and biallelic, autosomal or pseudoautosomal because it is associated with two relevant disorders one which shows biallelic and one which shows monoallelic inheritance ( Alport syndrome 2, autosomal recessive is AR and Hematuria, familial benign is AD).
Unexplained young onset end-stage renal disease v0.46 COL4A4 Eleanor Williams Mode of inheritance for gene: COL4A4 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.45 CLCN5 Eleanor Williams changed review comment from: Comment on mode of inheritance: PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate; to: Comment on mode of inheritance: PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate. However, this gene is associated with 4 renal diseases in OMIM (Dent disease, Hypophosphatemic rickets, Nephrolithiasis, type I, Proteinuria, low molecular weight, with hypercalciuric nephrocalcinosis) which are all reported as XLR so keeping as Xlinked (biallelic in females) just now.
Likely inborn error of metabolism v1.376 NNT Catherine Snow reviewed gene: NNT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27129361; Phenotypes: Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.376 NNT Catherine Snow Phenotypes for gene: NNT were changed from to Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency, 614736
Likely inborn error of metabolism v1.375 NNT Catherine Snow Classified gene: NNT as Green List (high evidence)
Likely inborn error of metabolism v1.375 NNT Catherine Snow Gene: nnt has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.375 NNT Catherine Snow Mode of inheritance for gene: NNT was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Unexplained young onset end-stage renal disease v0.45 ANOS1 Eleanor Williams Added comment: Comment on mode of inheritance: Changing mode of inheritance to X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not present with a disease phenotype.
Unexplained young onset end-stage renal disease v0.45 ANOS1 Eleanor Williams Mode of inheritance for gene: ANOS1 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
Unexplained young onset end-stage renal disease v0.44 ANOS1 Eleanor Williams commented on gene: ANOS1: Note on MOI - PMID: 11297579 - Oliveira et al 2001 - report that "Genetically proven female carriers of KAL mutations in 3 families all had normal pubertal development, with regular menstrual cycles and normal olfaction". They also evaluated three families in which anosmic women gave birth to sons with KS, and none had any mutation in the coding sequence of the KAL gene.

ANOS1 was previously known as KAL1.

Therefore I think the MOI should be X-LINKED: hemizygous mutation in males, biallelic mutations in females as monoallelic females do not appear to present with the relevant phenotype.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 TNFRSF11A Sophie Hambleton commented on gene: TNFRSF11A
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 SAMD9L Sophie Hambleton commented on gene: SAMD9L
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 PTEN Sophie Hambleton reviewed gene: PTEN: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 MBL2 Sophie Hambleton reviewed gene: MBL2: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 LYZ Sophie Hambleton reviewed gene: LYZ: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 SPPL2A Sophie Hambleton reviewed gene: SPPL2A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 RIPK1 Sophie Hambleton reviewed gene: RIPK1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30026316; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 POMP Sophie Hambleton reviewed gene: POMP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29805043; Phenotypes: combined immunodeficiency with autoinflammation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 RASGRP1 Sophie Hambleton reviewed gene: RASGRP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 WDR1 Sophie Hambleton reviewed gene: WDR1: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 USP18 Sophie Hambleton reviewed gene: USP18: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 ORAI1 Sophie Hambleton edited their review of gene: ORAI1: Added comment: As stated below, there is good evidence that AR mutations in this gene cause immunodeficiency; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 ISCA-37433-Loss Sophie Hambleton reviewed Region: ISCA-37433-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 ISCA-37446-Loss Sophie Hambleton reviewed Region: ISCA-37446-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 CSF3R Sophie Hambleton commented on gene: CSF3R: Agree there is good evidence that biallelic variation in this gene causes SCN
Unexplained kidney failure in young people v1.73 FAN1 John Sayer gene: FAN1 was added
gene: FAN1 was added to Unexplained kidney failure in young people. Sources: Expert list
Mode of inheritance for gene: FAN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAN1 were set to 22772369
Phenotypes for gene: FAN1 were set to interstitial nephritis; chronic kidney disease
Penetrance for gene: FAN1 were set to Complete
Review for gene: FAN1 was set to GREEN
Added comment: Important recessive cause of karyomegalic interstitial NEPHRITIS. May mimic nephronophthisis
Sources: Expert list
Likely inborn error of metabolism v1.374 UQCC3 Catherine Snow commented on gene: UQCC3
Likely inborn error of metabolism v1.374 UQCC2 Catherine Snow commented on gene: UQCC2
Likely inborn error of metabolism v1.374 TXN2 Catherine Snow commented on gene: TXN2
Early onset or syndromic epilepsy v1.377 CLN6 Rebecca Foulger Classified gene: CLN6 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.377 CLN6 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber based on Amber review by Tracy Lester and PMID:21549341 (Arsov et al., 2011) where seizures are a consistent feature across families.
Early onset or syndromic epilepsy v1.377 CLN6 Rebecca Foulger Gene: cln6 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.397 TRAP1 Catherine Snow Classified gene: TRAP1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.397 TRAP1 Catherine Snow Gene: trap1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.374 TRAP1 Catherine Snow Mode of inheritance for gene: TRAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.396 TRAP1 Catherine Snow gene: TRAP1 was added
gene: TRAP1 was added to Undiagnosed metabolic disorders. Sources: Expert list
Mode of inheritance for gene: TRAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRAP1 were set to 24152966
Phenotypes for gene: TRAP1 were set to VACTERL; CAKUT
Review for gene: TRAP1 was set to GREEN
Added comment: Not in OMIM or Gene2Phenotype. Recessive mutations reported in 2 families with CAKUT, and 3 families with VACTERL. Metabolism phenotype as the encoded protein has ATPase activity and interacts with tumor necrosis factor type I.
Sources: Expert list
Likely inborn error of metabolism v1.376 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Likely inborn error of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Likely inborn error of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Likely inborn error of metabolism v1.375 TRAP1 Catherine Snow Mode of inheritance for gene: TRAP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from VACTERL; CAKUT to VACTERL; CAKUT
Likely inborn error of metabolism v1.375 TRAP1 Catherine Snow Phenotypes for gene: TRAP1 were changed from to VACTERL; CAKUT
Likely inborn error of metabolism v1.374 TRAP1 Catherine Snow Classified gene: TRAP1 as Green List (high evidence)
Likely inborn error of metabolism v1.374 TRAP1 Catherine Snow Gene: trap1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.374 TRAP1 Catherine Snow Mode of inheritance for gene: TRAP1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.374 TRAP1 Catherine Snow Classified gene: TRAP1 as Green List (high evidence)
Likely inborn error of metabolism v1.374 TRAP1 Catherine Snow Gene: trap1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.373 TRAP1 Catherine Snow reviewed gene: TRAP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24152966; Phenotypes: VACTERL, CAKUT; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.373 OGDH Catherine Snow reviewed gene: OGDH: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Alpha-ketoglutarate dehydrogenase deficiency, 203740; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.376 NDUFS7 Rebecca Foulger Phenotypes for gene: NDUFS7 were changed from to Mitochondrial complex I deficiency, nuclear type 3, 618224
Early onset or syndromic epilepsy v1.375 CLN6 Rebecca Foulger Mode of inheritance for gene: CLN6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.374 CLN6 Rebecca Foulger Publications for gene: CLN6 were set to
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.99 DOK7 Louise Daugherty Added comment: Comment on phenotypes: removed Fetal akinesia deformation sequence 1, 208150- the phenotype is related to variants in the gene MUSK not the gene DOK7
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.99 DOK7 Louise Daugherty Phenotypes for gene: DOK7 were changed from Fetal akinesia deformation sequence 1, 208150; Congenital myasthenic syndrome; Limb-girdle muscular dystrophy to Congenital myasthenic syndrome; Limb-girdle muscular dystrophy
Early onset or syndromic epilepsy v1.373 ALG2 Rebecca Foulger Phenotypes for gene: ALG2 were changed from to ?Congenital disorder of glycosylation type Ii, 607906; Myasthenic syndrome congenital 14 with tubular aggregates, 616228
Early onset or syndromic epilepsy v1.372 ALG2 Rebecca Foulger Mode of inheritance for gene: ALG2 was changed from to BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.98 POGLUT1 Louise Daugherty Phenotypes for gene: POGLUT1 were changed from Limb-girdle muscular dystrophy to Muscular dystrophy, limb-girdle, autosomal recessive 21, 617232
Likely inborn error of metabolism v1.373 NFS1 Catherine Snow edited their review of gene: NFS1: Changed rating: RED
Likely inborn error of metabolism v1.373 NFS1 Catherine Snow commented on gene: NFS1
Likely inborn error of metabolism v1.373 NDUFA13 Catherine Snow reviewed gene: NDUFA13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v1.373 NDUFA13 Catherine Snow Publications for gene: NDUFA13 were set to
Likely inborn error of metabolism v1.372 MRPS7 Catherine Snow reviewed gene: MRPS7: Rating: RED; Mode of pathogenicity: None; Publications: 25556185; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v1.372 MRPS23 Catherine Snow reviewed gene: MRPS23: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger changed review comment from: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).; to: Comment on list classification: Added CLPB to panel based on epilepsy/seizure phenotype on the 'Inborn errors of metabolism' panel. Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Early onset or syndromic epilepsy v1.371 TXN2 Rebecca Foulger commented on gene: TXN2
Early onset or syndromic epilepsy v1.371 MT-CO3 Rebecca Foulger commented on gene: MT-CO3
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger Classified gene: EXT2 as Green List (high evidence)
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger Added comment: Comment on list classification: Relevant phenotype (MIM:616682) and sufficient cases of patients with seizures for inclusion on the panel: (PMIDs 26246518, 30075207, 30997052, 30288735).
Early onset or syndromic epilepsy v1.371 EXT2 Rebecca Foulger Gene: ext2 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.370 CLPB Rebecca Foulger commented on gene: CLPB
Early onset or syndromic epilepsy v1.370 TXN2 Rebecca Foulger gene: TXN2 was added
gene: TXN2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene: TXN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TXN2 were set to 26626369
Phenotypes for gene: TXN2 were set to ?Combined oxidative phosphorylation deficiency 29, 616811; infantile-onset neurodegenerative disorder with severe cerebellar atrophy, epilepsy, dystonia, optic atrophy, and peripheral neuropathy
Early onset or syndromic epilepsy v1.370 MT-CO3 Rebecca Foulger gene: MT-CO3 was added
gene: MT-CO3 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Red
Mode of inheritance for gene gene: MT-CO3 was set to MITOCHONDRIAL
Publications for gene: MT-CO3 were set to 8739943; 12915481
Phenotypes for gene: MT-CO3 were set to seizures
Early onset or syndromic epilepsy v1.370 EXT2 Rebecca Foulger gene: EXT2 was added
gene: EXT2 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: EXT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXT2 were set to 26246518; 30997052; 30288735; 30075207
Phenotypes for gene: EXT2 were set to Seizures, scoliosis, and macrocephaly syndrome, 616682
Early onset or syndromic epilepsy v1.370 CLPB Rebecca Foulger gene: CLPB was added
gene: CLPB was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Green
Mode of inheritance for gene: CLPB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLPB were set to 26916670; 25597510; 25597511
Phenotypes for gene: CLPB were set to Seizures; Generalised epilepsy; 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement and neutropenia, 616271
Undiagnosed metabolic disorders v1.395 MRPL12 Catherine Snow gene: MRPL12 was added
gene: MRPL12 was added to Undiagnosed metabolic disorders. Sources: Expert list
Mode of inheritance for gene: MRPL12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MRPL12 were set to 23603806
Phenotypes for gene: MRPL12 were set to Multiple respiratory chain complex deficiencies (disorders of protein synthesis)
Review for gene: MRPL12 was set to RED
Added comment: A single reported family in the literature therefore classified as Red.
Sources: Expert list
Early onset or syndromic epilepsy v1.369 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995; 22040219; 24561070
Early onset or syndromic epilepsy v1.368 GPHN Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from BIALLELIC to BOTH monoallelic and biallelic. Although OMIM records AR inheritance, a review by Tracy Lester notes PMIDs:24561070, 23393157 who report the association of hemizygous GPHN microdeletions with an epilepsy phenotype. The biallelic and monoallelic MOI matches the MOI of GPHN on the metabolism panels.
Early onset or syndromic epilepsy v1.368 GPHN Rebecca Foulger Mode of inheritance for gene: GPHN was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.394 LYRM4 Catherine Snow gene: LYRM4 was added
gene: LYRM4 was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: LYRM4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LYRM4 were set to 23814038
Phenotypes for gene: LYRM4 were set to ?Combined oxidative phosphorylation deficiency 19, 615595
Review for gene: LYRM4 was set to AMBER
Added comment: LYRM4 is in OMIM but not in Gene2Phenotype. Two related patients in PMID 23814038 and some functional work. As <3 unrelated patients, classifying LYRM4 as Amber.
Sources: Expert Review
Early onset or syndromic epilepsy v1.367 GPHN Rebecca Foulger Publications for gene: GPHN were set to 26613940; 12684523; 11095995
Likely inborn error of metabolism v1.372 LYRM4 Catherine Snow commented on gene: LYRM4
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 SMN1 Chiara Marini Bettolo reviewed gene: SMN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 CASQ1 Chiara Marini Bettolo reviewed gene: CASQ1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 ORAI1 Chiara Marini Bettolo reviewed gene: ORAI1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 STIM1 Chiara Marini Bettolo reviewed gene: STIM1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 TNPO3 Chiara Marini Bettolo reviewed gene: TNPO3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 POGLUT1 Chiara Marini Bettolo commented on gene: POGLUT1: new gene added after analysis. Currently provided by HSS for LGMDin Ncl via LGMD panel. Known form of LGMD2Z or LGMDR21
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 VMA21 Chiara Marini Bettolo edited their review of gene: VMA21: Added comment: XMEA. Differential diagnosis with LGMD (proximal weakness and raised CK) particularly in milder adult onset forms; Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 TTN Chiara Marini Bettolo commented on gene: TTN: Disese spectrum can be very variable from congenital myopathy, cardiomyopathy, distal weakness, HMERF to LGMD. Known form of LGMD2J or LGMDR10
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 TPM3 Chiara Marini Bettolo edited their review of gene: TPM3: Added comment: CAP myopathy, nemaline myopathy, congenital myopathy with fibre type disproportion; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 TPM2 Chiara Marini Bettolo reviewed gene: TPM2: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 TNNT3 Chiara Marini Bettolo edited their review of gene: TNNT3: Added comment: Arthrogryposis (distal); Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 SYNE2 Chiara Marini Bettolo commented on gene: SYNE2: Form of EDMD. Differential diagnosis with AD LGMD. (proximal weakness and raised CK)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 SMCHD1 Chiara Marini Bettolo commented on gene: SMCHD1: FSHD2, differential diagnosis with LGMD.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 SELENON Chiara Marini Bettolo commented on gene: SELENON: Rigid spine syndrome, but not all patients present with rigid spine. Muscle biopsy can range from myoathic to dystrophic. Differential diagnosis with LGMD.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 SCN4A Chiara Marini Bettolo edited their review of gene: SCN4A: Added comment: muscle channelopathy. ; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 RYR1 Chiara Marini Bettolo commented on gene: RYR1: Variable disease spectrum from congenital myopathy, metabolic myopathy, MH. Differential diagnosis with LGMD
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 RAPSN Chiara Marini Bettolo edited their review of gene: RAPSN: Added comment: CMS gene.; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 PYGM Chiara Marini Bettolo commented on gene: PYGM: McArdle's disease. Differential diagnosis with LGMD
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 POMK Chiara Marini Bettolo edited their review of gene: POMK: Added comment: Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), autosomal recessive disorder with congenital muscular dystrophy; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 POMGNT2 Chiara Marini Bettolo commented on gene: POMGNT2: Known form to muscular dystrophy.according to new classification is LGMDR24
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 POLG Chiara Marini Bettolo reviewed gene: POLG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 PHKA1 Chiara Marini Bettolo reviewed gene: PHKA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 PGK1 Chiara Marini Bettolo reviewed gene: PGK1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 PFKM Chiara Marini Bettolo reviewed gene: PFKM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 NEB Chiara Marini Bettolo edited their review of gene: NEB: Added comment: Nemaline myopathy. Variable disease spectrum from severe early onset to milder late onset. Usually CK normal or mildly raised ; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 MYH7 Chiara Marini Bettolo commented on gene: MYH7: Scapuloperoneal syndrome. Variable phenotype fromsevere cardiomyopathy, distal myopathy, proximal and distal myopathy and asymptomatic hyperCKemia.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 MYH14 Chiara Marini Bettolo reviewed gene: MYH14: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 MATR3 Chiara Marini Bettolo edited their review of gene: MATR3: Added comment: Predominantly distal myopathy with vocal cord parlysis and dysphagia. Raised CK; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 LPIN1 Chiara Marini Bettolo commented on gene: LPIN1: Recurrent episodes of myoglobinuria and high CK. Differential diagnosis with LGMD.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 LIMS2 Chiara Marini Bettolo edited their review of gene: LIMS2: Added comment: Rare form of muscular dystrophy; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 LAMP2 Chiara Marini Bettolo commented on gene: LAMP2: Danon disease. Differential diagnosis with LGMD.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 LAMA2 Chiara Marini Bettolo commented on gene: LAMA2: Form of congenital muscular dystrophy, now listed on new LGMD classification as LGMDR23
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 ISPD Chiara Marini Bettolo edited their review of gene: ISPD: Added comment: Known as LGMD 2U or LGMDR20 on new nomenclature; Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 HNRNPDL Chiara Marini Bettolo commented on gene: HNRNPDL: Listed as LGMD D3 on new nomenclature/classification.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 GYG1 Chiara Marini Bettolo reviewed gene: GYG1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 GNE Chiara Marini Bettolo commented on gene: GNE: currently provided through LGMD panel at HSS LGMD in Ncl. Proximal and distal weakness, differential diagnosis with LGMD.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 GFPT1 Chiara Marini Bettolo edited their review of gene: GFPT1: Added comment: CMS gene.; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 GBE1 Chiara Marini Bettolo reviewed gene: GBE1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 ETFDH Chiara Marini Bettolo reviewed gene: ETFDH: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 DPM3 Chiara Marini Bettolo edited their review of gene: DPM3: Added comment: MDDGC15. Rare form of muscular dystrophy with high CK; Changed rating: AMBER
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 DOK7 Chiara Marini Bettolo commented on gene: DOK7: CMS gene, but clinically can present as LGMD
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 DNM2 Chiara Marini Bettolo edited their review of gene: DNM2: Added comment: congenital myopathy; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 DES Chiara Marini Bettolo commented on gene: DES: currently provided through LGMD panel at HSS LGMD in Ncl. Form of myofibrillar myopathy that can present with variable phenotypes from distal weakness, scapuloperoneal weakness and cardiomyopathy and arrythmia
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 DAG1 Chiara Marini Bettolo commented on gene: DAG1: Known form of LGMD2P or LGMDR16
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 CRYAB Chiara Marini Bettolo commented on gene: CRYAB: currently provided through LGMD panel at HSS LGMD in Ncl. Rare form of myofibrillar myopathy
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 CPT2 Chiara Marini Bettolo commented on gene: CPT2: metabolic myoapthy, can present with high CK - differential diagnosis with LGMD
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 COLQ Chiara Marini Bettolo edited their review of gene: COLQ: Added comment: CMS; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 COL12A1 Chiara Marini Bettolo edited their review of gene: COL12A1: Added comment: congenital myopathy; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 CLCN1 Chiara Marini Bettolo edited their review of gene: CLCN1: Added comment: muscle channelopathy. Myotonia congenita; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 CHRND Chiara Marini Bettolo edited their review of gene: CHRND: Added comment: form of CMS; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 BVES Chiara Marini Bettolo edited their review of gene: BVES: Added comment: only reported in one family; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 BAG3 Chiara Marini Bettolo commented on gene: BAG3: currently provided through LGMD panel at HSS LGMD in Ncl. Rare and severe form of myopathy with proximal and distal weakness.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 ATP2A1 Chiara Marini Bettolo edited their review of gene: ATP2A1: Added comment: Brody myopathy; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 AGL Chiara Marini Bettolo edited their review of gene: AGL: Added comment: metabolic myopathy. Glycongen storage disease IIIa/b; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 ACTA1 Chiara Marini Bettolo edited their review of gene: ACTA1: Added comment: congenital myopathy; Changed rating: RED
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.97 ACADVL Chiara Marini Bettolo commented on gene: ACADVL: metabolic myopathy but differential diagnosis with LGMD
Likely inborn error of metabolism v1.372 LYRM4 Catherine Snow Classified gene: LYRM4 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.372 LYRM4 Catherine Snow Gene: lyrm4 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.372 LYRM4 Catherine Snow Classified gene: LYRM4 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.372 LYRM4 Catherine Snow Gene: lyrm4 has been classified as Amber List (Moderate Evidence).
Likely inborn error of metabolism v1.371 LYRM4 Catherine Snow Mode of inheritance for gene: LYRM4 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.370 LYRM4 Catherine Snow Publications for gene: LYRM4 were set to
Likely inborn error of metabolism v1.370 LYRM4 Catherine Snow Mode of inheritance for gene: LYRM4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.393 LARS Catherine Snow Classified gene: LARS as Green List (high evidence)
Undiagnosed metabolic disorders v1.393 LARS Catherine Snow Gene: lars has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow commented on gene: LARS: Added new-gene-name tag, new approved HGNC gene symbol for LARS is LARS1
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow Tag new-gene-name tag was added to gene: LARS.
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow changed review comment from: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to upgrade LARS1 from Red to Green.
Sources: Expert Review; to: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to classify LARS1 as Green.
Sources: Expert Review
Undiagnosed metabolic disorders v1.392 LARS Catherine Snow gene: LARS was added
gene: LARS was added to Undiagnosed metabolic disorders. Sources: Expert Review
Mode of inheritance for gene: LARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LARS were set to 28774368; 30349989; 22607940
Phenotypes for gene: LARS were set to ?Infantile liver failure syndrome 1, 615438
Review for gene: LARS was set to GREEN
Added comment: LARS1 has a relevant phenotype and is in OMIM, but not in Gene2Phenotype. PMID: 30349989 describes a premature girl who was identified to have compound hetrozygous variants in LARS1, this has caused infantile liver failure syndrome, type 1 (ILFS1). The paper also summarised the clinical features of reported patients with infantile liver failure syndrome type 1 caused by cytosolic leucine-tRNA synthetase deficiency, in total 6 compound hetrozygous variants identified in 14 patients in 7 families. Sufficient variants and relevant phenotype to upgrade LARS1 from Red to Green.
Sources: Expert Review
Likely inborn error of metabolism v1.369 LARS Catherine Snow Phenotypes for gene: LARS were changed from ?Infantile liver failure syndrome 1, 615438 to ?Infantile liver failure syndrome 1, 615438
Likely inborn error of metabolism v1.368 LARS Catherine Snow Publications for gene: LARS were set to 28774368; 30349989; 22607940
Likely inborn error of metabolism v1.368 LARS Catherine Snow Phenotypes for gene: LARS were changed from to ?Infantile liver failure syndrome 1, 615438
Likely inborn error of metabolism v1.367 LARS Catherine Snow Publications for gene: LARS were set to
Likely inborn error of metabolism v1.367 LARS Catherine Snow Mode of inheritance for gene: LARS was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.367 LARS Catherine Snow Classified gene: LARS as Green List (high evidence)
Likely inborn error of metabolism v1.367 LARS Catherine Snow Gene: lars has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.366 LARS Catherine Snow reviewed gene: LARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 28774368, 30349989, 22607940; Phenotypes: ?Infantile liver failure syndrome 1, 615438; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.96 SMN1 Louise Daugherty Source NHS GMS was added to SMN1.
Source Yorkshire and North East GLH was added to SMN1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.96 CASQ1 Louise Daugherty Source NHS GMS was added to CASQ1.
Source Yorkshire and North East GLH was added to CASQ1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.96 ORAI1 Louise Daugherty Source NHS GMS was added to ORAI1.
Source Yorkshire and North East GLH was added to ORAI1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.96 STIM1 Louise Daugherty Source NHS GMS was added to STIM1.
Source Yorkshire and North East GLH was added to STIM1.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.96 TNPO3 Louise Daugherty Source NHS GMS was added to TNPO3.
Source Yorkshire and North East GLH was added to TNPO3.
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.95 SMN1 Louise Daugherty gene: SMN1 was added
gene: SMN1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: SMN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SMN1 were set to Spinal muscular atrophy-4, 271150
Review for gene: SMN1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.94 CASQ1 Louise Daugherty gene: CASQ1 was added
gene: CASQ1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: CASQ1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: CASQ1 were set to Myopathy, vacuolar, with CASQ1 aggregates, 616231
Review for gene: CASQ1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.93 ORAI1 Louise Daugherty gene: ORAI1 was added
gene: ORAI1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: ORAI1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: ORAI1 were set to Myopathy, tubular aggregate, 2, 615883
Review for gene: ORAI1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.92 STIM1 Louise Daugherty gene: STIM1 was added
gene: STIM1 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: STIM1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: STIM1 were set to Myopathy, tubular aggregate, 1, 160565
Review for gene: STIM1 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
DDG2P v1.141 DCX Rebecca Foulger Mode of inheritance for gene: DCX was changed from X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
DDG2P v1.140 CASK Rebecca Foulger Mode of inheritance for gene: CASK was changed from X linked: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.91 TNPO3 Louise Daugherty gene: TNPO3 was added
gene: TNPO3 was added to Limb girdle muscular dystrophy. Sources: Expert Review
Mode of inheritance for gene: TNPO3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TNPO3 were set to Muscular dystrophy, limb-girdle, autosomal dominant 2, 608423
Review for gene: TNPO3 was set to AMBER
Added comment: New gene requested to be added to panel by Chiara Marini Bettolo (NUTH) on behalf of Yorkshire North East
Sources: Expert Review
DDG2P v1.139 STAG2 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from XLD to XLR to match 'hemizygous' allelic requirement in Gene2Phenotype.
DDG2P v1.139 STAG2 Rebecca Foulger Mode of inheritance for gene: STAG2 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
DDG2P v1.138 SLC35A2 Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating: confirmed for Epileptic Encephalopathy due to congenital disorder of glycosylation. DDG2P Allelic requirement: x-linked dominant. DDG2P mutation consequence: loss of function.
DDG2P v1.138 SLC35A2 Rebecca Foulger Added comment: Comment on mode of inheritance: Changed mode of inheritance to XLD to match Gene2Phenotype.
DDG2P v1.138 SLC35A2 Rebecca Foulger Mode of inheritance for gene: SLC35A2 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Paediatric disorders v4.258 Rebecca Foulger List of related panels changed from Acutely unwell children with a likely monogenic disorder; Congenital malformation and dysmorphism syndromes - microarray and sequencing to Acutely unwell children with a likely monogenic disorder; Congenital malformation and dysmorphism syndromes - microarray and sequencing; R14; R27
Paroxysmal central nervous system disorders v0.172 GLRA1 Rebecca Foulger Phenotypes for gene: GLRA1 were changed from Hyperekplexia, hereditary 1, 149400 to Hyperekplexia 1, 149400
Paroxysmal central nervous system disorders v0.171 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from Migraine, familial hemiplegic, 2, 602481; Migraine, familial basilar, 602481alternating hemiplegia of childhood 104290 to Migraine, familial hemiplegic, 2, 602481; Migraine, familial basilar, 602481; alternating hemiplegia of childhood 104290
Paroxysmal central nervous system disorders v0.170 ATP1A2 Rebecca Foulger Phenotypes for gene: ATP1A2 were changed from familial basilar migraine 602481; alternating hemiplegia of childhood 104290; familial hemiplegic migraine type 2, 602481 to Migraine, familial hemiplegic, 2, 602481; Migraine, familial basilar, 602481alternating hemiplegia of childhood 104290
Paroxysmal central nervous system disorders v0.169 ATAD1 Rebecca Foulger changed review comment from: Comment on list classification: Upgraded ATAD1 from Amber to Green to match Green rating of other Hyperkeplexia genes (GLRA1, GLRB, SLC6A5). A comment from Robyn Labrum (University College London Hospitals) on behalf of London North GLH for the GMS Neurology specialist test group (received via email, September 30th 2019) notes that Hyperkeplexia genes should be included on the panel if the clinicians agree.; to: Comment on list classification: Upgraded ATAD1 from Amber to Green to match Green rating of other Hyperkeplexia genes (GLRA1, GLRB, SLC6A5). A comment from Robyn Labrum (University College London Hospitals) on behalf of London North GLH for the GMS Neurology specialist test group (received via email, September 30th 2019) notes that Hyperekplexia genes should be included on the panel if the clinicians agree.
Early onset or syndromic epilepsy v1.366 ABAT Rebecca Foulger Publications for gene: ABAT were set to 20052547; 27376954
Paroxysmal central nervous system disorders v0.169 Rebecca Foulger List of related panels changed from Paroxysmal neurological disorders; pain disorders and sleep disorders to Paroxysmal neurological disorders; pain disorders and sleep disorders; R66
Unexplained young onset end-stage renal disease v0.44 CLCN5 Eleanor Williams Added comment: Comment on mode of inheritance: PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate
Unexplained young onset end-stage renal disease v0.44 CLCN5 Eleanor Williams Mode of inheritance for gene: CLCN5 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams changed review comment from: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms of Dents disease so Xlinked (monoalllelic in females) may be more appropriate.; to: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms of Dent disease so Xlinked (monoalllelic in females) may be more appropriate.
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams changed review comment from: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms so Xlinked (monoalllelic in females) may be more appropriate.; to: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms of Dents disease so Xlinked (monoalllelic in females) may be more appropriate.
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams changed review comment from: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females; to: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females. However, PMID: 25907713 reports that female carriers can have mild symptoms so Xlinked (monoalllelic in females) may be more appropriate.
Nephrocalcinosis or nephrolithiasis v1.22 PHEX Eleanor Williams changed review comment from: Associated with Hypophosphatemic rickets, X-linked dominant (#307800)(XLD) in OMIM.

PMID: 31514490 - Şıklar et al 2019 - From 24 centers in Turkey, 166 patients with Hypophosphatemic rickets were included in the study data. Genetic analysis (n:75) showed PHEX mutation in 80% patients (60 patients). 27 patients developed nephrocalcinosis. However, higher treatment dose of phosphate and calcitriol has been detected in nephrocalcinosis group.

PMID: 29460029 - Chesher et al 2018 - clinical records of 59 adult patients from 35 kindreds with X-linked hypophosphatemia attending a single inherited metabolic disease service from 1998 were retrospectively reviewed. All had PHEX mutations (either directly obtained or inferred from the result of a first degree relative). 37 distinct variants were identified (14 not previously reported). Nephrocalcinosis was reported in 16/38 patients (42%) with at least one renal ultrasound performed. Treatment with vitamin D was associated with a small increase in urine calcium but there was no association between the presence or absence of nephrocalcinosis and whether or not the patient was currently being treated with vitamin D.

Will consult with Genomics England Clinical team with regards to nephrocalcinosis being associated with PHEX variants or a result of treatment for Hypophosphatemic rickets.; to: Associated with Hypophosphatemic rickets, X-linked dominant (#307800)(XLD) in OMIM.

PMID: 31514490 - Şıklar et al 2019 - Study of 166 patients with Hypophosphatemic rickets from 24 centers in Turkey. Genetic analysis (n:75) showed PHEX mutation in 80% patients (60 patients). 27 patients developed nephrocalcinosis. However, higher treatment dose of phosphate and calcitriol has been detected in nephrocalcinosis group.

PMID: 29460029 - Chesher et al 2018 - clinical records of 59 adult patients from 35 kindreds with X-linked hypophosphatemia attending a single inherited metabolic disease service from 1998 were retrospectively reviewed. All had PHEX mutations (either directly obtained or inferred from the result of a first degree relative). 37 distinct variants were identified (14 not previously reported). Nephrocalcinosis was reported in 16/38 patients (42%) with at least one renal ultrasound performed. Treatment with vitamin D was associated with a small increase in urine calcium but there was no association between the presence or absence of nephrocalcinosis and whether or not the patient was currently being treated with vitamin D.

Will consult with Genomics England Clinical team with regards to nephrocalcinosis being associated with PHEX variants or a result of treatment for Hypophosphatemic rickets.
Nephrocalcinosis or nephrolithiasis v1.22 HNF4A Eleanor Williams commented on gene: HNF4A
Nephrocalcinosis or nephrolithiasis v1.22 FGF23 Eleanor Williams commented on gene: FGF23
Nephrocalcinosis or nephrolithiasis v1.22 FGF23 Eleanor Williams gene: FGF23 was added
gene: FGF23 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list
Mode of inheritance for gene: FGF23 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Nephrocalcinosis or nephrolithiasis v1.21 PHEX Eleanor Williams reviewed gene: PHEX: Rating: ; Mode of pathogenicity: None; 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)
Nephrocalcinosis or nephrolithiasis v1.21 PHEX Eleanor Williams gene: PHEX was added
gene: PHEX was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list,Literature
Mode of inheritance for gene: PHEX was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Nephrocalcinosis or nephrolithiasis v1.20 ZNF365 Eleanor Williams changed review comment from: Provisional association with {Nephrolithiasis, uric acid, susceptibility to} #605990 in OMIM.
PubMed search did not find any further papers beyond the association study of 2003 (PMID: 12740763)
Keep red rating.; to: Provisional association with {Nephrolithiasis, uric acid, susceptibility to} #605990 in OMIM.
PubMed search did not find any further papers beyond the study of 2003 (PMID: 12740763)
Keep red rating.
Nephrocalcinosis or nephrolithiasis v1.20 ZNF365 Eleanor Williams commented on gene: ZNF365
Nephrocalcinosis or nephrolithiasis v1.20 TRPM6 Eleanor Williams commented on gene: TRPM6
Nephrocalcinosis or nephrolithiasis v1.20 STRADA Eleanor Williams commented on gene: STRADA
Nephrocalcinosis or nephrolithiasis v1.20 SLC2A9 Eleanor Williams changed review comment from: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9) in renal hypouricemic patients who have no URAT1 mutations (R380W and R198C) but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case renal hypouricemia and with variant in SLC2A9 - no nephrolithiasis reported; to: Associated with Hypouricemia, renal, 2 #612076 (AD, AR) in OMIM.

PMID: 19926891 - Dinour et al 2010 - studied two unrelated consanguineous families who had severe hereditary hypouricemia and did not have a URAT1 defect. Both families had homozygous SLC2A9 mutations: A missense mutation (L75R) in six affected members of one family and a 36-kb deletion, resulting in a truncated protein, in the other. Nephrolithiasis was seen in some members of both families.

PMID: 21256783 - Stiburkova et al 2011 - proband and her brother from a Czech family with renal hypouricemia have a one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene resulting in a truncated protein (p.Ile118HisfsX27). The brother showed urolithiasis.

PMID: 19026395 - Matsuo et al 2008 - report two loss-of-function heterozygous mutations in GLUT9 (SLC2A9)(R380W and R198C) in renal hypouricemic patients who have no URAT1 mutations but it is not reported whether they have Nephrocalcinosis/nephrolithiasis.
PMID: 21810765 - 2 cases renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 29486147 - 2 cases with renal hypouricemia and variants in SLC2A9 - no nephrolithiasis reported
PMID: 27116386 - 1 case with renal hypouricemia and variant in SLC2A9 - no nephrolithiasis reported
PMID: 24940677 - 1 case with renal hypouricaemia and variant in SLC2A9 - no mention of nepthrolithiasis

Summary, clear association of variants in SLC2A9 with renal hypouricaemia . 3 cases reported with nepthrolithiasis/urothilthiasis but many more cases where it is not mentioned.
Nephrocalcinosis or nephrolithiasis v1.20 SLC2A9 Eleanor Williams commented on gene: SLC2A9
Nephrocalcinosis or nephrolithiasis v1.20 SLC22A12 Eleanor Williams edited their review of gene: SLC22A12: Changed publications: 29486147, 29958533, 18492088, 15912381; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Nephrocalcinosis or nephrolithiasis v1.20 SLC22A12 Eleanor Williams commented on gene: SLC22A12
Nephrocalcinosis or nephrolithiasis v1.20 HPRT1 Eleanor Williams changed review comment from: Associated with HPRT-related gout #300323 (XLR) and Lesch-Nyhan syndrome #300322 (XLR) in OMIM, both of which have Nephrolithiasis listed as a clinical feature.

HPRT encodes the Hypoxanthine-guanine phosphoribosyltransferase enzyme. Partial deficiency can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome.

PMID: 31129767 - Cho et al 2019 - studied 26 Korean LNS patients from 23 unrelated families. Twenty one of the 23 LNS patients with available data (91.3%) showed renal manifestations such as hyperuricemia, nephrocalcinosis, or urinary stones. 16 patients from 13 families had nephrocalcinosis. Twenty different mutations in HPRT1 were identified from the 23 independent pedigrees.

PMID: 27079129 - Vargiami E et al 2016 - report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.; to: Associated with HPRT-related gout #300323 (XLR) and Lesch-Nyhan syndrome #300322 (XLR) in OMIM, both of which have Nephrolithiasis listed as a clinical feature.

HPRT encodes the Hypoxanthine-guanine phosphoribosyltransferase enzyme. Partial deficiency can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes Lesch-Nyhan syndrome.

PMID: 31129767 - Cho et al 2019 - studied 26 Korean LNS patients from 23 unrelated families. Twenty one of the 23 LNS patients with available data (91.3%) showed renal manifestations such as hyperuricemia, nephrocalcinosis, or urinary stones. 16 patients from 13 families had nephrocalcinosis. Twenty different mutations in HPRT1 were identified from the 23 independent pedigrees.

PMID: 27079129 - Vargiami E et al 2016 - report of two cousins with Lesch-Nyhan syndrome and a confirmed novel HPRT gene mutation: c.65T>C, who both developed nephrocalcinosis and renal failure, findings not been previously published in children with HPRT deficiency.
Nephrocalcinosis or nephrolithiasis v1.20 HPRT1 Eleanor Williams commented on gene: HPRT1
Cerebral vascular malformations v1.48 Louise Daugherty List of related panels changed from Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease to Cerebrovascular disorders; Vein of Galen malformation; Cerebral arteriovenous malformations; Moyamoya disease; R336
Hydrocephalus v2.0 Louise Daugherty promoted panel to version 2.0
Hydrocephalus v1.39 Louise Daugherty List of related panels changed from Hydrocephalus;R86 to Hydrocephalus; R86
Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Holoprosencephaly v2.0 Louise Daugherty promoted panel to version 2.0
Holoprosencephaly v1.24 Louise Daugherty Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; Component Of Super Panel; GMS signed-off
Hereditary spastic paraplegia, childhood onset v2.0 Louise Daugherty promoted panel to version 2.0
Hereditary spastic paraplegia, childhood onset v1.180 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia;R61 to Childhood onset hereditary spastic paraplegia; R61
Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Dilated and arrhythmogenic cardiomyopathy v0.50 FKTN James Eden reviewed gene: FKTN: Rating: AMBER; Mode of pathogenicity: None; Publications: 19015585, 17036286, 27521547; Phenotypes: Cardiomyopathy, dilated, 1X 611615, Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 253800, Muscular dystrophy-dystroglycanopathy (congenital without mental retardation), type B, 4 613152, Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 4 611588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v1.0 Louise Daugherty promoted panel to version 1.0
Hereditary spastic paraplegia, adult onset v0.158 CCT5 Louise Daugherty Mode of inheritance for gene: CCT5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, adult onset v0.157 Louise Daugherty Panel types changed to GMS Rare Disease; GMS signed-off
Congenital myopathy v1.191 VPS33B Louise Daugherty changed review comment from: Comment on list classification: Changed from Amber to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Amber to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 ECEL1 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 MYBPC1 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 PIEZO2 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 TNNT3 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.; to: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 TNNT3 Louise Daugherty Classified gene: TNNT3 as Green List (high evidence)
Congenital myopathy v1.191 TNNT3 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.191 TNNT3 Louise Daugherty Gene: tnnt3 has been classified as Green List (High Evidence).
Congenital myopathy v1.190 VPS33B Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.; to: Comment on list classification: Changed from Amber to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.190 VPS33B Louise Daugherty Classified gene: VPS33B as Green List (high evidence)
Congenital myopathy v1.190 VPS33B Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.190 VPS33B Louise Daugherty Gene: vps33b has been classified as Green List (High Evidence).
Congenital myopathy v1.189 VPS33B Louise Daugherty Publications for gene: VPS33B were set to
Congenital myopathy v1.188 VPS33B Louise Daugherty Mode of inheritance for gene: VPS33B was changed from to BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.187 TNNI2 Louise Daugherty Classified gene: TNNI2 as Green List (high evidence)
Congenital myopathy v1.187 TNNI2 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.187 TNNI2 Louise Daugherty Gene: tnni2 has been classified as Green List (High Evidence).
Congenital myopathy v1.186 PIEZO2 Louise Daugherty Classified gene: PIEZO2 as Green List (high evidence)
Congenital myopathy v1.186 PIEZO2 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.186 PIEZO2 Louise Daugherty Gene: piezo2 has been classified as Green List (High Evidence).
Congenital myopathy v1.185 MYBPC1 Louise Daugherty Classified gene: MYBPC1 as Green List (high evidence)
Congenital myopathy v1.185 MYBPC1 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.185 MYBPC1 Louise Daugherty Gene: mybpc1 has been classified as Green List (High Evidence).
Congenital myopathy v1.184 ECEL1 Louise Daugherty Classified gene: ECEL1 as Green List (high evidence)
Congenital myopathy v1.184 ECEL1 Louise Daugherty Added comment: Comment on list classification: Changed from Red to Green. Gene referred to Genomics England clinical team due to review by the GMS Neurology specialist test group. It was agreed that as this represents a clinical continuum, we should represent the genes on both Congenital myopathy and Arthrogryposis panels as for Genomic Medicine Service it is possible that diagnoses could come from either route so we would not want to miss them. For the 100K Genomes Project participants we tended to apply both Congenital myopathy and Arthrogryposis panels, even though there was a more arbitrary line drawn between contractures / not for allocating genes to a particular panel.
Congenital myopathy v1.184 ECEL1 Louise Daugherty Gene: ecel1 has been classified as Green List (High Evidence).
Arthrogryposis v2.46 ZC4H2 Louise Daugherty Added comment: Comment on mode of inheritance: MOI changed to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as some female carriers also show signs of disease.
Arthrogryposis v2.46 ZC4H2 Louise Daugherty Mode of inheritance for gene: ZC4H2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital myopathy v1.183 ZC4H2 Louise Daugherty Added comment: Comment on mode of inheritance: MOI changed to 'X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)' as some female carriers also show signs of disease.
Congenital myopathy v1.183 ZC4H2 Louise Daugherty Mode of inheritance for gene: ZC4H2 was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Congenital myopathy v1.182 ZC4H2 Louise Daugherty edited their review of gene: ZC4H2: Added comment: After review with Genomics England clinical team this gene was deemed valid to include on the congenital myopathy panel, as affected individuals clearly have muscle weakness. The majority of boys with it have a level of severity that it is onset in utero, leading to contractures. Arthrogryposis and congenital myopathy are a clinical continuum and as long as the neuromuscular group do not disagree, so should on both panels.; Changed rating: GREEN
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies v1.90 Louise Daugherty List of related panels changed from to R82
Nephrocalcinosis or nephrolithiasis v1.20 FAM20A Eleanor Williams Publications for gene: FAM20A were set to
Nephrocalcinosis or nephrolithiasis v1.19 FAM20A Eleanor Williams Phenotypes for gene: FAM20A were changed from to Amelogenesis imperfecta, type IG (enamel-renal syndrome) 204690
Nephrocalcinosis or nephrolithiasis v1.18 FAM20A Eleanor Williams changed review comment from: Associated with Amelogenesis imperfecta, type IG (enamel-renal syndrome) (#204690)(AR) in OMIM and AMELOGENESIS IMPERFECTA AND GINGIVAL FIBROMATOSIS SYNDROME (confirmed, biallelic) in Gene2Phenotype.

PMID: 23468644 - Wang et al 2013 - Characterized three families (from the Carribean, Jordan and Iran) with amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS) and identified, in each case, recessive FAM20A mutations with different variants in each family. Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to Enamel-renal syndrome. Ultrasounds were not possible to obtain from families 1 and 3.

PMID: 30394349 - Dourado et al 2018 - investigated ERS characteristics in 11 patients from 5 Brazilian families.
All showed hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis. A biallelic loss of function variant in FAM20A [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect.

PMID: 28298625 - Kantaputra et al 2017 (Abstract only accessed) - report three patients and their families with findings suggestive of Enamel-renal-gingival syndrome. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications.

PMID: 22732358 - Vogel et al 2012 - two-thirds of Fam20a–/– mice had small kidneys with pitted surfaces, which showed widespread calcification (as well as a dental phenotype)

3 independent cases with nephrocalcinosis plus mouse knockout data. Not full penetrance for the renal phenotype.; to: Associated with Amelogenesis imperfecta, type IG (enamel-renal syndrome) (#204690)(AR) in OMIM and AMELOGENESIS IMPERFECTA AND GINGIVAL FIBROMATOSIS SYNDROME (confirmed, biallelic) in Gene2Phenotype.

PMID: 23468644 - Wang et al 2013 - Characterized three families (from the Caribbean, Jordan and Iran) with amelogenesis imperfecta and gingival fibromatosis syndrome (AIGFS) and identified, in each case, recessive FAM20A mutations with different variants in each family. Significantly, a kidney ultrasound of the family 2 proband revealed nephrocalcinosis, revising the diagnosis from AIGFS to Enamel-renal syndrome. Ultrasounds were not possible to obtain from families 1 and 3.

PMID: 30394349 - Dourado et al 2018 - investigated ERS characteristics in 11 patients from 5 Brazilian families.
All showed hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis. A biallelic loss of function variant in FAM20A [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect.

PMID: 28298625 - Kantaputra et al 2017 (Abstract only accessed) - report three patients and their families with findings suggestive of Enamel-renal-gingival syndrome. Mutation analysis of FAM20A was performed in all patients and their family members. Patients with homozygous frameshift and compound heterozygous mutations in FAM20A had typical clinical findings along with periodontitis. The other had a novel homozygous missense mutation in exon 10, mild gingival fibromatosis and renal calcifications.

PMID: 22732358 - Vogel et al 2012 - two-thirds of Fam20a–/– mice had small kidneys with pitted surfaces, which showed widespread calcification (as well as a dental phenotype)

3 independent cases with nephrocalcinosis plus mouse knockout data. Not full penetrance for the renal phenotype.
Nephrocalcinosis or nephrolithiasis v1.18 FAM20A Eleanor Williams commented on gene: FAM20A
Congenital myopathy v1.182 TNNC2 Louise Daugherty changed review comment from: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26924529 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene TRIP4, but for TNNC2 the publication field was blank (no data was supplied as evidence). The Green review rating for TNNC2 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.; to: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26924529 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene TRIP4, but for TNNC2 the publication field was blank (no data was supplied as evidence). The Green review rating for TNNC2 is the rating given by London South GLH. There is currently not enough evidence to support a Amber rating.
Congenital myopathy v1.182 TNNC2 Louise Daugherty commented on gene: TNNC2: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26924529 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene TRIP4, but for TNNC2 the publication field was blank (no data was supplied as evidence). The Green review rating for TNNC2 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Congenital myopathy v1.182 MYL1 Louise Daugherty edited their review of gene: MYL1: Changed rating: GREEN
Congenital myopathy v1.182 MYPN Louise Daugherty edited their review of gene: MYPN: Changed rating: GREEN
Undiagnosed metabolic disorders v1.391 TTC37 Catherine Snow Publications for gene: TTC37 were set to 27604308
Undiagnosed metabolic disorders v1.390 TTC37 Catherine Snow Classified gene: TTC37 as Green List (high evidence)
Undiagnosed metabolic disorders v1.390 TTC37 Catherine Snow Gene: ttc37 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.389 TTC37 Catherine Snow reviewed gene: TTC37: Rating: GREEN; Mode of pathogenicity: None; Publications: 25976726, 28292286, 31132033; Phenotypes: Trichohepatoenteric syndrome 1, 222470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.366 TTC37 Catherine Snow Classified gene: TTC37 as Green List (high evidence)
Likely inborn error of metabolism v1.366 TTC37 Catherine Snow Gene: ttc37 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.365 TTC37 Catherine Snow Publications for gene: TTC37 were set to 27604308
Likely inborn error of metabolism v1.364 TTC37 Catherine Snow reviewed gene: TTC37: Rating: GREEN; Mode of pathogenicity: None; Publications: 25976726, 28292286, 31132033; Phenotypes: Trichohepatoenteric syndrome 1, 222470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.182 MYH8 Louise Daugherty Phenotypes for gene: MYH8 were changed from Trismus-pseudocamptodactyly syndrome 158300 to Trismus-pseudocamptodactyly syndrome, 158300
Congenital myopathy v1.181 ACTN2 Louise Daugherty Deleted their comment
Congenital myopathy v1.181 ACTN2 Louise Daugherty Classified gene: ACTN2 as Green List (high evidence)
Congenital myopathy v1.181 ACTN2 Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (with functional work), and external review comment all support gene-disease association.
Congenital myopathy v1.181 ACTN2 Louise Daugherty Gene: actn2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.364 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Likely inborn error of metabolism v1.364 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308; 21907012; 23252400; 31584066
Likely inborn error of metabolism v1.363 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308
Likely inborn error of metabolism v1.363 ST3GAL3 Catherine Snow Classified gene: ST3GAL3 as Green List (high evidence)
Likely inborn error of metabolism v1.363 ST3GAL3 Catherine Snow Gene: st3gal3 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.389 ST3GAL3 Catherine Snow Publications for gene: ST3GAL3 were set to 27604308
Undiagnosed metabolic disorders v1.388 ST3GAL3 Catherine Snow Classified gene: ST3GAL3 as Green List (high evidence)
Undiagnosed metabolic disorders v1.388 ST3GAL3 Catherine Snow Gene: st3gal3 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.387 ST3GAL3 Catherine Snow reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907012, 23252400, 31584066; Phenotypes: Epileptic encephalopathy, early infantile, 15, 615006: Mental retardation, autosomal recessive 12, 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.362 ST3GAL3 Catherine Snow reviewed gene: ST3GAL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 21907012, 23252400, 31584066; Phenotypes: Epileptic encephalopathy, early infantile, 15, 615006: Mental retardation, autosomal recessive 12, 611090; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.180 LAMP2 Louise Daugherty Phenotypes for gene: LAMP2 were changed from vacuolar myopathy? to vacuolar myopathy?; Danon disease, 300257
Congenital myopathy v1.179 MTMR14 Louise Daugherty Phenotypes for gene: MTMR14 were changed from centronuclear myopathy to centronuclear myopathy; Centronuclear myopathy, autosomal, modifier of, 160150
Congenital myopathy v1.178 MYBPC3 Louise Daugherty Phenotypes for gene: MYBPC3 were changed from myopathy and cardiomyopathy to myopathy and cardiomyopathy; Cardiomyopathy, hypertrophic, 4, 115197
Congenital myopathy v1.177 MYL1 Louise Daugherty Classified gene: MYL1 as Green List (high evidence)
Congenital myopathy v1.177 MYL1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. New evidence PMID: 30215711 (2018) In 2 unrelated patients, each born of consanguineous Turkish parents, with congenital myopathy with fast-twitch (type II) fiber atrophy. Also a Zebrafish model indicated that myl1 is required for the normal formation and maintenance of myofibers.
Congenital myopathy v1.177 MYL1 Louise Daugherty Gene: myl1 has been classified as Green List (High Evidence).
Congenital myopathy v1.176 MYL1 Louise Daugherty Publications for gene: MYL1 were set to 21063730
Congenital myopathy v1.175 MYL1 Louise Daugherty Phenotypes for gene: MYL1 were changed from congenital myopathy to congenital myopathy; Myopathy, congenital, with fast-twitch (type II) fiber atrophy, 618414
Congenital myopathy v1.174 MYPN Louise Daugherty Classified gene: MYPN as Green List (high evidence)
Congenital myopathy v1.174 MYPN Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.174 MYPN Louise Daugherty Gene: mypn has been classified as Green List (High Evidence).
Congenital myopathy v1.173 ZC4H2 Louise Daugherty Classified gene: ZC4H2 as Green List (high evidence)
Congenital myopathy v1.173 ZC4H2 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red to Green based on recommendation from Guy's Hospital. Sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene as Green.
Congenital myopathy v1.173 ZC4H2 Louise Daugherty Gene: zc4h2 has been classified as Green List (High Evidence).
Congenital myopathy v1.172 ZC4H2 Louise Daugherty Publications for gene: ZC4H2 were set to 23623388, 26056227
Congenital myopathy v1.171 ECEL1 Louise Daugherty Publications for gene: ECEL1 were set to 23261301
Undiagnosed metabolic disorders v1.387 TH Catherine Snow reviewed gene: TH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753243; Phenotypes: Segawa syndrome, recessive, 605407; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myopathy v1.170 DOK7 Louise Daugherty Publications for gene: DOK7 were set to 15689448
Congenital myopathy v1.169 DMPK Louise Daugherty reviewed gene: DMPK: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Likely inborn error of metabolism v1.362 TH Catherine Snow Tag treatable tag was added to gene: TH.
Likely inborn error of metabolism v1.362 TREX1 Catherine Snow edited their review of gene: TREX1: Changed phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive, 225750
Congenital myopathy v1.169 ACTN2 Louise Daugherty changed review comment from: Comment on list classification: Changed rating from Red toProvisional Amber rating, this gene could be Green but given the discrepant ratings, this gene needs to be discussed by the Neurology Test Group to confirm; to: Comment on list classification: Changed rating from Red to provisional Amber rating. This gene could be Green based on cases and functional evidence but given the discrepant ratings this gene needs to be discussed by the Neurology Test Group to confirm.
Likely inborn error of metabolism v1.362 WFS1 Catherine Snow edited their review of gene: WFS1: Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Congenital myopathy v1.169 ACTN2 Louise Daugherty Classified gene: ACTN2 as Amber List (moderate evidence)
Congenital myopathy v1.169 ACTN2 Louise Daugherty Added comment: Comment on list classification: Changed rating from Red toProvisional Amber rating, this gene could be Green but given the discrepant ratings, this gene needs to be discussed by the Neurology Test Group to confirm
Congenital myopathy v1.169 ACTN2 Louise Daugherty Gene: actn2 has been classified as Amber List (Moderate Evidence).
Congenital myopathy v1.168 ACTN2 Louise Daugherty Phenotypes for gene: ACTN2 were changed from Multiple structured Core Disease to Multiple structured Core Disease; progressive early-onset muscle weakness
Congenital myopathy v1.167 ACTN2 Louise Daugherty Publications for gene: ACTN2 were set to 24692096
Hereditary neuropathy v1.334 Antonio Rueda removed STR:NOP56_GGCCTGTT from the panel
Congenital myopathy v1.166 SRPK3 Louise Daugherty changed review comment from: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446
is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.; to: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446 is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Congenital myopathy v1.166 SRPK3 Louise Daugherty commented on gene: SRPK3: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 26799446
is incorrect. The original file from London South GLH correctly associates PMID: 26799446 to the gene RYR1, but for SRPK3 the publication field was blank (no data was supplied as evidence). The Green review rating for SRPK3 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Congenital myopathy v1.166 KLHL9 Louise Daugherty commented on gene: KLHL9: Note : The review uploaded on behalf of Rachael Mein (Viapath at Guy's Hospital) publication PMID: 23746549 is incorrect. The original file from London South GLH correctly associates PMID: 23746549 to the gene KLHL40, but for KLHL9 the publication field was blank (no data was supplied as evidence). The Green review rating for KLHL9 is the rating given by London South GLH. There is currently not enough evidence to support a Green rating. Rating to be discussed by the Neurology Test Group to confirm rating.
Undiagnosed metabolic disorders v1.387 WFS1 Catherine Snow Publications for gene: WFS1 were set to 27604308
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Classified gene: WFS1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Added comment: Comment on list classification: Promoted from Amber to Green. WFS1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.386 WFS1 Catherine Snow Gene: wfs1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.362 WFS1 Catherine Snow Publications for gene: WFS1 were set to 27604308
Likely inborn error of metabolism v1.361 WFS1 Catherine Snow Classified gene: WFS1 as Green List (high evidence)
Likely inborn error of metabolism v1.361 WFS1 Catherine Snow Gene: wfs1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.360 WFS1 Catherine Snow reviewed gene: WFS1: Rating: GREEN; Mode of pathogenicity: None; Publications: 30171196; Phenotypes: Wolfram syndrome 1, 222300, Wolfram-like syndrome, autosomal dominant, 614296, Diabetes mellitus, noninsulin-dependent, association with, 125853; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.70 UNC13A Louise Daugherty edited their review of gene: UNC13A: Changed rating: RED
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow changed review comment from: Comment on list classification: Promoted from Amber to Green. PTS is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: Comment on list classification: Promoted from Amber to Green. VKORC1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow Classified gene: VKORC1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.385 VKORC1 Catherine Snow Gene: vkorc1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.384 VKORC1 Catherine Snow reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, 607473, Warfarin resistance, 122700; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.70 SYT15 Louise Daugherty changed review comment from: New gene added by reviewer. Rated as Red awaiting more information on this gene and potential disease association. gene-phenotype not listed in OMIM not publications to date supporting gene-disease association.; to: New gene added by reviewer. Rated as Red awaiting more information on this gene and potential disease association. gene-phenotype not listed in OMIM not publications to date supporting gene-disease association. To be highlighted to Test Group for further review due to potential research results
Likely inborn error of metabolism v1.360 VKORC1 Catherine Snow Classified gene: VKORC1 as Green List (high evidence)
Likely inborn error of metabolism v1.360 VKORC1 Catherine Snow Gene: vkorc1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.359 VKORC1 Catherine Snow reviewed gene: VKORC1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Vitamin K-dependent clotting factors, combined deficiency of, 2, 607473, Warfarin resistance, 122700; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.70 SNAP25 Louise Daugherty edited their review of gene: SNAP25: Added comment: Leave as Red, awaiting more information on this gene and potential disease association.; Changed rating: RED
Congenital myaesthenic syndrome v1.70 LAMA5 Louise Daugherty commented on gene: LAMA5: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.70 CACNA1A Louise Daugherty commented on gene: CACNA1A: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.70 LAMA5 Louise Daugherty edited their review of gene: LAMA5: Changed rating: RED
Congenital myaesthenic syndrome v1.70 CACNA1A Louise Daugherty edited their review of gene: CACNA1A: Changed rating: RED
Congenital myaesthenic syndrome v1.70 RYR1 Louise Daugherty Phenotypes for gene: RYR1 were changed from RYR1-related congenital myopathy with fatigable weakness to RYR1-related congenital myopathy
Congenital myaesthenic syndrome v1.69 RYR1 Louise Daugherty Publications for gene: RYR1 were set to 24951453; 30808424; 30406384
Congenital myaesthenic syndrome v1.68 RYR1 Louise Daugherty Publications for gene: RYR1 were set to 24951453; 30808424
Congenital myaesthenic syndrome v1.67 RYR1 Louise Daugherty Phenotypes for gene: RYR1 were changed from to RYR1-related congenital myopathy with fatigable weakness
Congenital myaesthenic syndrome v1.66 LAMA5 Louise Daugherty Phenotypes for gene: LAMA5 were changed from to myopia, facial tics, and failure of neuromuscular transmission
Congenital myaesthenic syndrome v1.65 CACNA1A Louise Daugherty Publications for gene: CACNA1A were set to
Congenital myaesthenic syndrome v1.64 CACNA1A Louise Daugherty Phenotypes for gene: CACNA1A were changed from episodic ataxia plus myasthenic syndrome to episodic ataxia plus myasthenic syndrome; hemiplegic migraine plus disturbed NMJ function
Congenital myaesthenic syndrome v1.63 CACNA1A Louise Daugherty Phenotypes for gene: CACNA1A were changed from to episodic ataxia plus myasthenic syndrome
Congenital myaesthenic syndrome v1.62 CACNA1A Louise Daugherty Mode of inheritance for gene: CACNA1A was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Congenital myaesthenic syndrome v1.61 MYO9A Louise Daugherty edited their review of gene: MYO9A: Changed rating: GREEN
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty edited their review of gene: VAMP1: Changed rating: GREEN
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty Classified gene: VAMP1 as Green List (high evidence)
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (new publication PMID: 28168212) plus animal model and external review comment all support gene-disease association.
Congenital myaesthenic syndrome v1.61 VAMP1 Louise Daugherty Gene: vamp1 has been classified as Green List (High Evidence).
Congenital myaesthenic syndrome v1.60 TOR1AIP1 Louise Daugherty edited their review of gene: TOR1AIP1: Added comment: Applicable to panel, but currently not enough evidence to support Amber/Green rating; Changed rating: RED
Congenital myaesthenic syndrome v1.60 TOR1AIP1 Louise Daugherty Publications for gene: TOR1AIP1 were set to
Congenital myaesthenic syndrome v1.59 TOR1AIP1 Louise Daugherty Phenotypes for gene: TOR1AIP1 were changed from to Muscular dystrophy, autosomal recessive, with rigid spine and distal joint contractures, 617072
Congenital myaesthenic syndrome v1.58 RYR1 Louise Daugherty Publications for gene: RYR1 were set to 24951453
Congenital myaesthenic syndrome v1.57 RYR1 Louise Daugherty changed review comment from: Leave as Red, awaiting more information on this gene and potential disease association.; to: Leave as Red, awaiting more information on this gene and potential disease association. From Orphanet review: GeneReview PMID: 30808424 : Primary myopathies may go along with secondary transmission disease, which does not represent congential CMS, such as in patients with congenital myopathy due to TPM2 mutations, or patients carrying mutations in KLHL40, BIN1, DNM2, MTM1, TPM3, or RYR1. Importantly, secondary transmission disease frequently responds beneficially to AchEI.
Congenital myaesthenic syndrome v1.57 RYR1 Louise Daugherty edited their review of gene: RYR1: Changed rating: RED
Congenital myaesthenic syndrome v1.57 SYT15 Louise Daugherty edited their review of gene: SYT15: Changed rating: RED
Congenital myaesthenic syndrome v1.57 SYT15 Louise Daugherty commented on gene: SYT15: New gene added by reviewer. Rated as Red awaiting more information on this gene and potential disease association. gene-phenotype not listed in OMIM not publications to date supporting gene-disease association.
Congenital myaesthenic syndrome v1.57 SLC25A1 Louise Daugherty Classified gene: SLC25A1 as Amber List (moderate evidence)
Congenital myaesthenic syndrome v1.57 SLC25A1 Louise Daugherty Added comment: Comment on list classification: New gene added by reviewer. Rated as Amber, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.57 SLC25A1 Louise Daugherty Gene: slc25a1 has been classified as Amber List (Moderate Evidence).
Congenital myaesthenic syndrome v1.56 RYR1 Louise Daugherty commented on gene: RYR1: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.56 PREPL Louise Daugherty edited their review of gene: PREPL: Changed rating: RED
Congenital myaesthenic syndrome v1.56 PREPL Louise Daugherty commented on gene: PREPL: Leave as Red, awaiting more information on this gene and potential disease association.
Congenital myaesthenic syndrome v1.56 MYO9A Louise Daugherty Publications for gene: MYO9A were set to 29462312; 27259756
Congenital myaesthenic syndrome v1.55 MYO9A Louise Daugherty Classified gene: MYO9A as Green List (high evidence)
Congenital myaesthenic syndrome v1.55 MYO9A Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (with functional work), and external review comment all support gene-disease association.
Congenital myaesthenic syndrome v1.55 MYO9A Louise Daugherty Gene: myo9a has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.384 VIPAS39 Catherine Snow Classified gene: VIPAS39 as Green List (high evidence)
Undiagnosed metabolic disorders v1.384 VIPAS39 Catherine Snow Gene: vipas39 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.383 VIPAS39 Catherine Snow reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 22753090, 26808426; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.54 LAMB2 Louise Daugherty edited their review of gene: LAMB2: Changed rating: RED
Likely inborn error of metabolism v1.359 VIPAS39 Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. VIPAS39 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. VIPAS39 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >23 cases in literature. Therefore, enough evidence for this gene to be promoted to Green status.
Likely inborn error of metabolism v1.359 VIPAS39 Catherine Snow Publications for gene: VIPAS39 were set to 27604308
Congenital myaesthenic syndrome v1.54 LAMB2 Louise Daugherty commented on gene: LAMB2: Leave as Red, awaiting more information on this gene and potential disease association.
Likely inborn error of metabolism v1.358 VIPAS39 Catherine Snow Classified gene: VIPAS39 as Green List (high evidence)
Likely inborn error of metabolism v1.358 VIPAS39 Catherine Snow Gene: vipas39 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.357 VIPAS39 Catherine Snow reviewed gene: VIPAS39: Rating: GREEN; Mode of pathogenicity: None; Publications: 22753090, 26808426; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 2, 613404; Mode of inheritance: None
Congenital myaesthenic syndrome v1.54 ALG2 Louise Daugherty Classified gene: ALG2 as Green List (high evidence)
Congenital myaesthenic syndrome v1.54 ALG2 Louise Daugherty Added comment: Comment on list classification: Upgraded from Amber to Green. Appropriate phenotypes, sufficient cases (with functional work), and external review comment all support gene-disease association.
Congenital myaesthenic syndrome v1.54 ALG2 Louise Daugherty Gene: alg2 has been classified as Green List (High Evidence).
Inherited polyposis and early onset colorectal cancer - germline testing v1.0 Rebecca Foulger promoted panel to version 1.0
Inherited polyposis and early onset colorectal cancer - germline testing v0.56 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Inherited pancreatic cancer v1.0 Rebecca Foulger promoted panel to version 1.0
Inherited pancreatic cancer v0.42 STK11 Rebecca Foulger Publications for gene: STK11 were set to
Inherited pancreatic cancer v0.41 PRSS1 Rebecca Foulger Publications for gene: PRSS1 were set to
Inherited pancreatic cancer v0.40 PMS2 Rebecca Foulger Publications for gene: PMS2 were set to
Inherited pancreatic cancer v0.39 MSH6 Rebecca Foulger Publications for gene: MSH6 were set to
Inherited pancreatic cancer v0.38 MSH2 Rebecca Foulger Publications for gene: MSH2 were set to
Inherited pancreatic cancer v0.37 MLH1 Rebecca Foulger Publications for gene: MLH1 were set to
Inherited pancreatic cancer v0.36 CDK4 Rebecca Foulger Publications for gene: CDK4 were set to
Inherited pancreatic cancer v0.35 BRCA1 Rebecca Foulger Publications for gene: BRCA1 were set to
Inherited pancreatic cancer v0.34 PALB2 Rebecca Foulger Publications for gene: PALB2 were set to
Undiagnosed metabolic disorders v1.383 VPS33B Catherine Snow Publications for gene: VPS33B were set to 27604308
Undiagnosed metabolic disorders v1.382 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Undiagnosed metabolic disorders v1.382 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Inherited pancreatic cancer v0.33 CDKN2A Rebecca Foulger Publications for gene: CDKN2A were set to
Inherited pancreatic cancer v0.32 BRCA2 Rebecca Foulger Publications for gene: BRCA2 were set to
Undiagnosed metabolic disorders v1.381 VPS33B Catherine Snow reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18853461; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1, 208085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited pancreatic cancer v0.31 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Likely inborn error of metabolism v1.357 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Likely inborn error of metabolism v1.357 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.356 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Likely inborn error of metabolism v1.356 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.356 VPS33B Catherine Snow Classified gene: VPS33B as Green List (high evidence)
Likely inborn error of metabolism v1.356 VPS33B Catherine Snow Gene: vps33b has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.356 VPS33B Catherine Snow Publications for gene: VPS33B were set to 27604308
Likely inborn error of metabolism v1.355 VPS33B Catherine Snow reviewed gene: VPS33B: Rating: GREEN; Mode of pathogenicity: None; Publications: 18853461; Phenotypes: Arthrogryposis, renal dysfunction, and cholestasis 1, 208085; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Inherited renal cancer v1.0 Rebecca Foulger promoted panel to version 1.0
Inherited renal cancer v0.50 Rebecca Foulger Panel types changed to GMS Rare Disease; GMS signed-off
Inherited renal cancer v0.49 TMEM127 Rebecca Foulger Publications for gene: TMEM127 were set to PMID: 24334765
Inherited renal cancer v0.48 SDHD Rebecca Foulger Publications for gene: SDHD were set to PMID: 27899189
Inherited renal cancer v0.47 SDHC Rebecca Foulger Publications for gene: SDHC were set to PMID: 27899189
Inherited renal cancer v0.46 MITF Rebecca Foulger Publications for gene: MITF were set to PMID: 27899189
Inherited renal cancer v0.45 VHL Rebecca Foulger Publications for gene: VHL were set to PMID: 27899189
Inherited renal cancer v0.44 SDHB Rebecca Foulger Publications for gene: SDHB were set to PMID: 27899189
Inherited renal cancer v0.43 MET Rebecca Foulger Publications for gene: MET were set to PMID: 27899189
Inherited renal cancer v0.42 FLCN Rebecca Foulger Publications for gene: FLCN were set to PMID: 27899189
Kabuki syndrome v1.2 PQBP1 Cristina Dias gene: PQBP1 was added
gene: PQBP1 was added to Kabuki syndrome. Sources: Literature
Mode of inheritance for gene: PQBP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PQBP1 were set to 30244542
Phenotypes for gene: PQBP1 were set to intellectual disability; long triangular face; bulbous nose; hypoplastic malar region; micrognathia; partial agenesis of corpus callosum; spasticity; contractures
Penetrance for gene: PQBP1 were set to unknown
Review for gene: PQBP1 was set to RED
Added comment: Kabuki-like features reported in Abdel-Salam et al, 2018 (PMID 30244542)
Sources: Literature
Additional findings health related v0.76 CFTR Ellen McDonagh Classified gene: CFTR as No list
Additional findings health related v0.76 CFTR Ellen McDonagh Added comment: Comment on list classification: A seperate panel will be used for analysis of this gene.
Additional findings health related v0.76 CFTR Ellen McDonagh Gene: cftr has been removed from the panel.
Additional findings reproductive carrier status v0.2 CFTR Ellen McDonagh Classified gene: CFTR as Green List (high evidence)
Additional findings reproductive carrier status v0.2 CFTR Ellen McDonagh Gene: cftr has been classified as Green List (High Evidence).
Additional findings reproductive carrier status v0.1 CFTR Ellen McDonagh gene: CFTR was added
gene: CFTR was added to Additional findings reproductive carrier status. Sources: Expert list
Mode of inheritance for gene: CFTR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: CFTR were set to ENST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only
Additional findings reproductive carrier status v0.0 Ellen McDonagh Added Panel Additional findings reproductive carrier status
Additional findings health related v0.75 Ellen McDonagh Panel name changed from Genomics England Additional Findings to Additional findings health related
Likely inborn error of metabolism v1.355 UROC1 Catherine Snow Publications for gene: UROC1 were set to 27604308
Likely inborn error of metabolism v1.354 UROC1 Catherine Snow reviewed gene: UROC1: Rating: AMBER; Mode of pathogenicity: None; Publications: 19304569, 30619714; Phenotypes: ?Urocanase deficiency, 276880; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital myaesthenic syndrome v1.53 Louise Daugherty List of related panels changed from Congenital myaesthenia; Congenital myasthenia to Congenital myaesthenia; Congenital myasthenia; R80
Early onset or syndromic epilepsy v1.365 ADAR Rebecca Foulger Publications for gene: ADAR were set to
Early onset or syndromic epilepsy v1.364 KCNJ11 Rebecca Foulger changed review comment from: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plu review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.; to: Comment on mode of inheritance: Most KCNJ11 seizure patients have heterozygous variants but PMID:27181099 report a patient with a homozygous variant in KCNJ11 (p.F315I) and congenital hyperinsulinism. The authors say the patient had severe hypoglycemia and seizure following birth, but no further seizure details are given. OMIM disorder 'Diabetes, permanent neonatal, with or without neurologic features (MIM:606176) has both AR and AD inheritance recorded. Therefore based on PMID:27181099 plus OMIM plus review by West Midlands, Oxford and Wessex GLH, have updated MOI from 'monoallelic' to 'BOTH monoallelic and biallelic'.
Undiagnosed metabolic disorders v1.381 UQCRB Catherine Snow Classified gene: UQCRB as Green List (high evidence)
Undiagnosed metabolic disorders v1.381 UQCRB Catherine Snow Gene: uqcrb has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.380 UQCRB Catherine Snow reviewed gene: UQCRB: Rating: GREEN; Mode of pathogenicity: None; Publications: 25446085 28604960 12709789 23454382; Phenotypes: Mitochondrial complex III deficiency, nuclear type 3, 615158; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.354 UQCRB Catherine Snow commented on gene: UQCRB
Congenital muscular dystrophy v1.68 PLEC Louise Daugherty Classified gene: PLEC as Green List (high evidence)
Congenital muscular dystrophy v1.68 PLEC Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Congenital muscular dystrophy v1.68 PLEC Louise Daugherty Gene: plec has been classified as Green List (High Evidence).
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty changed review comment from: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.; to: Added publications to support green rating. PMID: 28447722 second report on plectin associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel. From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.
Undiagnosed metabolic disorders v1.380 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow edited their review of gene: UMOD: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow changed review comment from: Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow Classified gene: UMOD as Green List (high evidence)
Undiagnosed metabolic disorders v1.379 UMOD Catherine Snow Gene: umod has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.354 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308; 31422399; 29180396
Likely inborn error of metabolism v1.354 UMOD Catherine Snow Publications for gene: UMOD were set to 27604308
Likely inborn error of metabolism v1.354 UMOD Catherine Snow Classified gene: UMOD as Green List (high evidence)
Likely inborn error of metabolism v1.354 UMOD Catherine Snow Gene: umod has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.378 UMOD Catherine Snow reviewed gene: UMOD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422399, 29180396; Phenotypes: Hyperuricemic nephropathy, familial juvenile 1, 162000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Likely inborn error of metabolism v1.353 UMOD Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. UMOD is associated with an appropriate phenotype on OMIM but not in Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty Deleted their comment
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty changed review comment from: From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.; to: From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty commented on gene: PLEC: From PMID: 20624679: report a boy presenting from birth with features of a congenital muscular dystrophy and late-onset myasthenic symptoms.
Likely inborn error of metabolism v1.353 UMOD Catherine Snow reviewed gene: UMOD: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422399, 29180396; Phenotypes: Hyperuricemic nephropathy, familial juvenile 1, 162000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty changed review comment from: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.; to: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty Classified gene: PLEC as Amber List (moderate evidence)
Congenital muscular dystrophy v1.67 PLEC Louise Daugherty Gene: plec has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty commented on gene: PLEC: Added publication to support second report on plectin‑associated Limb-girdle muscular dystrophy 2Q without other symptoms, although the genotype identified was novel- Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty Deleted their comment
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty Added comment: Comment on publications: added further publications to support the Green rating
Congenital muscular dystrophy v1.66 PLEC Louise Daugherty Publications for gene: PLEC were set to 21109228
Undiagnosed metabolic disorders v1.378 TUFM Catherine Snow Classified gene: TUFM as Green List (high evidence)
Undiagnosed metabolic disorders v1.378 TUFM Catherine Snow Gene: tufm has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow edited their review of gene: TUFM: Changed phenotypes: Combined oxidative phosphorylation deficiency 4, 610678
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow edited their review of gene: TUFM: Changed publications: 28132884, 25735936, 17160893, 26741492
Undiagnosed metabolic disorders v1.377 TUFM Catherine Snow reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: 28132884, 25735936, 17160893, 26741492; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v1.65 PLEC Louise Daugherty Deleted their comment
Congenital muscular dystrophy v1.65 PLEC Louise Daugherty commented on gene: PLEC: Only one case reported with variants in this gene and CMD, provisionally rated Red pending further cases or expert opinion.
Congenital muscular dystrophy v1.65 DPM1 Louise Daugherty commented on gene: DPM1: Only one case reported with variants in this gene and CMD, not sure it fulfils the criteria to be a green gene. Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.65 DPM3 Louise Daugherty commented on gene: DPM3: Only one case reported with variants in this gene and CMD, not sure it fulfils the criteria to be a green gene. Provisional rated Amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.65 DPM3 Louise Daugherty Phenotypes for gene: DPM3 were changed from congenital muscular dystrophies; Congenital disorder of glycosylation, type Io 612937 to congenital muscular dystrophies; Congenital disorder of glycosylation, type Io, 612937'Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 15, 612937
Likely inborn error of metabolism v1.353 TUFM Catherine Snow changed review comment from: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Likely inborn error of metabolism v1.353 TUFM Catherine Snow reviewed gene: TUFM: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Undiagnosed metabolic disorders v1.377 TTPA Catherine Snow Publications for gene: TTPA were set to 27604308
Undiagnosed metabolic disorders v1.376 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Undiagnosed metabolic disorders v1.376 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.375 TTPA Catherine Snow reviewed gene: TTPA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ataxia with isolated vitamin E deficiency, 277460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.353 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Likely inborn error of metabolism v1.353 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.353 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Likely inborn error of metabolism v1.353 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.353 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Likely inborn error of metabolism v1.353 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.352 TTPA Catherine Snow Publications for gene: TTPA were set to 27604308
Likely inborn error of metabolism v1.352 TTPA Catherine Snow Classified gene: TTPA as Green List (high evidence)
Likely inborn error of metabolism v1.352 TTPA Catherine Snow Gene: ttpa has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.351 TTPA Catherine Snow reviewed gene: TTPA: Rating: GREEN; Mode of pathogenicity: None; Publications: 26981194; Phenotypes: Ataxia with isolated vitamin E deficiency, 277460; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v1.64 COL4A1 Louise Daugherty Phenotypes for gene: COL4A1 were changed from walker warburg syndrome, muscle eye brain disease to walker warburg syndrome, muscle eye brain disease; Brain small vessel disease with or without ocular anomalies, 175780
Additional findings health related v0.74 CFTR Ellen McDonagh Phenotypes for gene: CFTR were changed from NST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only to ENST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only
Additional findings health related v0.73 CFTR Ellen McDonagh Phenotypes for gene: CFTR were changed from NM_000492.3; Carrier status; Cystic Fibrosis; Adult-only to NST00000003084.10; Carrier status; Cystic Fibrosis; Adult-only
Additional findings health related v0.72 CFTR Ellen McDonagh Deleted their review
Additional findings health related v0.72 CFTR Ellen McDonagh Deleted their comment
Additional findings health related v0.72 CFTR Ellen McDonagh Classified gene: CFTR as Green List (high evidence)
Additional findings health related v0.72 CFTR Ellen McDonagh Gene: cftr has been classified as Green List (High Evidence).
Inherited renal cancer v0.41 PTEN Rebecca Foulger Classified gene: PTEN as Amber List (moderate evidence)
Inherited renal cancer v0.41 PTEN Rebecca Foulger Added comment: Comment on list classification: PTEN has been changed from red to amber based on a comment by Shazia Mahamdallie (email communication, October 11th 2019) who notes that "amber status might be more appropriate, i.e. evidence of association but not significant".
Inherited renal cancer v0.41 PTEN Rebecca Foulger Gene: pten has been classified as Amber List (Moderate Evidence).
Congenital muscular dystrophy v1.63 GOLGA2 Louise Daugherty commented on gene: GOLGA2: After review with Genomics England clinical team this gene was provisionally rated Amber on the basis of one family, as it is difficult to be confident about the extent of the phenotype so amber pending further cases or expert opinion.
Congenital muscular dystrophy v1.63 Louise Daugherty List of related panels changed from to R79
Likely inborn error of metabolism v1.351 TREX1 Catherine Snow Deleted their comment
Likely inborn error of metabolism v1.351 TREX1 Catherine Snow Added comment: Comment on phenotypes: Aicardi-Goutieres syndrome 1, dominant and recessive TREX1 deficiency leads to the intracellular accumulation of DNA, and activation of the immune system by these accumulated NA.
Likely inborn error of metabolism v1.351 TREX1 Catherine Snow Phenotypes for gene: TREX1 were changed from Intellectual disability; Familial cerebral small vessel disease; Intracerebral calcification disorders; (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS1; Inherited white matter disorders to Intellectual disability; Familial cerebral small vessel disease; Intracerebral calcification disorders; (Disorders of nucleotide metabolism, Aicardi-Gouti res Syndrome) AGS1; Inherited white matter disorders
Likely inborn error of metabolism v1.350 TREX1 Catherine Snow Classified gene: TREX1 as Green List (high evidence)
Likely inborn error of metabolism v1.350 TREX1 Catherine Snow Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype
Likely inborn error of metabolism v1.350 TREX1 Catherine Snow Gene: trex1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.375 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308
Undiagnosed metabolic disorders v1.374 TREX1 Catherine Snow Classified gene: TREX1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.374 TREX1 Catherine Snow Gene: trex1 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.373 TREX1 Catherine Snow reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 12624136, 25604658; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.349 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308; 12624136; 25604658
Likely inborn error of metabolism v1.349 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308; 12624136; 25604658
Likely inborn error of metabolism v1.349 TREX1 Catherine Snow Publications for gene: TREX1 were set to 27604308
Likely inborn error of metabolism v1.348 TREX1 Catherine Snow reviewed gene: TREX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 12624136, 25604658; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger commented on Region: ISCA-37446-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: PMID:30977115: Eaton et al., 2019: Overall, 11% (12/108) of deletion carriers had an epilepsy diagnosis. 57/96 remaining deletion carriers (59.4%) had seizures or seizure-like symptoms (including febrile seizures). Most patients with 22q11.2 deletion syndrome had either deletion type A-D (ISCA-37446 75.9%) or deletion type A-B (ISCA-37433 6.5% 7/108 patients)- see Table 1.
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger commented on Region: ISCA-37433-Loss: Added CNV to panel on recommendation from Alisdair McNeill (SHEFFIELD CHILDREN'S NHS FOUNDATION TRUST) who notes that "Multiple case series demonstrate 22q11.2 deletion syndrome is associated with epilepsy, e.g. PubMed:30977115" (personal communication via email, October 7th 2019).
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger reviewed Region: ISCA-37433-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger reviewed Region: ISCA-37446-Loss: Rating: ; Mode of pathogenicity: None; Publications: 30977115; Phenotypes: Epilepsy, seizures, seizure-like symptoms; Mode of inheritance: None
Early onset or syndromic epilepsy v1.364 ISCA-37433-Loss Rebecca Foulger Region: ISCA-37433-Loss was added
Region: ISCA-37433-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for Region: ISCA-37433-Loss were set to 15545748; 15889418; 20301696
Phenotypes for Region: ISCA-37433-Loss were set to Learning difficulties; immune deficiency; renal anomalies; cleft palate, polydactyly; 22q11.2 deletion syndrome; diaphragmatic hernia; 192430; polyhydramnios; DiGeorge syndrome; Velocardiofacial syndrome; 188400; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; congenital heart disease
Early onset or syndromic epilepsy v1.364 ISCA-37446-Loss Rebecca Foulger Region: ISCA-37446-Loss was added
Region: ISCA-37446-Loss was added to Genetic epilepsy syndromes. Sources: ClinGen,Expert Review Green
Mode of inheritance for Region: ISCA-37446-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37446-Loss were set to micrognathia; neonatal hypocalcemia, which may present as tetany or seizures, due to hypoplasia of the parathyroid glands, and susceptibility to infection due to a deficit of T cells; clefting; DiGeorge syndrome; Velocardiofacial syndrome; 188400; cardiac malformations; Hearing deficits
Primary immunodeficiency or monogenic inflammatory bowel disease v1.132 PIK3CD Ilenia Simeoni reviewed gene: PIK3CD: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 29226301; Phenotypes: ; Mode of inheritance: None; Current diagnostic: yes
Additional findings health related v0.71 VHL Ellen McDonagh Phenotypes for gene: VHL were changed from NM_000551.3; Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child to ENST00000256474.2; Other cancer predisposition; Von Hippel Lindau Syndrome; Adult and child
Additional findings health related v0.70 RET Ellen McDonagh Phenotypes for gene: RET were changed from NM_020975.4; Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child to ENST00000355710.7; Other cancer predisposition; Myltiple endocrine Neoplasia Type 2; Adult and child
Additional findings health related v0.69 PCSK9 Ellen McDonagh Phenotypes for gene: PCSK9 were changed from NM_174936.3; Familial hypercholesterolaemia; Adult and child to ENST00000302118.5; Familial hypercholesterolaemia; Adult and child
Additional findings health related v0.68 MUTYH Ellen McDonagh Phenotypes for gene: MUTYH were changed from NM_001128425.1; Bowel cancer predisposition; MYH-associated polyposis; Adult only to ENST00000450313.5; Bowel cancer predisposition; MYH-associated polyposis; Adult only
Additional findings health related v0.67 MSH6 Ellen McDonagh Phenotypes for gene: MSH6 were changed from NM_000179.2; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to ENST00000234420.9; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related v0.66 MSH2 Ellen McDonagh Phenotypes for gene: MSH2 were changed from NM_000251.2; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to ENST00000233146.6; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related v0.65 MLH1 Ellen McDonagh Phenotypes for gene: MLH1 were changed from NM_000249.3; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only to ENST00000231790.6; Bowel cancer predisposition; Hereditary non-polyposis colorectal cancer; Adult only
Additional findings health related v0.64 MEN1 Ellen McDonagh Phenotypes for gene: MEN1 were changed from NM_000244.3; Other cancer predisposition; Myltiple endocrine Neoplasia Type 1; Adult and child to ENST00000394374.6; Other cancer predisposition; Myltiple endocrine Neoplasia Type 1; Adult and child
Additional findings health related v0.63 LDLR Ellen McDonagh Phenotypes for gene: LDLR were changed from NM_000527.4; Familial hypercholesterolaemia; Adult and child to ENST00000558518.5; Familial hypercholesterolaemia; Adult and child
Additional findings health related v0.62 CFTR Ellen McDonagh Classified gene: CFTR as No list
Additional findings health related v0.62 CFTR Ellen McDonagh Gene: cftr has been removed from the panel.
Additional findings health related v0.61 BRCA2 Ellen McDonagh Phenotypes for gene: BRCA2 were changed from NM_000059.3; Breast and ovarian cancer predisposition; Adult only to ENST00000544455.5; Breast and ovarian cancer predisposition; Adult only
Additional findings health related v0.60 BRCA1 Ellen McDonagh Phenotypes for gene: BRCA1 were changed from NM_007294.3; Breast and ovarian cancer predisposition; Adult only to ENST00000357654.8; Breast and ovarian cancer predisposition; Adult only
Additional findings health related v0.59 APC Ellen McDonagh Phenotypes for gene: APC were changed from ENST00000257430; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Additional findings health related v0.58 APOB Ellen McDonagh Phenotypes for gene: APOB were changed from NM_000384.2; Familial hypercholesterolaemia; Adult and child to ENST00000233242.5; Familial hypercholesterolaemia; Adult and child
Additional findings health related v0.57 APC Ellen McDonagh Phenotypes for gene: APC were changed from NM_000038.5; ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to ENST00000257430; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Additional findings health related v0.56 APC Ellen McDonagh Phenotypes for gene: APC were changed from NM_000038.5; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child to NM_000038.5; ENST00000257430.8; Bowel cancer predisposition; Familial Adenomatous Polyposis; Adult and child
Nephrocalcinosis or nephrolithiasis v1.18 CLCNKA Eleanor Williams commented on gene: CLCNKA
Nephrocalcinosis or nephrolithiasis v1.18 ADCY10 Eleanor Williams commented on gene: ADCY10
Cerebral malformation v2.74 Louise Daugherty List of related panels changed from Cerebral malformation to Cerebral malformation; R87
Pain syndromes v1.9 NMNAT2 Rebecca Foulger Classified gene: NMNAT2 as Red List (low evidence)
Pain syndromes v1.9 NMNAT2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Grey to Red. Gene was added to the panel and rated Green by external expert Michael Coleman (11 Sept 2019). Currently insufficient evidence for a Green rating: one case (2 siblings) with pain disorder in PMID:31132363, and a mouse model. Not currently associated with a phenotype in OMIM or Gene2Phenotype. Therefore rated Red awaiting further evidence.
Pain syndromes v1.9 NMNAT2 Rebecca Foulger Gene: nmnat2 has been classified as Red List (Low Evidence).
Pain syndromes v1.8 NMNAT2 Rebecca Foulger commented on gene: NMNAT2
Intellectual disability v2.1066 MED25 Rebecca Foulger Classified gene: MED25 as Green List (high evidence)
Intellectual disability v2.1066 MED25 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green based on the recent Lebanese cases reported by Nair et al (DOI:10.1159/000501114 and PMID:30800049). Advice and a Green review by Helen Brittain supports the upgrade to Green.
Intellectual disability v2.1066 MED25 Rebecca Foulger Gene: med25 has been classified as Green List (High Evidence).
DDG2P v1.137 SOX11 Rebecca Foulger commented on gene: SOX11: The rating of genes on the DDG2P panel directly reflects the Gene2Phenotype Disease confidence. Therefore I have added SOX11 to the panel 'Paediatric disorders - additional genes' as a Green gene based on the review by Alisdair McNeil, so that SOX11 will feature as a Green gene on the 'Paediatric disorders' Super panel.
Paediatric disorders - additional genes v0.33 SOX11 Rebecca Foulger commented on gene: SOX11: Alisdair McNeill (Sheffield Childrens Hospital) review, copied from DDG2P Panel Version: 1.128, Created: 7 Oct 2019, 2:38 p.m.: I have identified a series (unpublished) of around 20 children with de novo variants in SOX11 and overlapping clinical features. I think this is a real, though rare, cause of neurodevelopmental disorders.
Paediatric disorders - additional genes v0.33 SOX11 Rebecca Foulger Mode of inheritance for gene: SOX11 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paediatric disorders - additional genes v0.32 SOX11 Rebecca Foulger Classified gene: SOX11 as Green List (high evidence)
Paediatric disorders - additional genes v0.32 SOX11 Rebecca Foulger Gene: sox11 has been classified as Green List (High Evidence).
Paediatric disorders - additional genes v0.31 SOX11 Rebecca Foulger gene: SOX11 was added
gene: SOX11 was added to Paediatric disorders - additional genes. Sources: Expert list
Mode of inheritance for gene: SOX11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: SOX11 were set to MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27; Coffin-Siris syndrome 9, 615866
Added comment: Added SOX11 to the panel based on a Green review left by Alisdair McNeill (Sheffield Childrens Hospital) for SOX11 on the PanelApp DDG2P panel. SOX11 currently has a probable Disease confidence in Gene2Phenotype for MENTAL RETARDATION, AUTOSOMAL DOMINANT, 27, but Alisdair McNeil's review provides sufficient cases for a Green rating on the Paediatric disorders Super panel.
Sources: Expert list
Severe microcephaly v1.74 UFC1 Helen Brittain reviewed gene: UFC1: Rating: GREEN; Mode of pathogenicity: ; Publications: 29868776; Phenotypes: Neurodevelopmental disorder with spasticity and poor growth, 618076; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 ZNHIT3 Helen Brittain reviewed gene: ZNHIT3: Rating: RED; Mode of pathogenicity: ; Publications: 28335020; Phenotypes: PEHO syndrome, 260565; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 PCLO Helen Brittain reviewed gene: PCLO: Rating: RED; Mode of pathogenicity: ; Publications: 25832664; Phenotypes: ?Pontocerebellar hypoplasia, type 3, 608027; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 UFM1 Helen Brittain reviewed gene: UFM1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28931644, 29868776, 27545674; Phenotypes: Leukodystrophy, hypomyelinating, 14, 617899; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 UBA5 Helen Brittain reviewed gene: UBA5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Epileptic encephalopathy, early infantile, 44, 617132; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.74 CCDC88A Helen Brittain reviewed gene: CCDC88A: Rating: AMBER; Mode of pathogenicity: ; Publications: 26917597, 30392057; Phenotypes: ?PEHO syndrome-like, 617507; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Severe microcephaly v1.73 Louise Daugherty List of related panels changed from Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly to Primary Microcephaly - Microcephalic Dwarfism Spectrum; Severe microcephaly; R88
Congenital myopathy v1.166 TRIP4 Louise Daugherty changed review comment from: Reviewed by Ivone Leong (Genomics England Curator)
PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this.
There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case?

Genomics England clinical team who noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene

The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; to: Reviewed by Ivone Leong (Genomics England Curator)
PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this.
There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case?

Genomics England clinical team noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene

The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.
Proteinuric renal disease v1.225 OCRL Eleanor Williams changed review comment from: Associated with Dent disease 2 (300555) and Lowe syndrome (309000) in OMIM.

PMID: 21249396 - Tasic et al 2011 - 5 unrelated Macedonian patients with 4 different variants in OCRL. 2 diagnosed with Lowe Syndrome (both with LMWP and hypercalciuria) and 3 with Dent disease 2 (all with asymptomatic proteinuria). All five patients had LMWP and hypercalciuria/


PMID: 17384968 - Sekine et al 2007 - 3 distinct OCRL1 mutations in 3 patients with the Dent disease phenotype are described. All the patients manifested an extremely high degree of low-molecular-weight proteinuria and showed no ocular abnormalities or apparent mental retardation. Urinalysis and blood chemistry showed no findings suggestive of Fanconi syndrome with renal tubular acidosis. Mutations in CLCN5 were ruled out. The mutations identified in OCRL1 are one frame-shift mutation (I127stop) and two missense mutations (R301C and R476W).

PMID: 27625797 - Böckenhauer et al 2012 - 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease were assessed for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. All showed low molecular weight proteinuria.; to: Associated with Dent disease 2 (300555) and Lowe syndrome (309000) in OMIM.

PMID: 21249396 - Tasic et al 2011 - 5 unrelated Macedonian patients with 4 different variants in OCRL. 2 diagnosed with Lowe Syndrome (both with LMWP and hypercalciuria) and 3 with Dent disease 2 (all with asymptomatic proteinuria). All five patients had LMWP and hypercalciuria. Sex of patients not stated.


PMID: 17384968 - Sekine et al 2007 - 3 distinct OCRL1 mutations in 3 male patients with the Dent disease phenotype are described. All the patients manifested an extremely high degree of low-molecular-weight proteinuria and showed no ocular abnormalities or apparent mental retardation. Urinalysis and blood chemistry showed no findings suggestive of Fanconi syndrome with renal tubular acidosis. Mutations in CLCN5 were ruled out. The mutations identified in OCRL1 are one frame-shift mutation (I127stop) and two missense mutations (R301C and R476W).

PMID: 27625797 - Böckenhauer et al 2012 - 14 CLCN5-negative patients from 12 families with a phenotype resembling Dent disease were assessed for defects in OCRL. In six of these kindreds three novel (c.149+1G>A, c.1126A>T, c.1547T>C) and three repeatedly observed mutations (c.166_167delTT, c.901C>T, c.1426C>T) were discovered. All showed low molecular weight proteinuria. Sex of patients not explicitly stated but each had mothers who were 'carriers'.
Structural eye disease v0.93 CRYAA Catherine Snow Added comment: Comment on mode of inheritance: OMIM with publication support has this both AD and AR therefore changing MOI to both monoallelic and biallelic.
Structural eye disease v0.93 CRYAA Catherine Snow Mode of inheritance for gene: CRYAA was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Other rare neuromuscular disorders v1.11 Louise Daugherty List of related panels changed from Other rare neuromuscular disorders;R381 to Other rare neuromuscular disorders; R381
Other rare neuromuscular disorders v1.10 Louise Daugherty List of related panels changed from Other rare neuromuscular disorders to Other rare neuromuscular disorders;R381
Congenital myopathy v1.166 Louise Daugherty List of related panels changed from to R81
Congenital myopathy v1.165 TRIP4 Louise Daugherty Classified gene: TRIP4 as Green List (high evidence)
Congenital myopathy v1.165 TRIP4 Louise Daugherty Added comment: Comment on list classification: After review, it was agreed that it was an appropriate phenotype, sufficient cases to support gene-disease association. The gene is also Green on Neuromuscular disorders
Congenital myopathy v1.165 TRIP4 Louise Daugherty Gene: trip4 has been classified as Green List (High Evidence).
Congenital myopathy v1.164 TRIP4 Louise Daugherty Publications for gene: TRIP4 were set to 26924529
Congenital myopathy v1.163 TRIP4 Louise Daugherty edited their review of gene: TRIP4: Added comment: Reviewed by Ivone Leong (Genomics England Curator)
PMID: 26924529 reported on 3 families (2 Kosovo and 1 Albania) who have 2 different variants in TRIP4. The affected individuals presented with prenatal-onset SMA, multiple congenital contractures (arthrogryposis multiplex congenita), respiratory distress, and congenital bone fractures. The authors suspect a founder effect in the Kosovo families. I think I would count this as 2 cases because of this.
There is another paper (PMID: 27008887) which reported on a large family with TRIP4 variant who have neonatal hypotonia particularly marked in axial (neck and trunk) muscles, severe head lag, poor antigravity limb movements and in some patients, respiratory failure and feeding difficulties. There were no congenital contractures. OMIM has classified this variant as Davignon-Chauveau-type congenital muscular dystrophy. Could this be counted as a third case?

Genomics England clinical team who noted there was sufficient for a green rating. The fact that a second case has been found, besides the potential founder variant, and there is a supportive animal model would meet our criteria. additional paper adds evidence of a neuromuscular phenotype associated with this gene

The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN
Congenital muscular dystrophy v1.62 TRAPPC11 Louise Daugherty Classified gene: TRAPPC11 as Green List (high evidence)
Congenital muscular dystrophy v1.62 TRAPPC11 Louise Daugherty Added comment: Comment on list classification: After review, it was agreed that it was an appropriate phenotype, sufficient cases to support gene-disease association.
Congenital muscular dystrophy v1.62 TRAPPC11 Louise Daugherty Gene: trappc11 has been classified as Green List (High Evidence).
Congenital muscular dystrophy v1.61 TRAPPC11 Louise Daugherty edited their review of gene: TRAPPC11: Added comment: Reviewed by Genomics England clinical team who noted the phenotype described in the OMIM cases have significant overlap with those described as 'Congenital muscular dystrophy'. There is a relevant muscular phenotype with onset in infancy / early childhood, a raised CK and dystrophic changes on muscle biopsy. The GLH representative has rated it green so would support green rating based on the evidence. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN
Retinal disorders v1.199 KIZ Mohammed Abdallah changed review comment from: Although this gene is reported under the specified human phenotype ontology, and Retnet genes, it had the misfortune of being classified historically as non-coding gene in the Ensembl grch37 release, which has been archived since then, but by consulting the new hg38 Ensembl release and both Refseq grch37 and grch38 we could see that this gene is actually an important protein-coding gene that has been identified as a causal gene for Retinitis pigmentosa. Moreover it has three pathogenic mutations reported in Clinvar and from more than three unrelated families reported by three different and independent studies.; to: Although this gene is reported under the specified human phenotype ontology, and Retnet genes, it had the misfortune of being classified historically as non-coding gene in the Ensembl grch37 release, which has been archived since then, However, when consulting the new hg38 Ensembl release and both Refseq grch37 and grch38 we can clearly see that this gene is actually an important protein-coding gene that has been identified as a causal gene for Retinitis pigmentosa. Moreover it has three pathogenic mutations reported in Clinvar and from more than three unrelated families reported by three different and independent studies.
Retinal disorders v1.199 KIZ Mohammed Abdallah reviewed gene: KIZ: 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 ( 31556760, 29057815, 28837078, 24680887); Phenotypes: Phenotypes (HP:0000556, HP:0000510); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital muscular dystrophy v1.61 SIL1 Louise Daugherty Classified gene: SIL1 as Green List (high evidence)
Congenital muscular dystrophy v1.61 SIL1 Louise Daugherty Added comment: Comment on list classification: After review, it was agreed that it was an appropriate phenotype, sufficient cases to support gene-disease association.
Congenital muscular dystrophy v1.61 SIL1 Louise Daugherty Gene: sil1 has been classified as Green List (High Evidence).
Congenital muscular dystrophy v1.60 SIL1 Louise Daugherty edited their review of gene: SIL1: Added comment: Reviewed by Genomics England clinical team who noted it is associated with a raised CK, muscle weakness and abnormalities on biopsy so a relevant phenotype. The GLH representative has rated it green so would support green rating. The panel has not yet been discussed with the Test Group, but all genes will be reviewed before sign off.; Changed rating: GREEN
Congenital myopathy v1.163 PAX7 Louise Daugherty Classified gene: PAX7 as Green List (high evidence)
Congenital myopathy v1.163 PAX7 Louise Daugherty Added comment: Comment on list classification: New gene added from recommendation by Genomics Clinical team. Appropriate phenotype, sufficient cases and external expert review all support gene-disease association and relevance to this panel to rate gene to Green.
Congenital myopathy v1.163 PAX7 Louise Daugherty Gene: pax7 has been classified as Green List (High Evidence).
Congenital myopathy v1.162 PAX7 Louise Daugherty gene: PAX7 was added
gene: PAX7 was added to Congenital myopathy. Sources: Expert Review
Mode of inheritance for gene: PAX7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PAX7 were set to 31092906
Phenotypes for gene: PAX7 were set to Hypotonia; Axial hypotonia; Ptosis; Scoliosis; Delayed motor milestones; Myopathy, congenital, progressive, with scoliosis, 618578
Review for gene: PAX7 was set to GREEN
Added comment: As a result of adding PAX7 to Neuromuscular Disorders panel as recommended by external reviewer, Genomics England clinical team recommended this gene was added to Congenital Myopathy panel.

Original review:
Feichtinger et. al. report four independent consanguineous families with four different (homozygous) mutations in PAX7. Sources: Literature
Cristina Dias (The Francis Crick Institute), 17 Sep 2019
Sources: Expert Review
Proteinuric renal disease v1.225 CLCN5 Eleanor Williams edited their review of gene: CLCN5: Added comment: Note on Mode of inheritance - OMIM list the mode of inheritance for both Dent disease #300009; Proteinuria low molecular weight #308990 as XLR so have left mode of inheritance as X-LINKED: hemizygous mutation in males, biallelic mutations in females; Changed publications: PMID27757584, PMID: 25907713; Changed phenotypes: Dent disease #300009, Proteinuria low molecular weight #308990
Proteinuric renal disease v1.225 LAMA5 Eleanor Williams Phenotypes for gene: LAMA5 were changed from to Nephrotic syndrome
Proteinuric renal disease v1.224 LAMA5 Eleanor Williams Mode of inheritance for gene: LAMA5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Proteinuric renal disease v1.223 LAMA5 Eleanor Williams Classified gene: LAMA5 as Amber List (moderate evidence)
Proteinuric renal disease v1.223 LAMA5 Eleanor Williams Added comment: Comment on list classification: Changing the rating of this gene to Amber. 3 cases with homozygous missense variants reported but authors classify as VUS as there is no experimental evidence to link the impact of these genetic variants on protein function to disease pathogenesis.
Proteinuric renal disease v1.223 LAMA5 Eleanor Williams Gene: lama5 has been classified as Amber List (Moderate Evidence).
Renal tubulopathies v1.193 GATM Eleanor Williams Mode of pathogenicity for gene: GATM 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
Genodermatoses with malignancies v1.6 ACTRT1 Catherine Snow Phenotypes for gene: ACTRT1 were changed from Basal cell carcinoma to Basal cell carcinoma; Bazex–Dupré–Christol syndrome
Likely inborn error of metabolism v1.348 TH Catherine Snow Publications for gene: TH were set to 27604308
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow changed review comment from: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.; to: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.
Membranoproliferative glomerulonephritis including C3 glomerulopathy v2.1 Ellen McDonagh List of related panels changed from PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; R197 to PMG; MPGN; Primary Membranoproliferative Glomerulonephritis; Primary membranoproliferative glomerulonephritis; R197
Ehlers Danlos syndrome with a likely monogenic cause v2.1 Ellen McDonagh List of related panels changed from Classical Ehlers Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; R101 to Classical Ehlers Danlos Syndrome; Classical Ehlers-Danlos Syndrome; Ehlers-Danlos Syndrome (unusual phenotypes e.g. absent pain sense); Ehlers-Danlos syndrome type 3; Kyphoscoliotic Ehlers-Danlos syndrome; EDS; Ehlers-Danlos syndromes; R101
Familial hypercholesterolaemia (GMS) v0.5 LDLRAP1 Rebecca Foulger Phenotypes for gene: LDLRAP1 were changed from Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia; Hypercholesterolemia, familial, 4, 603813 to Hypercholesterolemia, familial, autosomal recessive; Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia; Hypercholesterolemia, familial, 4, 603813
Familial hypercholesterolaemia (GMS) v0.4 LDLR Rebecca Foulger Phenotypes for gene: LDLR were changed from LDL cholesterol level QTL2, 143890; Familial Hypercholesterolaemia; Hypercholesterolemia; Familial Hypercholesterolemia; Hypercholesterolemia, familial, 1, 143890 to LDL cholesterol level QTL2, 143890; Familial Hypercholesterolaemia; Hypercholesterolemia; Familial Hypercholesterolemia; Hypercholesterolemia, familial, 1, 143890; C3 Hypercholesterolemia, familial
Familial hypercholesterolaemia (GMS) v0.3 PCSK9 Rebecca Foulger commented on gene: PCSK9
Familial hypercholesterolaemia (GMS) v0.3 LDLR Rebecca Foulger commented on gene: LDLR
Familial hypercholesterolaemia (GMS) v0.3 APOB Rebecca Foulger commented on gene: APOB
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow changed review comment from: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located
in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1
expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.; to: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1 expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow edited their review of gene: ACTRT1: Added comment: PMID: 28869610 reported on 6 families with Bazex–Dupré–Christol syndrome. Of these 6 families two families had
the same (c.547_548insA, p.Met183Asnfs*17) variant in ACTRT1. The other four families variants were located
in transcribed sequences encoding enhancer RNAs (eRNAs) and were shown to impair enhancer activity and ACTRT1
expression.
Rating as red as only one variant identified among the six families with limited pedigree information about the families and not in OMIM or Gene2Phenotype.; Changed rating: RED; Changed phenotypes: Basal cell carcinoma, Bazex–Dupré–Christol syndrome
Genodermatoses with malignancies v1.5 ACTRT1 Catherine Snow gene: ACTRT1 was added
gene: ACTRT1 was added to Genodermatoses with malignancies. Sources: Literature,Expert list
Mode of inheritance for gene: ACTRT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ACTRT1 were set to 28869610; 30653245
Phenotypes for gene: ACTRT1 were set to Basal cell carcinoma
Review for gene: ACTRT1 was set to AMBER
Added comment: Sources: Literature, Expert list
DDG2P v1.137 AIFM1 Rebecca Foulger Phenotypes for gene: AIFM1 were changed from COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6 319521; COWCHOCK SYNDROME to COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 6 300816; COWCHOCK SYNDROME 310490
DDG2P v1.136 SMAD4 Rebecca Foulger Phenotypes for gene: SMAD4 were changed from JUVENILE POLYPOSIS SYNDROME 174900; MYHRE SYNDROME; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME 175050 to JUVENILE POLYPOSIS SYNDROME 174900; MYHRE SYNDROME 139210; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME 175050
DDG2P v1.135 ALX4 Rebecca Foulger Phenotypes for gene: ALX4 were changed from PARIETAL FORAMINA 2 221704; FRONTONASAL DYSPLASIA 2 605420 to PARIETAL FORAMINA 2 609597; FRONTONASAL DYSPLASIA 2 613451
DDG2P v1.134 SALL4 Rebecca Foulger Phenotypes for gene: SALL4 were changed from ACRO-RENAL-OCULAR SYNDROME 217001; DUANE-RADIAL RAY SYNDROME 173212 to ACRO-RENAL-OCULAR SYNDROME 607323; DUANE-RADIAL RAY SYNDROME 607323
Likely inborn error of metabolism v1.347 TH Catherine Snow Classified gene: TH as Green List (high evidence)
Likely inborn error of metabolism v1.347 TH Catherine Snow Gene: th has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.346 TH Catherine Snow reviewed gene: TH: Rating: GREEN; Mode of pathogenicity: None; Publications: 24753243; Phenotypes: Segawa syndrome, recessive, 605407; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v1.133 COG4 Rebecca Foulger Phenotypes for gene: COG4 were changed from COG4-CDG 319493; Saul-Wilson syndrome to COG4-CDG 319493; Saul-Wilson syndrome 618150
DDG2P v1.132 ARID1B Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed (for all listed disorders). ; to: Original DDG2P rating: confirmed (for both disorders: MENTAL RETARDATION, AUTOSOMAL DOMINANT 12 135900; COFFIN SIRIS SYNDROME 135900).
DDG2P v1.132 ARID1B Rebecca Foulger Phenotypes for gene: ARID1B were changed from MENTAL RETARDATION, AUTOSOMAL DOMINANT 12 614562; COFFIN SIRIS SYNDROME to MENTAL RETARDATION, AUTOSOMAL DOMINANT 12 135900; COFFIN SIRIS SYNDROME 135900
DDG2P v1.131 MUT Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for METHYLMALONIC ACIDURIA TYPE MUT: confirmed. DDG2P allelic requirement: biallelic. DDG2P mutation consequence: loss of function.
DDG2P v1.131 KARS Rebecca Foulger commented on gene: KARS: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CHARCOT-MARIE-TOOTH DISEASE, RECESSIVE INTERMEDIATE, B; DEAFNESS, AUTOSOMAL RECESSIVE 89.
DDG2P v1.131 SMCHD1 Rebecca Foulger commented on gene: SMCHD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Isolated Arhinia/Bosma Arhinia syndrome.
DDG2P v1.131 FAM161A Rebecca Foulger commented on gene: FAM161A: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RETINITIS PIGMENTOSA 28.
DDG2P v1.131 ALDOB Rebecca Foulger commented on gene: ALDOB: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for HEREDITARY FRUCTOSE INTOLERANCE.
DDG2P v1.131 CISD2 Rebecca Foulger commented on gene: CISD2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for WOLFRAM SYNDROME TYPE 2.
DDG2P v1.131 DARS2 Rebecca Foulger commented on gene: DARS2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LEUKOENCEPHALOPATHY WITH BRAINSTEM AND SPINAL CORD INVOLVEMENT AND LACTATE ELEVATION.
DDG2P v1.131 ATP13A2 Rebecca Foulger commented on gene: ATP13A2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for PARKINSON DISEASE 9.
DDG2P v1.131 SLC4A11 Rebecca Foulger commented on gene: SLC4A11: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CORNEAL DYSTROPHY, FUCHS ENDOTHELIAL, 4.
DDG2P v1.131 THAP1 Rebecca Foulger commented on gene: THAP1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for DYSTONIA 6, TORSION.
DDG2P v1.131 PDCD10 Rebecca Foulger commented on gene: PDCD10: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CEREBRAL CAVERNOUS MALFORMATIONS TYPE 3.
DDG2P v1.131 ANO5 Rebecca Foulger commented on gene: ANO5: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for MIYOSHI MUSCULAR DYSTROPHY TYPE 3; GNATHODIAPHYSEAL DYSPLASIA.
DDG2P v1.131 SYNE1 Rebecca Foulger commented on gene: SYNE1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE 8; EMERY-DREIFUSS MUSCULAR DYSTROPHY 4, AUTOSOMAL RECESSIVE.
DDG2P v1.131 AIRE Rebecca Foulger commented on gene: AIRE: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for AUTOIMMUNE POLYENDOCRINOPATHY SYNDROME TYPE 1.
DDG2P v1.131 ACADS Rebecca Foulger commented on gene: ACADS: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for SHORT CHAIN ACYL-COA DEHYDROGENASE DEFICIENCY.
DDG2P v1.131 CLN6 Rebecca Foulger commented on gene: CLN6: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CEROID LIPOFUSCINOSIS, NEURONAL, 6; CEROID LIPOFUSCINOSIS, NEURONAL, KUFS TYPE, ADULT ONSET.
DDG2P v1.131 GBA Rebecca Foulger commented on gene: GBA: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for GAUCHER DISEASE PERINATAL LETHAL; GAUCHER DISEASE TYPE 3C; GAUCHER DISEASE TYPE 1; GAUCHER DISEASE; GAUCHER DISEASE TYPE 2; GAUCHER DISEASE TYPE 3.
DDG2P v1.131 LDB3 Rebecca Foulger commented on gene: LDB3: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CARDIOMYOPATHY DILATED TYPE 1C; LEFT VENTRICULAR NON-COMPACTION TYPE 3; MYOPATHY MYOFIBRILLAR TYPE 4.
DDG2P v1.131 SPTLC2 Rebecca Foulger commented on gene: SPTLC2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IC.
DDG2P v1.131 RRM2B Rebecca Foulger commented on gene: RRM2B: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Mitochondrial depletion syndrome.
DDG2P v1.131 AGXT Rebecca Foulger commented on gene: AGXT: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for HYPEROXALURIA, PRIMARY, TYPE 1.
DDG2P v1.131 KRIT1 Rebecca Foulger commented on gene: KRIT1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for CEREBRAL CAVERNOUS MALFORMATIONS TYPE 1.
DDG2P v1.131 PLA2G6 Rebecca Foulger commented on gene: PLA2G6: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for INFANTILE NEUROAXONAL DYSTROPHY 1; NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2B.
DDG2P v1.131 GJB3 Rebecca Foulger commented on gene: GJB3: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA; DEAFNESS AUTOSOMAL DOMINANT TYPE 2B; DEAFNESS, AUTOSOMAL RECESSIVE.
DDG2P v1.131 SMAD4 Rebecca Foulger commented on gene: SMAD4: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for JUVENILE POLYPOSIS SYNDROME; JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME.
DDG2P v1.131 BRCA2 Rebecca Foulger commented on gene: BRCA2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for FANCONI ANEMIA COMPLEMENTATION GROUP D TYPE 1.
DDG2P v1.131 AR Rebecca Foulger commented on gene: AR: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ANDROGEN INSENSITIVITY SYNDROME; SPINAL AND BULBAR MUSCULAR ATROPHY.
DDG2P v1.131 FMR1 Rebecca Foulger commented on gene: FMR1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for FRAGILE X TREMOR/ATAXIA SYNDROME; PREMATURE OVARIAN FAILURE SYNDROME TYPE 1.
DDG2P v1.131 BGN Rebecca Foulger commented on gene: BGN: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Severe syndromic form of thoracic aortic aneurysm & dissection.
DDG2P v1.131 AMER1 Rebecca Foulger commented on gene: AMER1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for OSTEOPATHIA STRIATA WITH CRANIAL SCLEROSIS.
DDG2P v1.131 ABCD1 Rebecca Foulger commented on gene: ABCD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ADRENOLEUKODYSTROPHY, X-LINKED.
DDG2P v1.131 TIMM8A Rebecca Foulger commented on gene: TIMM8A: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for JENSEN SYNDROME; MOHR-TRANEBJAERG SYNDROME.
DDG2P v1.131 MYO7A Rebecca Foulger commented on gene: MYO7A: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for DEAFNESS AUTOSOMAL RECESSIVE TYPE 2; USHER SYNDROME TYPE 1B.
DDG2P v1.131 CDH1 Rebecca Foulger commented on gene: CDH1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for Blepharo-cheiro-dontic syndrome.
DDG2P v1.131 TGFB2 Rebecca Foulger commented on gene: TGFB2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LOEYS-DIETZ SYNDROME, TYPE 4.
DDG2P v1.131 NR5A1 Rebecca Foulger commented on gene: NR5A1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for 46XY SEX REVERSAL 3; SPERMATOGENIC FAILURE 8.
DDG2P v1.131 ATP1A3 Rebecca Foulger commented on gene: ATP1A3: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RAPID-ONSET DYSTONIA-PARKINSONISM; ALTERNATING HEMIPLEGIA OF CHILDHOOD.
DDG2P v1.131 KCNE1 Rebecca Foulger commented on gene: KCNE1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for JERVELL AND LANGE-NIELSEN SYNDROME TYPE 2.
DDG2P v1.131 POLD1 Rebecca Foulger commented on gene: POLD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for SUBCUTANEOUS LIPODYSTROPHY, DEAFNESS, MANDIBULAR HYPOPLASIA AND MALE HYPOGONADISM .
DDG2P v1.131 KIT Rebecca Foulger commented on gene: KIT: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for HUMAN PIEBALDISM.
DDG2P v1.131 RET Rebecca Foulger commented on gene: RET: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RENAL AGENESIS; MULTIPLE ENDOCRINE NEOPLASIA IIB.
DDG2P v1.131 MYH8 Rebecca Foulger commented on gene: MYH8: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for DISTAL ARTHROGRYPOSIS TYPE; CARNEY COMPLEX VARIANT.
DDG2P v1.131 LMNA Rebecca Foulger commented on gene: LMNA: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LETHAL TIGHT SKIN CONTRACTURE SYNDROME; FAMILIAL PARTIAL LIPODYSTROPHY TYPE 2; EMERY-DREIFUSS MUSCULAR DYSTROPHY TYPE 2; MANDIBULOACRAL DYSPLASIA WITH TYPE A LIPODYSTROPHY; HEART-HAND SYNDROME SLOVENIAN TYPE;HUTCHINSON-GILFORD PROGERIA SYNDROME; CHARCOT-MARIE-TOOTH DISEASE TYPE 2B1; MUSCULAR DYSTROPHY CONGENITAL LMNA-RELATED;CARDIOMYOPATHY DILATED TYPE 1A; CARDIOMYOPATHY DILATED WITH HYPERGONADOTROPIC HYPOGONADISM; LIMB-GIRDLE MUSCULAR DYSTROPHY TYPE 1B.
DDG2P v1.131 ALAD Rebecca Foulger commented on gene: ALAD: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for ACUTE HEPATIC PORPHYRIA.
DDG2P v1.131 COL4A1 Rebecca Foulger commented on gene: COL4A1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for PORENCEPHALY 1.
DDG2P v1.131 COL4A2 Rebecca Foulger commented on gene: COL4A2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for PORENCEPHALY 2.
DDG2P v1.131 HSPD1 Rebecca Foulger commented on gene: HSPD1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for LEUKODYSTROPHY HYPOMYELINATING TYPE 4.
DDG2P v1.131 SLC4A1 Rebecca Foulger commented on gene: SLC4A1: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for RENAL TUBULAR ACIDOSIS, DISTAL, AR; RENAL TUBULAR ACIDOSIS, DISTAL, AD.
DDG2P v1.131 ACTA2 Rebecca Foulger commented on gene: ACTA2: September 2019: G2P confidence terminology was updated: DD-G2P rating is now 'both RD and IF' for AORTIC ANEURYSM, FAMILIAL THORACIC 6; MOYAMOYA DISEASE 5.
DDG2P v1.130 TARS Rebecca Foulger reviewed gene: TARS: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 FAM149B1 Rebecca Foulger reviewed gene: FAM149B1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 LEMD2 Rebecca Foulger reviewed gene: LEMD2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DHX37 Rebecca Foulger reviewed gene: DHX37: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DHX34 Rebecca Foulger reviewed gene: DHX34: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DDX54 Rebecca Foulger reviewed gene: DDX54: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 TAOK1 Rebecca Foulger reviewed gene: TAOK1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 RINT1 Rebecca Foulger reviewed gene: RINT1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 BRSK2 Rebecca Foulger reviewed gene: BRSK2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 BNC2 Rebecca Foulger reviewed gene: BNC2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 PIGU Rebecca Foulger reviewed gene: PIGU: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 ROBO4 Rebecca Foulger reviewed gene: ROBO4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 HNRNPR Rebecca Foulger reviewed gene: HNRNPR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DLL1 Rebecca Foulger reviewed gene: DLL1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 B3GAT3 Rebecca Foulger reviewed gene: B3GAT3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 MYOCD Rebecca Foulger reviewed gene: MYOCD: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 FBXW11 Rebecca Foulger reviewed gene: FBXW11: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 PIGB Rebecca Foulger reviewed gene: PIGB: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DHX16 Rebecca Foulger reviewed gene: DHX16: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 DYNC1I2 Rebecca Foulger reviewed gene: DYNC1I2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 CDK8 Rebecca Foulger reviewed gene: CDK8: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 KCNN3 Rebecca Foulger reviewed gene: KCNN3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 POU3F3 Rebecca Foulger reviewed gene: POU3F3: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 SMARCD1 Rebecca Foulger reviewed gene: SMARCD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 AP2M1 Rebecca Foulger reviewed gene: AP2M1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 CACNA1B Rebecca Foulger reviewed gene: CACNA1B: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 RRAS2 Rebecca Foulger reviewed gene: RRAS2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 WDR37 Rebecca Foulger reviewed gene: WDR37: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 POLA1 Rebecca Foulger reviewed gene: POLA1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 GPC4 Rebecca Foulger reviewed gene: GPC4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 VAMP2 Rebecca Foulger reviewed gene: VAMP2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 POLR2A Rebecca Foulger reviewed gene: POLR2A: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 CSF1R Rebecca Foulger reviewed gene: CSF1R: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 GOT2 Rebecca Foulger reviewed gene: GOT2: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.130 NUP214 Rebecca Foulger reviewed gene: NUP214: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
DDG2P v1.129 TARS Rebecca Foulger gene: TARS was added
gene: TARS was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: TARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TARS were set to 31374204
Phenotypes for gene: TARS were set to Non-photosensitive trichothiodystrophy
DDG2P v1.129 FAM149B1 Rebecca Foulger gene: FAM149B1 was added
gene: FAM149B1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Ciliopathy-related syndromic intellectual disability
DDG2P v1.129 LEMD2 Rebecca Foulger gene: LEMD2 was added
gene: LEMD2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: LEMD2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: LEMD2 were set to 30905398
Phenotypes for gene: LEMD2 were set to Nuclear Envelopathy with Early Progeroid Appearance
Mode of pathogenicity for gene: LEMD2 was set to Other - please provide details in the comments
DDG2P v1.129 DHX37 Rebecca Foulger gene: DHX37 was added
gene: DHX37 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DHX37 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHX37 were set to 31256877
Phenotypes for gene: DHX37 were set to Intellectual Disability and Central Nervous System anomalies
Mode of pathogenicity for gene: DHX37 was set to Other - please provide details in the comments
DDG2P v1.129 DHX34 Rebecca Foulger gene: DHX34 was added
gene: DHX34 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DHX34 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DHX34 were set to 31256877
Phenotypes for gene: DHX34 were set to INTELLECTUAL DISABILITY 616579
Mode of pathogenicity for gene: DHX34 was set to Other - please provide details in the comments
DDG2P v1.129 DDX54 Rebecca Foulger gene: DDX54 was added
gene: DDX54 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DDX54 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDX54 were set to 31256877
Phenotypes for gene: DDX54 were set to Intellectual Disability and Central Nervous System anomalies
Mode of pathogenicity for gene: DDX54 was set to Other - please provide details in the comments
DDG2P v1.129 TAOK1 Rebecca Foulger gene: TAOK1 was added
gene: TAOK1 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: TAOK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TAOK1 were set to 31230721
Phenotypes for gene: TAOK1 were set to INTELLECTUAL DISABILITY 616579
DDG2P v1.129 RINT1 Rebecca Foulger gene: RINT1 was added
gene: RINT1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to 31204009
Phenotypes for gene: RINT1 were set to Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities
DDG2P v1.129 BRSK2 Rebecca Foulger gene: BRSK2 was added
gene: BRSK2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: BRSK2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BRSK2 were set to 30879638
Phenotypes for gene: BRSK2 were set to Neurodevelopmental Disorder
DDG2P v1.129 BNC2 Rebecca Foulger gene: BNC2 was added
gene: BNC2 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: BNC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BNC2 were set to 31051115
Phenotypes for gene: BNC2 were set to Congenital Lower Urinary Tract Obstruction
DDG2P v1.129 PIGU Rebecca Foulger gene: PIGU was added
gene: PIGU was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: PIGU was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PIGU were set to 31353022
Phenotypes for gene: PIGU were set to Intellectual Disability, Central Nervous System anomalies and Scoliosis
Mode of pathogenicity for gene: PIGU was set to Other - please provide details in the comments
DDG2P v1.129 ROBO4 Rebecca Foulger gene: ROBO4 was added
gene: ROBO4 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: ROBO4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ROBO4 were set to 30455415
Phenotypes for gene: ROBO4 were set to Bicuspid Aortic Valve and Aortic Aneurysm 618496
DDG2P v1.129 HNRNPR Rebecca Foulger gene: HNRNPR was added
gene: HNRNPR was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: HNRNPR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HNRNPR were set to 31079900
Phenotypes for gene: HNRNPR were set to INTELLECTUAL DISABILITY 616579
DDG2P v1.129 DLL1 Rebecca Foulger gene: DLL1 was added
gene: DLL1 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DLL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DLL1 were set to 31353024
Phenotypes for gene: DLL1 were set to INTELLECTUAL DISABILITY 616579
DDG2P v1.129 B3GAT3 Rebecca Foulger gene: B3GAT3 was added
gene: B3GAT3 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: B3GAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B3GAT3 were set to 31438591
Phenotypes for gene: B3GAT3 were set to MULTIPLE JOINT DISLOCATIONS, SHORT STATURE, AND CRANIOFACIAL DYSMORPHISM WITH OR WITHOUT CONGENITAL HEART DEFECTS 245600
Mode of pathogenicity for gene: B3GAT3 was set to Other - please provide details in the comments
DDG2P v1.129 MYOCD Rebecca Foulger gene: MYOCD was added
gene: MYOCD was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: MYOCD was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MYOCD were set to 31513549
Phenotypes for gene: MYOCD were set to Congenital megabladder
DDG2P v1.129 FBXW11 Rebecca Foulger gene: FBXW11 was added
gene: FBXW11 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: FBXW11 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: FBXW11 were set to 31402090
Phenotypes for gene: FBXW11 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: FBXW11 was set to Other - please provide details in the comments
DDG2P v1.129 PIGB Rebecca Foulger gene: PIGB was added
gene: PIGB was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality
DDG2P v1.129 DHX16 Rebecca Foulger gene: DHX16 was added
gene: DHX16 was added to DDG2P. Sources: Expert Review Red,DD-Gene2Phenotype
Mode of inheritance for gene: DHX16 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: DHX16 were set to 31256877
Phenotypes for gene: DHX16 were set to Intellectual Disability, Central Nervous System anomalies and Seizures
Mode of pathogenicity for gene: DHX16 was set to Other - please provide details in the comments
DDG2P v1.129 DYNC1I2 Rebecca Foulger gene: DYNC1I2 was added
gene: DYNC1I2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: DYNC1I2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DYNC1I2 were set to 31079899
Phenotypes for gene: DYNC1I2 were set to NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY AND STRUCTURAL BRAIN ANOMALIES 618492
DDG2P v1.129 CDK8 Rebecca Foulger gene: CDK8 was added
gene: CDK8 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: CDK8 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CDK8 were set to 30905399
Phenotypes for gene: CDK8 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: CDK8 was set to Other - please provide details in the comments
DDG2P v1.129 KCNN3 Rebecca Foulger gene: KCNN3 was added
gene: KCNN3 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: KCNN3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KCNN3 were set to 31155282
Phenotypes for gene: KCNN3 were set to ZIMMERMANN-LABAND SYNDROME
Mode of pathogenicity for gene: KCNN3 was set to Other - please provide details in the comments
DDG2P v1.129 POU3F3 Rebecca Foulger gene: POU3F3 was added
gene: POU3F3 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: POU3F3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POU3F3 were set to 31303265
Phenotypes for gene: POU3F3 were set to INTELLECTUAL DISABILITY 616579
Mode of pathogenicity for gene: POU3F3 was set to Other - please provide details in the comments
DDG2P v1.129 SMARCD1 Rebecca Foulger gene: SMARCD1 was added
gene: SMARCD1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: SMARCD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SMARCD1 were set to 30879640
Phenotypes for gene: SMARCD1 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: SMARCD1 was set to Other - please provide details in the comments
DDG2P v1.129 AP2M1 Rebecca Foulger gene: AP2M1 was added
gene: AP2M1 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: AP2M1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: AP2M1 were set to 31104773
Phenotypes for gene: AP2M1 were set to Developmental and Epileptic Encephalopathy
Mode of pathogenicity for gene: AP2M1 was set to Other - please provide details in the comments
DDG2P v1.129 CACNA1B Rebecca Foulger gene: CACNA1B was added
gene: CACNA1B was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: CACNA1B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CACNA1B were set to 30982612
Phenotypes for gene: CACNA1B were set to NEURODEVELOPMENTAL DISORDER WITH SEIZURES AND NONEPILEPTIC HYPERKINETIC MOVEMENTS 618497
DDG2P v1.129 RRAS2 Rebecca Foulger gene: RRAS2 was added
gene: RRAS2 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: RRAS2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RRAS2 were set to 31130282; 31130285; 24705357
Phenotypes for gene: RRAS2 were set to Noonan syndrome
Mode of pathogenicity for gene: RRAS2 was set to Other - please provide details in the comments
DDG2P v1.129 WDR37 Rebecca Foulger gene: WDR37 was added
gene: WDR37 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: WDR37 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WDR37 were set to 31327508; 31327510
Phenotypes for gene: WDR37 were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: WDR37 was set to Other - please provide details in the comments
DDG2P v1.129 POLA1 Rebecca Foulger gene: POLA1 was added
gene: POLA1 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: POLA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: POLA1 were set to 31006512
Phenotypes for gene: POLA1 were set to VAN ESCH-O'DRISCOLL SYNDROME 301030
DDG2P v1.129 GPC4 Rebecca Foulger gene: GPC4 was added
gene: GPC4 was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: GPC4 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: GPC4 were set to 30982611
Phenotypes for gene: GPC4 were set to KEIPERT SYNDROME 301026
DDG2P v1.129 VAMP2 Rebecca Foulger gene: VAMP2 was added
gene: VAMP2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: VAMP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VAMP2 were set to 30929742
Phenotypes for gene: VAMP2 were set to INTELLECTUAL DISABILITY 616579
Mode of pathogenicity for gene: VAMP2 was set to Other - please provide details in the comments
DDG2P v1.129 POLR2A Rebecca Foulger gene: POLR2A was added
gene: POLR2A was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: POLR2A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: POLR2A were set to 31353023
Phenotypes for gene: POLR2A were set to SYNDROMIC INTELLECTUAL DISABILITY 612100
Mode of pathogenicity for gene: POLR2A was set to Other - please provide details in the comments
DDG2P v1.129 CSF1R Rebecca Foulger gene: CSF1R was added
gene: CSF1R was added to DDG2P. Sources: DD-Gene2Phenotype,Expert Review Green
Mode of inheritance for gene: CSF1R was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CSF1R were set to 30982608; 30982609
Phenotypes for gene: CSF1R were set to BRAIN ABNORMALITIES, NEURODEGENERATION, AND DYSOSTEOSCLEROSIS 618476
DDG2P v1.129 GOT2 Rebecca Foulger gene: GOT2 was added
gene: GOT2 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: GOT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GOT2 were set to 31422819
Phenotypes for gene: GOT2 were set to Malate-Aspartate Shuttle-Related Encephalopathy
Mode of pathogenicity for gene: GOT2 was set to Other - please provide details in the comments
DDG2P v1.129 NUP214 Rebecca Foulger gene: NUP214 was added
gene: NUP214 was added to DDG2P. Sources: Expert Review Amber,DD-Gene2Phenotype
Mode of inheritance for gene: NUP214 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUP214 were set to 31178128
Phenotypes for gene: NUP214 were set to Acute Febrile Encephalopathy 618426
Renal tubulopathies v1.192 AVPR2 Eleanor Williams Added comment: Comment on mode of pathogenicity: From Emma Ashton - NSIAD caused by gain of function mutations (mainly codon 137)
Renal tubulopathies v1.192 AVPR2 Eleanor Williams Mode of pathogenicity for gene: AVPR2 was changed from None to Other
Renal tubulopathies v1.191 AVPR2 Eleanor Williams commented on gene: AVPR2: Note: left mode of inheritance as X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males as there are reports of heterozygous females with NDI due to X-inactivation.
Undiagnosed metabolic disorders v1.373 TCN2 Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases reported in the literature.
Undiagnosed metabolic disorders v1.373 TCN2 Catherine Snow Publications for gene: TCN2 were set to 27604308
Undiagnosed metabolic disorders v1.372 TCN2 Catherine Snow Classified gene: TCN2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.372 TCN2 Catherine Snow Gene: tcn2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.371 TCN2 Catherine Snow reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 19373259; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.346 TCN2 Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases reported in the literature.
Likely inborn error of metabolism v1.346 TCN2 Catherine Snow Publications for gene: TCN2 were set to 27604308
Likely inborn error of metabolism v1.346 TCN2 Catherine Snow Classified gene: TCN2 as Green List (high evidence)
Likely inborn error of metabolism v1.346 TCN2 Catherine Snow Gene: tcn2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.345 TCN2 Catherine Snow reviewed gene: TCN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 19373259; Phenotypes: Transcobalamin II deficiency, 275350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.371 TAT Catherine Snow Publications for gene: TAT were set to 27604308
Undiagnosed metabolic disorders v1.370 TAT Catherine Snow Classified gene: TAT as Green List (high evidence)
Undiagnosed metabolic disorders v1.370 TAT Catherine Snow Gene: tat has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.369 TAT Catherine Snow reviewed gene: TAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 27604308, 28255985; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Likely inborn error of metabolism v1.345 TAT Catherine Snow Added comment: Comment on publications: PMID: 28255985 Reports on 106 families, represented by 143 individuals, carrying a total of 36 genetic variants. Variants include large deletions, non‐synonymous and nonsense amino‐acid changes, frameshifts and
splice variants.
Likely inborn error of metabolism v1.345 TAT Catherine Snow Publications for gene: TAT were set to 27604308; 28255985
Likely inborn error of metabolism v1.344 TAT Catherine Snow Publications for gene: TAT were set to 27604308; 28255985
Likely inborn error of metabolism v1.344 TAT Catherine Snow Publications for gene: TAT were set to 27604308
Likely inborn error of metabolism v1.343 TAT Catherine Snow Classified gene: TAT as Green List (high evidence)
Likely inborn error of metabolism v1.343 TAT Catherine Snow Gene: tat has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.342 TAT Catherine Snow reviewed gene: TAT: Rating: GREEN; Mode of pathogenicity: None; Publications: 28255985; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary systemic amyloidosis v1.0 Eleanor Williams promoted panel to version 1.0
Hereditary systemic amyloidosis v0.19 Eleanor Williams Panel types changed to GMS Rare Disease; GMS signed-off
Hereditary systemic amyloidosis v0.18 CST3 Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic case from a non-Icelandic individual.; to: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic case from a non-Icelandic individual. Agreement for the amber rating was confirmed with members of the GMS renal specialist test group.
Hereditary systemic amyloidosis v0.18 B2M Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber as only 1 family has been reported.; to: Comment on list classification: Demoting from green to amber as only 1 family has been reported. Agreement for the amber rating was confirmed with members of the GMS renal specialist test group.
Hereditary systemic amyloidosis v0.18 APOC3 Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber as only 1 family reported.; to: Comment on list classification: Demoting from green to amber as only 1 family reported. Agreement for the amber rating was confirmed with members of the GMS renal specialist test group.
Hereditary systemic amyloidosis v0.18 CST3 Eleanor Williams changed review comment from: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic cases from a non-Icelandic individual.; to: Comment on list classification: Demoting from green to amber. Same substitution L68Q in all cases reported so far, with it appearing to be a founder mutation in the Icelandic cases, with only one sporadic case from a non-Icelandic individual.
Hereditary systemic amyloidosis v0.18 TTR Eleanor Williams changed review comment from: Associated with Amyloidosis, hereditary, transthyretin-related (#105210) in OMIM. Lots of cases reported in OMIM.; to: Associated with Amyloidosis, hereditary, transthyretin-related (#105210) (AD) in OMIM. Lots of cases reported in OMIM.
Hereditary systemic amyloidosis v0.18 GSN Eleanor Williams commented on gene: GSN: OMIM reports that Maury, 1993 (PMID: 8395367, abstract only accessed) reports that 2 2 sibs, the offspring of 2 affected parents, who were by DNA test homozygous for the mutation and showed unusually early onset and severity of the disease , thus the BIALLELIC mutations cause a more SEVERE disease form mode of inheritiance seems appropriate.
Hereditary systemic amyloidosis v0.18 APOC2 Eleanor Williams commented on gene: APOC2: Checked that the variants are heterozygous in the two reported cases with amyloidosis (PMID: 30197986 and 27297947). Hyperlipoproteinemia, type Ib (#207750) is reported at autosomal recessive inheritance in OMIM.
Dilated Cardiomyopathy and conduction defects v1.63 PRDM16 Matthew Edwards reviewed gene: PRDM16: Rating: AMBER; Mode of pathogenicity: None; Publications: 24387996, 24387995; Phenotypes: Cardiomyopathy, LVNC; Mode of inheritance: None
Likely inborn error of metabolism v1.342 STS Catherine Snow Publications for gene: STS were set to 27604308; 1539590; 29672931
Likely inborn error of metabolism v1.341 STS Catherine Snow Publications for gene: STS were set to 27604308; 1539590; 29672931
Pain syndromes v1.8 PRDM12 Rebecca Foulger commented on gene: PRDM12
Likely inborn error of metabolism v1.341 STS Catherine Snow Publications for gene: STS were set to 27604308
Pain syndromes v1.8 PRDM12 Rebecca Foulger Phenotypes for gene: PRDM12 were changed from Hereditary sensory and autonomic neuropathy type VIII; HSAN 8; Neuropathy, hereditary sensory and autonomic, type VIII, 616488 to HSAN VIII; insensitivity to pain; Hereditary sensory and autonomic neuropathy type VIII; HSAN 8; Neuropathy, hereditary sensory and autonomic, type VIII, 616488
Likely inborn error of metabolism v1.340 STS Catherine Snow Classified gene: STS as Green List (high evidence)
Likely inborn error of metabolism v1.340 STS Catherine Snow Gene: sts has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.339 STS Catherine Snow edited their review of gene: STS: Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Pain syndromes v1.7 PRDM12 Rebecca Foulger Publications for gene: PRDM12 were set to 26005867; 26975306
Likely inborn error of metabolism v1.339 STS Catherine Snow reviewed gene: STS: Rating: GREEN; Mode of pathogenicity: None; Publications: 1539590, 29672931; Phenotypes: Ichthyosis, X-linked, 308100; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.369 STS Catherine Snow Added comment: Comment on publications: There are >3 unrelated cases.
Undiagnosed metabolic disorders v1.369 STS Catherine Snow Publications for gene: STS were set to 27604308; 1539590; 29672931
Undiagnosed metabolic disorders v1.368 STS Catherine Snow changed review comment from: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: Comment on list classification: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.
Undiagnosed metabolic disorders v1.368 STS Catherine Snow Publications for gene: STS were set to 27604308
Undiagnosed metabolic disorders v1.367 STS Catherine Snow Classified gene: STS as Green List (high evidence)
Undiagnosed metabolic disorders v1.367 STS Catherine Snow Gene: sts has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.366 STS Catherine Snow reviewed gene: STS: Rating: GREEN; Mode of pathogenicity: None; Publications: 1539590, 29672931; Phenotypes: Ichthyosis, X-linked, 308100; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early onset or syndromic epilepsy v1.363 NDUFAF4 Rebecca Foulger commented on gene: NDUFAF4: Amber ratings from Tracy Lester and Zornitza Stark support the current Amber rating of NDUFAF4.
Early onset or syndromic epilepsy v1.363 NDUFAF4 Rebecca Foulger Publications for gene: NDUFAF4 were set to
Early onset or syndromic epilepsy v1.362 NDUFAF4 Rebecca Foulger Phenotypes for gene: NDUFAF4 were changed from to Mitochondrial complex I deficiency, nuclear type 15, 618237
Early onset or syndromic epilepsy v1.361 NDUFAF4 Rebecca Foulger Mode of inheritance for gene: NDUFAF4 was changed from to BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Marked gene: CCND2 as ready
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Classified gene: CCND2 as Red List (low evidence)
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Added comment: Comment on list classification: Demoted CCND2 from Amber to Red following Red reviews by Zornitza Stark and Tracy Lester- as noted previously by Sarah Leigh: epilepsy is not a reported feature of the disorder.
Early onset or syndromic epilepsy v1.360 CCND2 Rebecca Foulger Gene: ccnd2 has been classified as Red List (Low Evidence).
Early onset or syndromic epilepsy v1.359 CCND2 Rebecca Foulger Mode of inheritance for gene: CCND2 was changed from to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.358 CCND2 Rebecca Foulger Publications for gene: CCND2 were set to
Early onset or syndromic epilepsy v1.357 CCND2 Rebecca Foulger Phenotypes for gene: CCND2 were changed from to Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3, 615938
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger Marked gene: ARID1B as ready
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger Gene: arid1b has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger commented on gene: ARID1B: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ARID1B.
Early onset or syndromic epilepsy v1.356 ARID1B Rebecca Foulger Publications for gene: ARID1B were set to
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger Marked gene: ASAH1 as ready
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger Gene: asah1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger commented on gene: ASAH1: The Green rating by Dr Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ASAH1.
Early onset or syndromic epilepsy v1.355 ASAH1 Rebecca Foulger Phenotypes for gene: ASAH1 were changed from Spinal muscular atrophy with progressive myoclonic epilepsy, 159950 to Spinal muscular atrophy with progressive myoclonic epilepsy, 159950; SMA with myoclonic epilepsy
Early onset or syndromic epilepsy v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 8955159; 22703880; 29169047; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Early onset or syndromic epilepsy v1.354 ASAH1 Rebecca Foulger Publications for gene: ASAH1 were set to 29169047; 22703880; 24164096; 30291339; 27026573; 29169047; 30291339; 27026573; 26526000; 25578555; 31216804; 27723502
Early onset or syndromic epilepsy v1.353 ISCA-37429-Loss Rebecca Foulger changed review comment from: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.; to: The Green rating by Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Early onset or syndromic epilepsy v1.353 CREBBP Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from 'imprinted status unknown' to 'NOT imprinted' to match reviews from GLH experts Tracy Lester and Alisdair McNeill.
Early onset or syndromic epilepsy v1.353 CREBBP Rebecca Foulger Mode of inheritance for gene: CREBBP was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 CREBBP Rebecca Foulger commented on gene: CREBBP: The Green rating by Dr Alisdair McNeill (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of CREBBP.
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss Rebecca Foulger Marked Region: ISCA-37429-Loss as ready
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss Rebecca Foulger Region: isca-37429-loss has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss Rebecca Foulger commented on Region: ISCA-37429-Loss: The Green rating by Alisdair McNeil (Sheffield Children's Hospital, Yorkshire and North East GLH) supports the current Green rating of ISCA-37429-Loss CNV.
Retinal disorders v1.199 IKBKG Catherine Snow Added comment: Comment on mode of inheritance: IKBKG is associated with IP as commented by Robert Henderson GOSH. IP is XLD in OMIM
Retinal disorders v1.199 IKBKG Catherine Snow Mode of inheritance for gene: IKBKG was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.198 IKBKG Catherine Snow Added comment: Comment on phenotypes: IKBKG is associated with IP as commented by Robert Henderson GOSH
Retinal disorders v1.198 IKBKG Catherine Snow Phenotypes for gene: IKBKG were changed from Incontinentia pigmenti, 308300 to Incontinentia pigmenti, 308300
Retinal disorders v1.197 IKBKG Catherine Snow Phenotypes for gene: IKBKG were changed from to Incontinentia pigmenti, 308300
Retinal disorders v1.196 IKBKG Catherine Snow Mode of inheritance for gene: IKBKG was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.195 IKBKG Catherine Snow Classified gene: IKBKG as Green List (high evidence)
Retinal disorders v1.195 IKBKG Catherine Snow Gene: ikbkg has been classified as Green List (High Evidence).
Retinal disorders v1.194 IKBKG Catherine Snow reviewed gene: IKBKG: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Incontinentia pigmenti, 308300; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.194 AIRE Catherine Snow Phenotypes for gene: AIRE were changed from to Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300
Retinal disorders v1.193 AIRE Catherine Snow Mode of inheritance for gene: AIRE was changed from to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v1.192 AIRE Catherine Snow Classified gene: AIRE as Green List (high evidence)
Retinal disorders v1.192 AIRE Catherine Snow Gene: aire has been classified as Green List (High Evidence).
Retinal disorders v1.191 AIRE Catherine Snow reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Retinal disorders v1.191 TPP1 Catherine Snow Mode of inheritance for gene: TPP1 was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.190 TPP1 Catherine Snow Phenotypes for gene: TPP1 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 2, 204500
Retinal disorders v1.189 TPP1 Catherine Snow Mode of inheritance for gene: TPP1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.188 TPP1 Catherine Snow Classified gene: TPP1 as Green List (high evidence)
Retinal disorders v1.188 TPP1 Catherine Snow Gene: tpp1 has been classified as Green List (High Evidence).
Retinal disorders v1.187 TPP1 Catherine Snow reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, 204500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.187 TIMM8A Catherine Snow Phenotypes for gene: TIMM8A were changed from Eye Disorders to Eye Disorders; Mohr-Tranebjaerg syndrome, 304700
Retinal disorders v1.186 TIMM8A Catherine Snow Mode of inheritance for gene: TIMM8A was changed from to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Retinal disorders v1.185 TIMM8A Catherine Snow Classified gene: TIMM8A as Green List (high evidence)
Retinal disorders v1.185 TIMM8A Catherine Snow Gene: timm8a has been classified as Green List (High Evidence).
Retinal disorders v1.184 TIMM8A Catherine Snow reviewed gene: TIMM8A: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Mohr-Tranebjaerg syndrome, 304700; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Retinal disorders v1.184 PPT1 Catherine Snow Phenotypes for gene: PPT1 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 1, 256730
Retinal disorders v1.183 PPT1 Catherine Snow Mode of inheritance for gene: PPT1 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.182 PPT1 Catherine Snow Classified gene: PPT1 as Green List (high evidence)
Retinal disorders v1.182 PPT1 Catherine Snow Gene: ppt1 has been classified as Green List (High Evidence).
Retinal disorders v1.181 PPT1 Catherine Snow reviewed gene: PPT1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 1, 256730; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Congenital disorders of glycosylation v1.32 Louise Daugherty Panel types changed to Rare Disease 100K; Component Of Super Panel
Retinal disorders v1.181 HCCS Catherine Snow Phenotypes for gene: HCCS were changed from Eye Disorders to Eye Disorders; Linear skin defects with multiple congenital anomalies 1, 309801
Retinal disorders v1.180 HCCS Catherine Snow Mode of inheritance for gene: HCCS was changed from to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.179 HCCS Catherine Snow Classified gene: HCCS as Green List (high evidence)
Retinal disorders v1.179 HCCS Catherine Snow Gene: hccs has been classified as Green List (High Evidence).
Retinal disorders v1.178 HCCS Catherine Snow reviewed gene: HCCS: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Linear skin defects with multiple congenital anomalies 1, 309801; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Retinal disorders v1.178 CTSD Catherine Snow Phenotypes for gene: CTSD were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 10, 610127
Retinal disorders v1.177 CTSD Catherine Snow Mode of inheritance for gene: CTSD was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.176 CTSD Catherine Snow Classified gene: CTSD as Green List (high evidence)
Retinal disorders v1.176 CTSD Catherine Snow Gene: ctsd has been classified as Green List (High Evidence).
Retinal disorders v1.175 COL18A1 Catherine Snow changed review comment from: COL18A1 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: COL18A1 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CLN5 Catherine Snow changed review comment from: CLN5 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CLN5 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CLN6 Catherine Snow changed review comment from: CLN6 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CLN6 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CLN8 Catherine Snow changed review comment from: CLN8 rated as Green and with a relevant phenotype following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CLN8 rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CTSD Catherine Snow changed review comment from: CTSD rated as Green and with a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.; to: CTSD rated as Green as has a relevant phenotype to be included on the panel following discussion in Genomics England Clinical Team Meeting, 7th October 2019.
Retinal disorders v1.175 CTSD Catherine Snow reviewed gene: CTSD: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 10, 610127; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.175 COL18A1 Catherine Snow Classified gene: COL18A1 as Green List (high evidence)
Retinal disorders v1.175 COL18A1 Catherine Snow Gene: col18a1 has been classified as Green List (High Evidence).
Retinal disorders v1.174 COL18A1 Catherine Snow reviewed gene: COL18A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Knobloch syndrome, type 1, 267750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.174 CLN8 Catherine Snow Phenotypes for gene: CLN8 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 8, 600143
Retinal disorders v1.173 CLN8 Catherine Snow Mode of inheritance for gene: CLN8 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.172 CLN8 Catherine Snow Classified gene: CLN8 as Green List (high evidence)
Retinal disorders v1.172 CLN8 Catherine Snow Gene: cln8 has been classified as Green List (High Evidence).
Retinal disorders v1.171 CLN8 Catherine Snow reviewed gene: CLN8: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 8, 600143; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.171 CLN6 Catherine Snow Phenotypes for gene: CLN6 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 6 601780
Retinal disorders v1.170 CLN6 Catherine Snow Mode of inheritance for gene: CLN6 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.169 CLN6 Catherine Snow Classified gene: CLN6 as Green List (high evidence)
Retinal disorders v1.169 CLN6 Catherine Snow Gene: cln6 has been classified as Green List (High Evidence).
Retinal disorders v1.168 CLN6 Catherine Snow reviewed gene: CLN6: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 6 601780; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.168 CLN5 Catherine Snow Classified gene: CLN5 as Green List (high evidence)
Retinal disorders v1.168 CLN5 Catherine Snow Gene: cln5 has been classified as Green List (High Evidence).
Retinal disorders v1.167 CLN5 Catherine Snow Mode of inheritance for gene: CLN5 was changed from to BIALLELIC, autosomal or pseudoautosomal
Retinal disorders v1.166 CLN5 Catherine Snow Phenotypes for gene: CLN5 were changed from Eye Disorders to Eye Disorders; Ceroid lipofuscinosis, neuronal, 5, 256731
Familial hypercholesterolaemia (GMS) v0.2 Rebecca Foulger Panel status changed from internal to public
Retinal disorders v1.165 CLN5 Catherine Snow reviewed gene: CLN5: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Ceroid lipofuscinosis, neuronal, 5, 256731; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Familial hypercholesterolaemia v1.26 Rebecca Foulger Panel types changed to Rare Disease 100K
Familial hypercholesterolaemia (GMS) v0.1 PCSK9 Rebecca Foulger gene: PCSK9 was added
gene: PCSK9 was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: PCSK9 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: PCSK9 were set to 16224054; 23433573
Phenotypes for gene: PCSK9 were set to Hypercholesterolemia, familial, 3, 603776; Familial Hypercholesterolaemia; Hypercholesterolemia; {Low density lipoprotein cholesterol level QTL 1}, 603776; Familial Hypercholesterolemia
Mode of pathogenicity for gene: PCSK9 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Familial hypercholesterolaemia (GMS) v0.1 LDLRAP1 Rebecca Foulger gene: LDLRAP1 was added
gene: LDLRAP1 was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: LDLRAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LDLRAP1 were set to 12417523
Phenotypes for gene: LDLRAP1 were set to Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia; Hypercholesterolemia, familial, 4, 603813
Familial hypercholesterolaemia (GMS) v0.1 LDLR Rebecca Foulger gene: LDLR was added
gene: LDLR was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: LDLR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LDLR were set to 17142622; 25414277; 23433573
Phenotypes for gene: LDLR were set to LDL cholesterol level QTL2, 143890; Familial Hypercholesterolaemia; Hypercholesterolemia; Familial Hypercholesterolemia; Hypercholesterolemia, familial, 1, 143890
Familial hypercholesterolaemia (GMS) v0.1 APOE Rebecca Foulger gene: APOE was added
gene: APOE was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,Emory Genetics Laboratory,Expert Review Green
Mode of inheritance for gene: APOE was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: APOE were set to 11095479; 23433584; 24267230; 26802169; 16094309; 22481068; 22949395
Phenotypes for gene: APOE were set to Hyperlipoproteinemia, type III 617347
Familial hypercholesterolaemia (GMS) v0.1 APOB Rebecca Foulger gene: APOB was added
gene: APOB was added to Familial hypercholesterolaemia - targeted panel. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green,Illumina TruGenome Clinical Sequencing Services,Emory Genetics Laboratory
Mode of inheritance for gene: APOB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: APOB were set to 8141833; 25414277; 23433573
Phenotypes for gene: APOB were set to Familial Hypercholesterolemia; Familial Hypercholesterolaemia; Hypercholesterolemia, familial, 2, 144010; Hypercholesterolemia
Mode of pathogenicity for gene: APOB was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Familial hypercholesterolaemia (GMS) v0.0 Rebecca Foulger Added Panel Familial hypercholesterolaemia - targeted panel
Set panel types to: GMS Rare Disease
DDG2P v1.128 SOX11 alisdair mcneill reviewed gene: SOX11: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 ISCA-37429-Loss alisdair mcneill reviewed Region: ISCA-37429-Loss: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 FLNA alisdair mcneill reviewed gene: FLNA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 CREBBP alisdair mcneill reviewed gene: CREBBP: Rating: GREEN; Mode of pathogenicity: None; Publications: 29460469; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early onset or syndromic epilepsy v1.352 ASAH1 alisdair mcneill reviewed gene: ASAH1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: SMA with myoclonic epilepsy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.352 ARID1B alisdair mcneill reviewed gene: ARID1B: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Intellectual disability v2.1065 FBXW11 Catherine Snow Classified gene: FBXW11 as Green List (high evidence)
Intellectual disability v2.1065 FBXW11 Catherine Snow Gene: fbxw11 has been classified as Green List (High Evidence).
Intellectual disability v2.1064 FBXW11 Catherine Snow reviewed gene: FBXW11: Rating: GREEN; Mode of pathogenicity: None; Publications: 31402090, 16865294; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1064 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Intellectual disability v2.1064 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, support gene-disease association.
Intellectual disability v2.1064 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Intellectual disability v2.1063 SMPD4 Louise Daugherty Tag watchlist was removed from gene: SMPD4.
Intellectual disability v2.1063 SMPD4 Louise Daugherty Added comment: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Intellectual disability v2.1063 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Arthrogryposis v2.45 SMPD4 Louise Daugherty changed review comment from: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.; to: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases support gene-disease association.
Cerebellar hypoplasia v1.39 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Cerebellar hypoplasia v1.39 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, support gene-disease association.
Cerebellar hypoplasia v1.39 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Cerebellar hypoplasia v1.38 SMPD4 Louise Daugherty Added comment: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Cerebellar hypoplasia v1.38 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Arthrogryposis v2.45 SMPD4 Louise Daugherty changed review comment from: Comment on publications: Publication Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.; to: Comment on publications: Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Arthrogryposis v2.45 SMPD4 Louise Daugherty Classified gene: SMPD4 as Green List (high evidence)
Arthrogryposis v2.45 SMPD4 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Arthrogryposis v2.45 SMPD4 Louise Daugherty Gene: smpd4 has been classified as Green List (High Evidence).
Arthrogryposis v2.44 SMPD4 Louise Daugherty Tag watchlist was removed from gene: SMPD4.
Arthrogryposis v2.44 SMPD4 Louise Daugherty Added comment: Comment on publications: Publication Magini P et al. (October 2019) Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.
Arthrogryposis v2.44 SMPD4 Louise Daugherty Publications for gene: SMPD4 were set to
Early onset or syndromic epilepsy v1.352 KCNA1 Rebecca Foulger Publications for gene: KCNA1 were set to 29056246; 11026449; 9581771
Early onset or syndromic epilepsy v1.351 KCNA1 Rebecca Foulger edited their review of gene: KCNA1: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Early onset or syndromic epilepsy v1.351 SCN9A Rebecca Foulger edited their review of gene: SCN9A: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Early onset or syndromic epilepsy v1.351 FLNA Rebecca Foulger edited their review of gene: FLNA: Added comment: Added a Red review to highlight the comment from Diane Cairns (Manchester University NHS, North West GLH) that it would be acceptable to remove this gene from the Epilepsy Panel.; Changed rating: RED
Undiagnosed monogenic disorder seen in a specialist genetics clinic v1.0 Ellen McDonagh promoted panel to version 1.0
Undiagnosed monogenic disorder seen in a specialist genetics clinic v0.4 Ellen McDonagh List of related panels changed from to
Panel status changed from internal to public
Ultra-rare undescribed monogenic disorders v1.0 Ellen McDonagh promoted panel to version 1.0
Ultra-rare undescribed monogenic disorders v0.5 Ellen McDonagh Panel status changed from internal to public
Early onset or syndromic epilepsy v1.351 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
------------

[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature
Intellectual disability v2.1062 TDP2 Konstantinos Varvagiannis gene: TDP2 was added
gene: TDP2 was added to Intellectual disability. Sources: Literature,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TDP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TDP2 were set to 24658003; 30109272; 31410782
Phenotypes for gene: TDP2 were set to Spinocerebellar ataxia, autosomal recessive 23, 616949)
Penetrance for gene: TDP2 were set to unknown
Review for gene: TDP2 was set to GREEN
gene: TDP2 was marked as current diagnostic
Added comment: Biallelic pathogenic TGP2 variants cause Spinocerebellar ataxia, autosomal recessive 23 (MIM 616949). At least 6 affected individuals from 4 families have been reported, in all cases homozygous for LoF variants (3 different). ID, epilepsy and ataxia are consistent features of the disorder.

TDP2 encodes a phosphodiesterase that is required for efficient repair of double strand breaks (DSBs) produced by abortive topoisomerase II (TOP2) activity.

The gene is expressed in fetal and adult human brain.

Evidence at the variant level (mRNA, protein levels) and additional studies for impairment of TOP2-induced DSB repair support a role.

Animal models (primarily mice) reproduce the DSB repair defect, provide some histopathological evidence, show transcriptional dysregulation of genes (in line with the role of TOP2 in transcription). They have however failed to reproduce relevant neurological phenotypes.

Published studies are summarized below.

TDP2 is included in gene panels for ID offered by some diagnostic laboratories (incl. Radboudumc and GeneDx). There is no associated phenotype in G2P. TDP2 is listed among the current primary ID genes in SysID.

Overall, this gene could be considered for inclusion in the ID and epilepsy panels probably as green (>=3 patients/families/variants, relevant ID and seizures in all, expression in brain, mRNA/protein levels tested, impaired activity) or amber (absence of neurological phenotypes in mouse model).
------------

[1] - PMID: 24658003 (Gómez-Herreros et al. 2014):
Reports 3 individuals from a consanguineous Irish family. Features included seizures (onset by 2m, 6m and 12y), ID (3/3) and ataxia (3/3).

A splicing variant (NM_016614.3:c.425+1G>A) was found in a 9.08-Mb region of homozygosity shared by all. A further ZNF193 missense variant localizing in the same region was thought unlikely to contribute to the phenotype (evidence also provided in subsequent study).

The effect of the specific variant was proven by abnormal mRNA size, lower mRNA levels due to NMD (corrected upon cyclohexamide treatment), loss of TDP2 protein upon WB, loss of protein activity in lymphoblastoid cells from affected individuals, decreased repair of DSBs and increased cell death upon addition of etoposide (which promotes TOP2 abortive activity).

The authors report very briefly on a further patient (from Egypt), with ID, 'reports of fits' and ataxia. This individual, with also affected sibs, was homozygous LoF (c.413_414delinsAA / p.Ser138*). Again, the authors were not able to detect TDP2 activity in blood from this subject.

As also commented:
- TDP2 has relevant expression in human (particularly adult) brain.
- Mouse model : Tdp2 is expressed in relevant tissues, absence of Tdp2 activity was observed in neural tissue of mice homoyzgous for an ex1-3 del, with impairment of DSB repair. The authors were unable to detect a neurological phenotype with behavioral analyses, preliminary assesment of seizure propensity. Mice did not show developmental defects. Histopathology however, revealed ~25% reduction in the density of interneurons in cerebellum (a 'hallmark of DSB repair' and associated with seizures and ataxia). Transcription of several genes was shown to be disregulated.
- Knockdown in zebrafish appears to affect left-right axis detremination (cited PMID: 18039968).

[2] - PMID: 30109272 (Zagnoli-Vieira et al. 2018):
A 6 y.o. male with seizures (onset by 5m), hypotonia, DD and ID, microcephaly and some additional clinical features and testing (ETC studies on muscle biopsy, +lactate, +(lactate/pyruvate) ratio) which could be suggestive of mitochondrial disorder. This individual from the US was homozygous for the c.425+1G>A variant but lacked the ZNF193 one (despite a shared haplotype with the Irish patients). Again absence of the protein was shown upon WB in patient fibroblasts, also supported by its activity. Complementation studies restored the DSB repair defect. The defect was specific to TOP2-induced DSBs as suggested by hypersensitivity to etoposide but not to ionizing radiation. CRISPR/Cas9 generated mutant human A549 cells demonstrated abnormal DSB repair. Fibroblasts / edited A549 cells failed to show mitochondrial defects (which were noted in muscle).

[3] - PMID: 31410782 (Ciaccio et al. 2019):
A girl born to consanguineous Italian parents, presented with moderate/severe ID, seizures (onset at 12y) and - among others - gait ataxia, tremor and dysmetria. MRI at the age of 12, demonstrated cerebellar atrophy (although previous exams were N). WES revealed a homozygous nonsense variant (c.400C>T / p.Arg134Ter) for which each parent was found to be carrier. Previous investigations included aCGH, NGS testing for epilepsy and metabolic testing.
Sources: Literature, Radboud University Medical Center, Nijmegen
Intellectual disability v2.1062 PCDH12 Konstantinos Varvagiannis reviewed gene: PCDH12: Rating: ; Mode of pathogenicity: None; Publications: 27164683, 28804758, 29556033, 30178464, 30459466, 18477666; Phenotypes: Microcephaly, seizures, spasticity, and brain calcification, 251280; Mode of inheritance: None; Current diagnostic: yes
Intellectual disability v2.1062 NKAP Konstantinos Varvagiannis reviewed gene: NKAP: Rating: GREEN; Mode of pathogenicity: None; Publications: DOI: 10.1016/j.ajhg.2019.09.009; Phenotypes: Global developmental delay, Intellectual disability, Tall stature, Scoliosis, Pectus excavatum, Pectus carinatum, Arachnodactyly, Camptodactyly, Abnormality of the cardiovascular system, Abnormality of the genitourinary system, Abnormality of the face, Obesity; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early onset or syndromic epilepsy v1.351 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Genetic epilepsy syndromes. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set 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
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to AMBER
Added comment: This gene was reviewed for the ID panel (details below).

It could be also be considered for inclusion in the epilepsy panel as amber/green.

[Seizures in 8/14 individuals (generalized tonic-clonic/myoclonic, onset 3m - 6yrs) although some individuals were too young when last examined (eg. 8m) and sibs in one family (F7) were discordant for this feature at the ages of 4y7m (+) and 6y (-). Lissencephaly is often associated with seizures which have occasionally been observed in Apc2-deficient mice (PMID cited: 22573669)].

-----

Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
Sources: Literature
Intellectual disability v2.1062 APC2 Konstantinos Varvagiannis gene: APC2 was added
gene: APC2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: APC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APC2 were set to 31585108; 25753423; 19759310; 22573669
Phenotypes for gene: APC2 were set to Global developmental delay; Intellectual disability; Seizures; Morphological abnormality of the central nervous system
Penetrance for gene: APC2 were set to Complete
Review for gene: APC2 was set to GREEN
gene: APC2 was marked as current diagnostic
Added comment: Probably 14 individuals from 9 families (8 consanguineous) with biallelic APC2 LoF variants have been reported.

ID and brain abnormalities were features in all, although the presentation was quite different between sibs in the first report (PMID: 25753423 - mild/mod ID, ventriculomegaly and CC anomalies, macrocephaly with variable height, Sotos-like facial features) and 12 subsequently described patients (PMID: 31585108 - severe ID, P>A lissencephaly/CC anomalies/ventriculomegaly/paucity of white matter in (almost) all, gT-C/myoclonic seizures in 8/12 with onset 3m-6y, OFC in the low percentiles).

In all cases relevant alternative diagnoses (eg. macrocephaly/overgrowth syndromes - 1st report, mutations in other lissencephaly genes, metabolic disorders - 2nd) were ruled out.

APC2 encodes Adenomatous polyposis coli protein 2, expressed in the CNS.

All variants reported to date were LoF (stopgain/frameshift/splicing) and were supported by parental-only studies. Mutations in the 1st report as well as 4/8 variants from the 2nd report localized within the last exon (NM_005883.2 / longest of >=3 isoforms), although the 2nd report did not observe obvious genotype-phenotype correlations.

Despite a pLI of 1 in gnomAD, Lee et al. comment that heterozygous carriers did not have any noticeable phenotype. They further note that carriers were not examined by brain MRI, though. 27 heterozygous high-confidence variants appear in individuals in gnomAD. Finally as commented on, APC2 is not mutated in colon cancer.

Animal models: Apc -/- mice displayed disrupted neuronal migration, with defects of lamination of cerebral cortex and cerebellum supporting the observed brain abnormalities. In addition Apc2-deficient mice also presented impaired learning and memory abilities. Extensive additional studies have shown Apc2 co-localization with microtubules affecting their stabilization, distribution along actin fibers (all supporting a role in cytoskeletal organization) and regulation of Rac1 (a Rho GTPase). Generation of Neuro2a cells demonstrated abnormal localization mainly in cell bodies of mutant hAPC2 proteins (due to frameshift in the last exon / deletion of the C-terminal part) - different from wt (neurites, growth cones, cell bodies). The first patient report also provided evidence for Apc2 being a downstream effector of Nsd1, with Nsd1 knockdown brains displaying impaired migration / laminar positioning of cortical neurons (similar to Apc2-/- model) and rescued by forced expression of Apc2.

Relevant articles:
PMIDs: 19759310 and 22573669 (Shintani et al. 2009 & 2012) [mouse model]
PMID: 25753423 (Almuriekhi et al. 2015) [2 individuals + mouse model]
PMID: 31585108 (Lee et al. 2019) [12 individuals from 8 families]
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In OMIM, the APC2-related phenotype is ?Sotos syndrome 3 (MIM 617169 - AR). G2P does not have any associated phenotype for this gene. In SysID, APC2 belongs to the Current primary ID genes.
APC2 is included in gene panels for ID offered by some diagnostic laboratories (eg. Radboudumc, GeneDx).
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Overall, this gene could be considered for inclusion in the ID panel probably as green (>3 individuals/families/variants, highly specific pattern of lissencephaly in 12/14, mouse model supporting migration defects and impaired learning/memory) rather than amber (differences between the 1st and the other families reported as for the OFC and presence of lissencephaly).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis changed review comment from: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature; to: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Intellectual disability v2.1062 CDH2 Konstantinos Varvagiannis gene: CDH2 was added
gene: CDH2 was added to Intellectual disability. Sources: Literature
Mode of inheritance for gene: CDH2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CDH2 were set to 31585109; 9015265; 17222817
Phenotypes for gene: CDH2 were set to Abnormality of the corpus callosum; Abnormality of neuronal migration; Bimanual synkinesia; Duane anomaly; Abnormality of cardiovascular system; Abnormality of the eye; Abnormality of the genital system; Global developmental delay; Intellectual disability
Penetrance for gene: CDH2 were set to unknown
Review for gene: CDH2 was set to AMBER
Added comment: Accogli et al. (2019 - PMID: 31585109) report on 9 individuals with de novo pathogenic CDH2 variants.

Overlapping features included axon pathfinding defects (corpus callosum agenesis/hypoplasia, mirror movements, Duane anomaly), cardiac, ocular and genital anomalies. Neurodevelopmental phenotypes included DD (8/9), ID (2/8 mild and 2/8 moderate, the remaining had either low-average/borderline int. functioning (2), did not present ID (2) or did not have relevant age for evaluation) and ASD (in 2).

CDH2 encodes cadherin-2 (N-cadherin) with high expression in neural tissue. As the authors note, the gene has important role in neural development, incl. proliferation and differentiation of neural progenitor cells, neural tube formation, synaptogenesis, neuronal migration and axon elongation. N-cadherin, similar to other classical cadherins has an extracellular domain with 5 extracellular cadherin (EC) domain repeats that mediate cell adhesion either in cis or in trans (between molecules of the same / different cells).

Mutations in other cadherins have been associated among others with neurodevelopmental disorders (eg. PCDH19, PCDH12, etc).

Variants in all cases were de novo, identified following trio-WES. 7 missense variants (6 of which clustering within the EC4-EC5 linker region or the EC5 domain - calculated p=1.37x10-4) and 2 frameshift ones predicted not to lead to NMD were identified.

One individual had an additional DNM1 variant, formally fulfilling ACMG criteria for pathogenic. The authors however felt that presentation of the specific subject (low-average/borderline int. functioning, absence of seizures and microcephaly) was not compatible with the phenotype of DNM1-encephalopathy .

Missense SNVs within the EC4-EC5 region, were shown to impair cell-cell adhesion by affecting both self-binding and trans adhesion to wt N-cadherin (in L cells studied). This supported a possible dominant-negative effect. A single variant in the EC2 domain - previously shown to be critical for adhesion - was thought to have a similar effect. The authors speculated that truncating variants may also act in a dominant-negative manner (as has been demonstrated for other cadherins) although LoF remains possible.

Cdh2 knockout in mice is embryonically lethal. Mouse with conditional inactivation of Cdh2 in the cerebral cortex leads to cortical disorganization and CCA similar to the human phenotypes (PMIDs cited: 9015265, 17222817). Other animal studies (mouse, zebrafish, chicken, dog, etc) are also cited to link with specific defects.

Heterozygous CDH2 variants affecting the ectodomain have been associated with ARVC (2 variants, one of which segregated with the disorder in a 3-generation family, the other identified in two unrelated families with several affecteds - refs. provided in the article). Cardiac abnormalities were noted in several subjects (incl. electrical activity in 2). [Amber rating of this gene in Arrhythmogenic cardiomyopathy panel].
------
The gene is not associated with any phenotype in OMIM / G2P / SysID and not commonly included in panels for ID.
------
As a result CDH2 could be considered for inclusion in the ID panel probably as amber (mild/moderate ID in 4/8, uncertainty regarding the underlying effect of some variants or additional phenotypes (ARVC)) or green (>3 individuals/variants/families, ID is a feature and in some cases of moderate degree).
Sources: Literature
Likely inborn error of metabolism v1.339 PIGM Sarah Leigh Deleted their comment
Undiagnosed metabolic disorders v1.366 ISCA2 Sarah Leigh Classified gene: ISCA2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.366 ISCA2 Sarah Leigh Gene: isca2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.339 ISCA2 Sarah Leigh Classified gene: ISCA2 as Green List (high evidence)
Likely inborn error of metabolism v1.339 ISCA2 Sarah Leigh Gene: isca2 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.365 ISCA2 Sarah Leigh gene: ISCA2 was added
gene: ISCA2 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ISCA2 were set to 25539947; 29359243
Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4 616370
Review for gene: ISCA2 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two different ethinicities. Rated green based on review of Anna de Burca (Clinical Fellow, Genomic England).
Sources: Literature
Likely inborn error of metabolism v1.338 ISCA2 Sarah Leigh Added comment: Comment on phenotypes: infantile neurodegenerative mitochondrial disorder
Likely inborn error of metabolism v1.338 ISCA2 Sarah Leigh Phenotypes for gene: ISCA2 were changed from Multiple mitochondrial dysfunctions syndrome 4 616370 to Multiple mitochondrial dysfunctions syndrome 4 616370
Likely inborn error of metabolism v1.337 ISCA2 Sarah Leigh Publications for gene: ISCA2 were set to 25539947; 29359243; 29122497
Intellectual disability v2.1062 MED25 Helen Brittain edited their review of gene: MED25: Added comment: There are now different variants (potentially each founders) in three populations, and several families, that have been reported in association with ID. Therefore the evidence for a green rating in terms of a gene:disease association now seems sufficient. To determine the extent of the phenotype, in terms of associated features, further cases would be beneficial. Therefore I would currently recommend a green rating for the ID panel.; Changed rating: GREEN; Changed phenotypes: Basel-Vanagait-Smirin-Yosef syndrome 616449; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v1.77 MT-TI James Eden reviewed gene: MT-TI: Rating: AMBER; Mode of pathogenicity: None; Publications: 12767666; Phenotypes: ; Mode of inheritance: MITOCHONDRIAL
Intellectual disability v2.1062 INTS1 Rebecca Foulger Phenotypes for gene: INTS1 were changed from Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system to Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies, 618571; Hypotonia; Global developmental delay; Cataract; Abnormality of the skeletal system
Intellectual disability v2.1061 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Early onset or syndromic epilepsy v1.351 AP2M1 Rebecca Foulger Phenotypes for gene: AP2M1 were changed from Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior to Intellectual developmental disorder 60 with seizures, 618587; Seizures; Ataxia; Generalized hypotonia; Intellectual disability; Global developmental delay; Autistic behavior
Intellectual disability v2.1060 RAC3 Rebecca Foulger Phenotypes for gene: RAC3 were changed from 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, 618577; Abnormality of brain morphology, Abnormal muscle tone, Neurodevelopmental delay, Intellectual disability; Abnormality of brain morphology; Abnormal muscle tone; Neurodevelopmental delay; Intellectual disability
Intellectual disability v2.1059 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Early onset or syndromic epilepsy v1.350 PIGU Rebecca Foulger Phenotypes for gene: PIGU were changed from myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis to Glycosylphosphatidylinositol biosynthesis defect 2, 618590; myoclonic seizures; focal myoclonic seizures; Global developmental delay; Intellectual disability; Seizures; Cerebral atrophy; Cerebellar hypoplasia; Scoliosis
Early onset or syndromic epilepsy v1.349 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome to Epileptic encephalopathy, early infantile, 77, 618548; Intractable seizures; developmental delay; optic atrophy; epilepsy; Ohtahara syndrome
Intellectual disability v2.1058 PIGQ Rebecca Foulger Phenotypes for gene: PIGQ were changed from SEVERE EARLY-ONSET EPILEPSY to SEVERE EARLY-ONSET EPILEPSY; Epileptic encephalopathy, early infantile, 77, 618548
Intellectual disability v2.1057 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Early onset or syndromic epilepsy v1.348 PIGB Rebecca Foulger Phenotypes for gene: PIGB were changed from Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot to Epileptic encephalopathy, early infantile, 80, 618580; Generalized hypotonia; Global developmental delay; Intellectual disability; Seizures; Hearing abnormality; Abnormality of vision; Elevated alkaline phosphatase; Abnormality of the head; Abnormality of the hand; Abnormality of the foot
Intellectual disability v2.1056 HNRNPR Catherine Snow Classified gene: HNRNPR as Green List (high evidence)
Intellectual disability v2.1056 HNRNPR Catherine Snow Gene: hnrnpr has been classified as Green List (High Evidence).
Intellectual disability v2.1055 HNRNPR Catherine Snow reviewed gene: HNRNPR: Rating: GREEN; Mode of pathogenicity: None; Publications: 31079900, 26795593; Phenotypes: Intellectual Disability; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Intellectual disability v2.1055 DDX6 Catherine Snow Classified gene: DDX6 as Green List (high evidence)
Intellectual disability v2.1055 DDX6 Catherine Snow Gene: ddx6 has been classified as Green List (High Evidence).
Intellectual disability v2.1054 DDX6 Catherine Snow reviewed gene: DDX6: Rating: GREEN; Mode of pathogenicity: None; Publications: 31422817; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic right ventricular cardiomyopathy v1.41 FLNC Ellen McDonagh Phenotypes for gene: FLNC were changed from to v
Arrhythmogenic right ventricular cardiomyopathy v1.40 CDH2 Ellen McDonagh Classified gene: CDH2 as Amber List (moderate evidence)
Arrhythmogenic right ventricular cardiomyopathy v1.40 CDH2 Ellen McDonagh Added comment: Comment on list classification: Was agreed by the GMS Cardiology Specialist Group that this should be Amber rating on a call on Thursday 3rd October 2019.
Arrhythmogenic right ventricular cardiomyopathy v1.40 CDH2 Ellen McDonagh Gene: cdh2 has been classified as Amber List (Moderate Evidence).
Dilated and arrhythmogenic cardiomyopathy v0.50 LAMP2 Ellen McDonagh Classified gene: LAMP2 as Red List (low evidence)
Dilated and arrhythmogenic cardiomyopathy v0.50 LAMP2 Ellen McDonagh Gene: lamp2 has been classified as Red List (Low Evidence).
Dilated and arrhythmogenic cardiomyopathy v0.49 FLNC Ellen McDonagh Classified gene: FLNC as Red List (low evidence)
Dilated and arrhythmogenic cardiomyopathy v0.49 FLNC Ellen McDonagh Gene: flnc has been classified as Red List (Low Evidence).
Dilated and arrhythmogenic cardiomyopathy v0.48 DMD Ellen McDonagh Classified gene: DMD as Red List (low evidence)
Dilated and arrhythmogenic cardiomyopathy v0.48 DMD Ellen McDonagh Gene: dmd has been classified as Red List (Low Evidence).
Dilated and arrhythmogenic cardiomyopathy v0.47 BAG3 Ellen McDonagh Classified gene: BAG3 as Red List (low evidence)
Dilated and arrhythmogenic cardiomyopathy v0.47 BAG3 Ellen McDonagh Gene: bag3 has been classified as Red List (Low Evidence).
Arrhythmogenic right ventricular cardiomyopathy v1.39 CDH2 Ellen McDonagh Mode of inheritance for gene: CDH2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Arrhythmogenic right ventricular cardiomyopathy v1.38 CDH2 Ellen McDonagh Publications for gene: CDH2 were set to
Arrhythmogenic right ventricular cardiomyopathy v1.37 CDH2 Ellen McDonagh gene: CDH2 was added
gene: CDH2 was added to Arrhythmogenic cardiomyopathy. Sources: Expert list
Mode of inheritance for gene: CDH2 was set to Unknown
DDG2P v1.127 SNORD118 Rebecca Foulger Phenotypes for gene: SNORD118 were changed from Leukoencephalopathy with cerebral calcification & cysts to Leukoencephalopathy with cerebral calcification & cysts 614561
DDG2P v1.126 SNORD118 Rebecca Foulger changed review comment from: Original DDG2P rating: both DD and IF. ; to: Original DDG2P rating for Leukoencephalopathy with cerebral calcification & cysts: both DD and IF. DDG2P Mutation consequence: loss of function; DDG2P allelic requirement: biallelic.
Paediatric or syndromic cardiomyopathy v0.13 ACADVL James Eden reviewed gene: ACADVL: Rating: GREEN; Mode of pathogenicity: None; Publications: 24285112, 9973285; Phenotypes: VLCAD deficiency 201475; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
DDG2P v1.126 SNORD118 Rebecca Foulger commented on gene: SNORD118: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is now 'both RD and IF' for Leukoencephalopathy with cerebral calcification & cysts.
DDG2P v1.126 MYH6 Rebecca Foulger changed review comment from: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is no 'RD and IF' for all three disorders: ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY DILATED TYPE 1EE; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14.; to: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is now 'RD and IF' for all three disorders: ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY DILATED TYPE 1EE; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14.
DDG2P v1.126 MYH6 Rebecca Foulger changed review comment from: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder).; to: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder). Therefore the rating is no 'RD and IF' for all three disorders: ATRIAL SEPTAL DEFECT TYPE 3; CARDIOMYOPATHY DILATED TYPE 1EE; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14.
DDG2P v1.126 MYH6 Rebecca Foulger Phenotypes for gene: MYH6 were changed from CARDIOMYOPATHY DILATED TYPE 1EE 613252; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14 613251; ATRIAL SEPTAL DEFECT TYPE 3 160710 to CARDIOMYOPATHY DILATED TYPE 1EE 613252; CARDIOMYOPATHY FAMILIAL HYPERTROPHIC TYPE 14 613251; ATRIAL SEPTAL DEFECT TYPE 3 614089
DDG2P v1.125 MYH6 Rebecca Foulger commented on gene: MYH6: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder).
DDG2P v1.125 BRCA1 Rebecca Foulger commented on gene: BRCA1: In a Gene2Phenotype update (September 2019) the G2P confidence rating of 'both DD and IF' was changed to 'both RD and IF' (where RD = relevant disease and IF = incidental disorder).
DDG2P v1.125 BRCA1 Rebecca Foulger Phenotypes for gene: BRCA1 were changed from INTELLECTUAL DISABILITY to INTELLECTUAL DISABILITY 616579
DDG2P v1.124 KDM5B Rebecca Foulger Publications for gene: KDM5B were set to 24307393; 28720891
DDG2P v1.123 KDM5B Rebecca Foulger Added comment: Comment on mode of inheritance: Changed Mode of inheritance from 'monoallelic' to 'BOTH monoallelic and biallelic' to match the September 2019 DDG2P update.
DDG2P v1.123 KDM5B Rebecca Foulger Mode of inheritance for gene: KDM5B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.122 KDM5B Rebecca Foulger Classified gene: KDM5B as Amber List (moderate evidence)
DDG2P v1.122 KDM5B Rebecca Foulger Added comment: Comment on list classification: Updated rating of KDM5B from Red to Amber: A DDG2P update (September 2019) has changed the rating from 'possible' to 'probable'. The Mode of inheritance was also changed in the September 2019 update from monoallelic to both monoallelic and biallelic.
DDG2P v1.122 KDM5B Rebecca Foulger Gene: kdm5b has been classified as Amber List (Moderate Evidence).
DDG2P v1.121 KDM5B Rebecca Foulger changed review comment from: Original DDG2P rating: possible. ; to: Original DDG2P rating for Autism: possible. DDG2P Mutation consequence: loss of function. Mode of inheritance: monoallelic.
Early onset or syndromic epilepsy v1.347 ACTL6B Rebecca Foulger commented on gene: ACTL6B: ACTL6B now has a 'confirmed' rating for 'EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE' in the DD panel of Gene2Phenotype (DDG2P update, 18/09/2019), supporting the Green rating of ACTL6B on this panel.
DDG2P v1.121 ACTL6B Rebecca Foulger Classified gene: ACTL6B as Green List (high evidence)
DDG2P v1.121 ACTL6B Rebecca Foulger Added comment: Comment on list classification: Updated rating of ACTL6B from Red to Green, to match 'confirmed' rating of new DDG2P disorder: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE.
DDG2P v1.121 ACTL6B Rebecca Foulger Gene: actl6b has been classified as Green List (High Evidence).
DDG2P v1.120 ACTL6B Rebecca Foulger Added comment: Comment on mode of pathogenicity: Changed MOP from 'Other' to default, since the confirmed (EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE) disorder has loss of function listed as the DDG2P mutation consequence.
DDG2P v1.120 ACTL6B Rebecca Foulger Mode of pathogenicity for gene: ACTL6B was changed from Other - please provide details in the comments to None
DDG2P v1.119 ACTL6B Rebecca Foulger Added comment: Comment on mode of inheritance: Changed MOI from MONOALLELIC to BIALLELIC to match the MOI of the confirmed disorder. Only the new biallelic disorder (EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE) has a 'confirmed' rating. Both monoallelic disorders have 'possible' ratings.
DDG2P v1.119 ACTL6B Rebecca Foulger Mode of inheritance for gene: ACTL6B was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v0.13 ABCC9 James Eden reviewed gene: ABCC9: Rating: AMBER; Mode of pathogenicity: None; Publications: 15034580; Phenotypes: Atrial fibrillation, familial, 12 614050, Cardiomyopathy, dilated, 1O 608569, Hypertrichotic osteochondrodysplasia 239850; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.118 ACTL6B Rebecca Foulger commented on gene: ACTL6B: Two new gene:disorder associations added to DDG2P for ACTL6B, September 2019:

New gene:disorder association: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE. Disease confidence rating in DDG2P: confirmed. DDG2P mutation consequence: loss of function; DDG2P allelic requirement: biallelic.

New gene:disorder association: INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEVERE SPEECH AND AMBULATION DEFECTS. Disease confidence rating in DDG2P: possible. DDG2P mutation consequence: all missense/in frame; DDG2P allelic requirement: monoallelic.
DDG2P v1.118 ACTL6B Rebecca Foulger Publications for gene: ACTL6B were set to 28867141
DDG2P v1.117 ACTL6B Rebecca Foulger Phenotypes for gene: ACTL6B were changed from Unspecified Neurodevelopmental Disorder to Unspecified Neurodevelopmental Disorder; EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE 618468; INTELLECTUAL DEVELOPMENTAL DISORDER WITH SEVERE SPEECH AND AMBULATION DEFECTS 618470
DDG2P v1.116 ACTL6B Rebecca Foulger changed review comment from: Original DDG2P rating: possible. DDG2P mode of pathogenicity: all missense/in frame ; to: Original DDG2P rating for Unspecified Neurodevelopmental Disorder: possible. DDG2P mode of pathogenicity: all missense/in frame; DG2P allelic requirement: monoallelic.
DDG2P v1.116 FAT4 Rebecca Foulger commented on gene: FAT4: Two new gene:disorders added to DDG2P for FAT4, September 2019:

New gene:disorder association: HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2. Disease confidence rating in DDG2P: confirmed. DDG2P mutation consequence: uncertain; DDG2P allelic requirement: biallelic.

New gene:disorder association: VAN MALDERGEM SYNDROME. Disease confidence rating in DDG2P: confirmed. DDG2P mutation consequence: loss of function; DDG2P allelic requirement: biallelic.
DDG2P v1.116 FAT4 Rebecca Foulger Phenotypes for gene: FAT4 were changed from PERIVENTRICULAR NEURONAL HETEROTOPIA to PERIVENTRICULAR NEURONAL HETEROTOPIA; HENNEKAM LYMPHANGIECTASIA-LYMPHEDEMA SYNDROME 2 616006; VAN MALDERGEM SYNDROME 615546
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL9A3 James Eden reviewed gene: COL9A3: Rating: RED; Mode of pathogenicity: None; Publications: 24765306; Phenotypes: Epiphyseal dysplasia, multiple, 3, with or without myopathy 600969; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.115 FAT4 Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for PERIVENTRICULAR NEURONAL HETEROTOPIA: confirmed. DDG2P Mutation consequence: loss of function; DDG2P allelic requirement: biallelic.
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL9A2 James Eden reviewed gene: COL9A2: Rating: RED; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: ?Stickler syndrome, type V 614284, Epiphyseal dysplasia, multiple, 2 600204; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.115 KDM3B Rebecca Foulger commented on gene: KDM3B: New gene:disorder association added to DDG2P for KDM3B, September 2019: Intellectual Disability, Short Stature, and Facial Dysmorphism. Disease confidence rating in DDG2P: probable; DDG2P mutation consequence: loss of function; DDG2P mode of inheritance: monoallelic.
DDG2P v1.115 KDM3B Rebecca Foulger Phenotypes for gene: KDM3B were changed from KDM3B-related intellectual disability, short stature and facial dysmorphism to Intellectual Disability, Short Stature, and Facial Dysmorphism; KDM3B-related intellectual disability, short stature and facial dysmorphism
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL9A1 James Eden reviewed gene: COL9A1: Rating: RED; Mode of pathogenicity: None; Publications: 30071989; Phenotypes: ?Epiphyseal dysplasia, multiple, 6 614135, Stickler syndrome, type IV 614134; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.114 KMT2E Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for INTELLECTUAL DISABILITY: confirmed. DDG2P Mode of Pathogenicity/Mutation consequence: loss of function; DDG2P Mode of inheritance/allelic requirement: monoallelic.
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL4A1 James Eden reviewed gene: COL4A1: Rating: RED; Mode of pathogenicity: None; Publications: 20558831; Phenotypes: ?Retinal arteries, tortuosity of 180000, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps 611773, Brain small vessel disease with or without ocular anomalies 175780, Microangiopathy and leukoencephalopathy, pontine, autosomal dominant 618564; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.114 KMT2E Rebecca Foulger commented on gene: KMT2E: New gene:disorder association added to DDG2P for KMT2E, September 2019: Neurodevelopmental disorder and Epilepsy. Disease confidence rating in DDG2P: possible; DDG2P mutation consequence: uncertain; DDG2P mode of inheritance: monoallelic.
DDG2P v1.114 KMT2E Rebecca Foulger Publications for gene: KMT2E were set to
DDG2P v1.113 KMT2E Rebecca Foulger Phenotypes for gene: KMT2E were changed from INTELLECTUAL DISABILITY to INTELLECTUAL DISABILITY 616579; Neurodevelopmental disorder and Epilepsy 618512
DDG2P v1.112 NBAS Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. ; to: Original DDG2P rating for ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD: confirmed. DDG2P Mode of Pathogenicity: loss of function; DDG2P Mode of Inheritance: biallelic.
DDG2P v1.112 NBAS Rebecca Foulger commented on gene: NBAS: New gene:disorder association added to DDG2P for NBAS, September 2019: ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD; SHORT STATURE, OPTIC NERVE ATROPHY, AND PELGER-HUET ANOMALY. Disease confidence rating in DDG2P: confirmed; DDG2P mutation consequence: loss of function. DDG2P mode of inheritance: biallelic.
DDG2P v1.112 NBAS Rebecca Foulger Phenotypes for gene: NBAS were changed from ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD to ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD; ACUTE LIVER FAILURE (ALF) IN INFANCY AND CHILDHOOD; SHORT STATURE, OPTIC NERVE ATROPHY, AND PELGER-HUET ANOMALY 616483
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL2A1 James Eden reviewed gene: COL2A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Stickler syndrome, type I 108300, Spondyloperipheral dysplasia 271700; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
DDG2P v1.111 CNOT1 Rebecca Foulger Phenotypes for gene: CNOT1 were changed from pancreatic agenesis and holoprosencephaly syndrome to pancreatic agenesis and holoprosencephaly syndrome; HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS 618500
DDG2P v1.110 CNOT1 Rebecca Foulger commented on gene: CNOT1: New gene:disorder association added to DDG2P for CNOT1, September 2019: HOLOPROSENCEPHALY 12 WITH OR WITHOUT PANCREATIC AGENESIS. Disease confidence rating in DDG2P: probable; DDG2P mutation consequence: all missense/in frame. DDG2P mode of inheritance: monoallelic.
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL11A2 James Eden reviewed gene: COL11A2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Deafness, autosomal dominant 13 601868, Deafness, autosomal recessive 53 609706, Fibrochondrogenesis 2 614524, Otospondylomegaepiphyseal dysplasia, autosomal dominant 184840, Otospondylomegaepiphyseal dysplasia, autosomal recessive 215150; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.110 SCN11A Rebecca Foulger changed review comment from: Original DDG2P rating: confirmed. DDG2P mode of pathogenicity: activating ; to: Original DDG2P rating for CONGENITAL INABILITY TO EXPERIENCE PAIN: confirmed. DDG2P mode of pathogenicity: activating. DDG2P mode of inheritance: monoallelic.
DDG2P v1.110 SCN11A Rebecca Foulger commented on gene: SCN11A: New gene:disorder association added to DDG2P for SCN11A, September 2019: EPISODIC PAIN SYNDROME, FAMILIAL. Disease confidence rating in DDG2P: both RD and IF; DDG2P mutation consequence: activating. DDG2P mode of inheritance: monoallelic.
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL11A1 James Eden reviewed gene: COL11A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ?Deafness, autosomal dominant 37 618533, Fibrochondrogenesis 1 228520, Marshall syndrome 154780, Stickler syndrome, type II 604841; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
DDG2P v1.110 SCN11A Rebecca Foulger Phenotypes for gene: SCN11A were changed from CONGENITAL INABILITY TO EXPERIENCE PAIN to CONGENITAL INABILITY TO EXPERIENCE PAIN; EPISODIC PAIN SYNDROME, FAMILIAL 615552
DDG2P v1.109 FLNA Rebecca Foulger commented on gene: FLNA: New gene:disorder association added to DDG2P, September 2019: PERIVENTRICULAR NODULAR HETEROTOPIA 1. Disease confidence rating in DDG2P: confirmed; DDG2P mutation consequence: loss of function. DDG2P mode of inheritance: x-linked dominant.
DDG2P v1.109 FLNA Rebecca Foulger Phenotypes for gene: FLNA were changed from FRONTOMETAPHYSEAL DYSPLASIA 305620; FG SYNDROME TYPE 2 300321; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION 300048; MELNICK-NEEDLES SYNDROME 309350; Childhood Interstitial Lung Disease; EPILEPTIC ENCEPHALOPATHY; OTOPALATODIGITAL SYNDROME TYPE 1 311300; OTOPALATODIGITAL SYNDROME TYPE 2 304120; TERMINAL OSSEOUS DYSPLASIA 300244 to PERIVENTRICULAR NODULAR HETEROTOPIA 1 300049; FRONTOMETAPHYSEAL DYSPLASIA 305620; FG SYNDROME TYPE 2 300321; X-LINKED CONGENITAL IDIOPATHIC INTESTINAL PSEUDOOBSTRUCTION 300048; MELNICK-NEEDLES SYNDROME 309350; Childhood Interstitial Lung Disease; EPILEPTIC ENCEPHALOPATHY; OTOPALATODIGITAL SYNDROME TYPE 1 311300; OTOPALATODIGITAL SYNDROME TYPE 2 304120; TERMINAL OSSEOUS DYSPLASIA 300244
DDG2P v1.108 CLIC2 Rebecca Foulger Phenotypes for gene: CLIC2 were changed from Mental retardation, X-linked, syndromic 32 to Mental retardation, X-linked, syndromic 32 300886
DDG2P v1.107 DKC1 Rebecca Foulger Phenotypes for gene: DKC1 were changed from DYSKERATOSIS CONGENITA, X-LINKED; DKC1-RELATED DYSKERATOSIS CONGENITA 314912 to DYSKERATOSIS CONGENITA, X-LINKED, 305000; DKC1-RELATED DYSKERATOSIS CONGENITA 314912
DDG2P v1.106 GDI1 Rebecca Foulger Phenotypes for gene: GDI1 were changed from MENTAL RETARDATION X-LINKED TYPE 48 300104; MENTAL RETARDATION X-LINKED TYPE 41 300104 to MENTAL RETARDATION X-LINKED TYPE 48 300849; MENTAL RETARDATION X-LINKED TYPE 41 300849
Limb disorders v1.61 HDAC4 Eleanor Williams Classified gene: HDAC4 as Amber List (moderate evidence)
Limb disorders v1.61 HDAC4 Eleanor Williams Added comment: Comment on list classification: Changing rating from green to amber, as there are only 2 cases where patients with variants in this gene have a reported brachydactyly phenotype. But the CNV covering this region has been added to the panel - ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss) as there is more evidence that loss of the region results in a relevant phenotype.
Limb disorders v1.61 HDAC4 Eleanor Williams Gene: hdac4 has been classified as Amber List (Moderate Evidence).
Limb disorders v1.60 ISCA-37394-Loss Eleanor Williams Classified Region: ISCA-37394-Loss as Green List (high evidence)
Limb disorders v1.60 ISCA-37394-Loss Eleanor Williams Added comment: Comment on list classification: Changing rating from red to green. Sufficient evidence that CNVs covering this region (HDAC4 in particular) result in a brachydactyly phenotype (PMID: 25329715, PMID: 24715439, PMID: 25402011)
Limb disorders v1.60 ISCA-37394-Loss Eleanor Williams Region: isca-37394-loss has been classified as Green List (High Evidence).
Limb disorders v1.59 ISCA-37394-Loss Eleanor Williams Region: ISCA-37394-Loss was added
Region: ISCA-37394-Loss was added to Limb disorders. Sources: ClinGen
Mode of inheritance for Region: ISCA-37394-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for Region: ISCA-37394-Loss were set to 2q37 deletion syndrome is a condition that can affect many parts of the body. This condition is characterized by weak muscle tone (hypotonia) in infancy, mild to severe intellectual disability and developmental delay, behavioral problems, characteristic facial features, and other physical abnormalities. PMID 23188045 brachydactyly-mental retardation syndrome, Albright hereditary osteodystrophy-like syndrome, developmental delay and behavioural abnormalities in combination; 600430
Review for Region: ISCA-37394-Loss was set to GREEN
Added comment: Adding this CNV as is associated with brachydactyly. The CNV is also on the skeletal dsyplasia panel
Sources: ClinGen
Pain syndromes v1.6 PRDM12 Tomislav Kokotovic reviewed gene: PRDM12: Rating: GREEN; Mode of pathogenicity: None; Publications: 25891934; Phenotypes: HSAN VIII, insensitivity to pain; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams changed review comment from: Comment on list classification: After review with members of the GMS Musculoskeletal specialist test group and Genomics England Clinicians it was decided to rate the HDAC4 gene amber for SNVs, but to keep the region
ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss) green.; to: Comment on list classification: After review with members of the GMS Musculoskeletal specialist test group and Genomics England Clinicians it was decided to rate the HDAC4 gene amber for SNVs, but to keep the region covering this gene green (ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss))
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams Classified gene: HDAC4 as Amber List (moderate evidence)
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams Added comment: Comment on list classification: After review with members of the GMS Musculoskeletal specialist test group and Genomics England Clinicians it was decided to rate the HDAC4 gene amber for SNVs, but to keep the region
ISCA-37394-Loss (2q37.3 terminal region (includes HDAC4) Loss) green.
Skeletal dysplasia v1.203 HDAC4 Eleanor Williams Gene: hdac4 has been classified as Amber List (Moderate Evidence).
DDG2P v1.105 TUBB Rebecca Foulger Phenotypes for gene: TUBB were changed from Circumferential Skin Creases Kunze Type; CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6 615771 to Circumferential Skin Creases Kunze Type 156610; CORTICAL DYSPLASIA, COMPLEX, WITH OTHER BRAIN MALFORMATIONS 6 615771
DDG2P v1.104 TPM2 Rebecca Foulger Phenotypes for gene: TPM2 were changed from ARTHROGRYPOSIS, DISTAL, TYPE 1 to ARTHROGRYPOSIS, DISTAL, TYPE 1 108120
DDG2P v1.103 TGFB3 Rebecca Foulger Phenotypes for gene: TGFB3 were changed from LOEYS-DIETZ SYNDROME to LOEYS-DIETZ SYNDROME 615582
DDG2P v1.102 TGFBR1 Rebecca Foulger Phenotypes for gene: TGFBR1 were changed from LOEYS-DIETZ SYNDROME TYPE 2A 608967; LOEYS-DIETZ SYNDROME TYPE 1A 609192; AORTIC ANEURYSM FAMILIAL THORACIC TYPE 5 608967 to LOEYS-DIETZ SYNDROME TYPE 2A 608967; LOEYS-DIETZ SYNDROME TYPE 1A 609192; AORTIC ANEURYSM FAMILIAL THORACIC TYPE 5 609192
DDG2P v1.101 ABL1 Rebecca Foulger Phenotypes for gene: ABL1 were changed from Congenital heart defects and skeletal malformations to Congenital heart defects and skeletal malformations 617602
DDG2P v1.100 POLG Rebecca Foulger Phenotypes for gene: POLG were changed from MITOCHONDRIAL DNA DEPLETION SYNDROME 4A 607459 to MITOCHONDRIAL DNA DEPLETION SYNDROME 4A 203700
DDG2P v1.99 PAX9 Rebecca Foulger Phenotypes for gene: PAX9 were changed from TOOTH AGENESIS, SELECTIVE, 3 318869 to TOOTH AGENESIS, SELECTIVE, 3 604625
DDG2P v1.98 GLI3 Rebecca Foulger Phenotypes for gene: GLI3 were changed from PREAXIAL POLYDACTYLY TYPE IV 269157; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME 175700; POSTAXIAL POLYDACTYLY TYPE A 149847; PALLISTER-HALL SYNDROME 146510 to PREAXIAL POLYDACTYLY TYPE IV 269157; GREIG CEPHALOPOLYSYNDACTYLY SYNDROME 175700; POSTAXIAL POLYDACTYLY TYPE A 174200; PALLISTER-HALL SYNDROME 146510
DDG2P v1.97 MYH9 Rebecca Foulger Phenotypes for gene: MYH9 were changed from DEAFNESS AUTOSOMAL DOMINANT TYPE 17 603622; SEBASTIAN SYNDROME 605249; MACROTHROMBOCYTOPENIA WITH PROGRESSIVE SENSORINEURAL DEAFNESS 600208; EPSTEIN SYNDROME 153650; MAY-HEGGLIN ANOMALY 155100; FECHTNER SYNDROME 153640 to DEAFNESS AUTOSOMAL DOMINANT TYPE 17 603622; SEBASTIAN SYNDROME 155100; MACROTHROMBOCYTOPENIA WITH PROGRESSIVE SENSORINEURAL DEAFNESS 155100; EPSTEIN SYNDROME 155100; MAY-HEGGLIN ANOMALY 155100; FECHTNER SYNDROME 155100
DDG2P v1.96 MITF Rebecca Foulger Phenotypes for gene: MITF were changed from Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness; WAARDENBURG SYNDROME TYPE 2 WITH OCULAR ALBINISM 103470; TIETZ SYNDROME 103500; WAARDENBURG SYNDROME TYPE 2A 193510 to Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness 617306; WAARDENBURG SYNDROME TYPE 2 WITH OCULAR ALBINISM 103470; TIETZ SYNDROME 103500; WAARDENBURG SYNDROME TYPE 2A 193510
DDG2P v1.95 LAMA1 Rebecca Foulger Phenotypes for gene: LAMA1 were changed from CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY; AUTOSOMAL RECESSIVE MENTAL RETARDATION to CEREBELLAR DYSPLASIA WITH CYSTS WITH OR WITHOUT RETINAL DYSTROPHY 615960; AUTOSOMAL RECESSIVE MENTAL RETARDATION
DDG2P v1.94 ITPR1 Rebecca Foulger Phenotypes for gene: ITPR1 were changed from SPINOCEREBELLAR ATAXIA TYPE15 606658; SPINOCEREBELLAR ATAXIA 29, CONGENITAL NONPROGRESSIVE 117360; Gillespie Syndrome to SPINOCEREBELLAR ATAXIA TYPE15 606658; SPINOCEREBELLAR ATAXIA 29, CONGENITAL NONPROGRESSIVE 117360; Gillespie Syndrome 206700
DDG2P v1.93 SLC2A2 Rebecca Foulger Phenotypes for gene: SLC2A2 were changed from FANCONI-BICKEL SYNDROME 269871 to FANCONI-BICKEL SYNDROME 227810
DDG2P v1.92 FGFR1 Rebecca Foulger Phenotypes for gene: FGFR1 were changed from PFEIFFER SYNDROME 101600; OSTEOGLOPHONIC DYSPLASIA 166250; Hartsfield syndrome; KALLMANN SYNDROME TYPE 2 147950; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM 146110; Encephalocraniocutaneous lipomatosis to PFEIFFER SYNDROME 101600; OSTEOGLOPHONIC DYSPLASIA 166250; Hartsfield syndrome 615465; KALLMANN SYNDROME TYPE 2 147950; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM 146110; Encephalocraniocutaneous lipomatosis 613001
DDG2P v1.91 FN1 Rebecca Foulger Phenotypes for gene: FN1 were changed from Spondylometaphyseal Dysplasia with Corner Fractures to Spondylometaphyseal Dysplasia with Corner Fractures 184255
DDG2P v1.90 EDNRA Rebecca Foulger Phenotypes for gene: EDNRA were changed from MANDIBULOFACIAL DYSOSTOSIS WITH ALOPECIA to MANDIBULOFACIAL DYSOSTOSIS WITH ALOPECIA 616367
DDG2P v1.89 ERCC1 Rebecca Foulger Phenotypes for gene: ERCC1 were changed from FANCONI ANEMIA 229154; CEREBROOCULOFACIOSKELETAL SYNDROME 4 298956 to FANCONI ANEMIA 229154; CEREBROOCULOFACIOSKELETAL SYNDROME 4 610758
DDG2P v1.88 DSG1 Rebecca Foulger Phenotypes for gene: DSG1 were changed from SEVERE DERMATITIS, MULTIPLE ALLERGIES AND METABOLIC WASTING to SEVERE DERMATITIS, MULTIPLE ALLERGIES AND METABOLIC WASTING, 615508
DDG2P v1.87 CRYGD Rebecca Foulger Phenotypes for gene: CRYGD were changed from CATARACT CONGENITAL CERULEAN TYPE 3 608983; CATARACT AUTOSOMAL DOMINANT 604219; CATARACT CONGENITAL NON-NUCLEAR POLYMORPHIC AUTOSOMAL DOMINANT 123690; CATARACT CRYSTALLINE ACULEIFORM 115700 to CATARACT CONGENITAL CERULEAN TYPE 3 115700; CATARACT AUTOSOMAL DOMINANT 604219; CATARACT CONGENITAL NON-NUCLEAR POLYMORPHIC AUTOSOMAL DOMINANT 123690; CATARACT CRYSTALLINE ACULEIFORM 115700
DDG2P v1.86 CRYAA Rebecca Foulger Phenotypes for gene: CRYAA were changed from CATARACT, NUCLEAR 123580; CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 1 123580 to CATARACT, NUCLEAR 123580; CATARACT, AUTOSOMAL RECESSIVE CONGENITAL 1 604219
DDG2P v1.85 COL18A1 Rebecca Foulger Phenotypes for gene: COL18A1 were changed from KNOBLOCH SYNDROME TYPE I 315926 to KNOBLOCH SYNDROME TYPE I 267750
DDG2P v1.84 COL11A2 Rebecca Foulger Phenotypes for gene: COL11A2 were changed from WEISSENBACHER-ZWEYMUELLER SYNDROME 277610; AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA 215150; DEAFNESS AUTOSOMAL DOMINANT TYPE 13 601868; STICKLER SYNDROME TYPE 3 184840; DEAFNESS AUTOSOMAL RECESSIVE TYPE 53 609706 to WEISSENBACHER-ZWEYMUELLER SYNDROME 184840; AUTOSOMAL RECESSIVE OTOSPONDYLOMEGAEPIPHYSEAL DYSPLASIA 215150; DEAFNESS AUTOSOMAL DOMINANT TYPE 13 601868; STICKLER SYNDROME TYPE 3 184840; DEAFNESS AUTOSOMAL RECESSIVE TYPE 53 609706
DDG2P v1.83 CDH3 Rebecca Foulger Phenotypes for gene: CDH3 were changed from EEM SYNDROME 280238; HYPOTRICHOSIS, CONGENITAL, WITH JUVENILE MACULAR DYSTROPHY 601553 to EEM SYNDROME 225280; HYPOTRICHOSIS, CONGENITAL, WITH JUVENILE MACULAR DYSTROPHY 601553
DDG2P v1.82 ACTA1 Rebecca Foulger Phenotypes for gene: ACTA1 were changed from NEMALINE MYOPATHY 3 to NEMALINE MYOPATHY 3, 161800
Thoracic aortic aneurysm or dissection (GMS) v0.32 CHST14 James Eden reviewed gene: CHST14: Rating: RED; Mode of pathogenicity: None; Publications: 26373698; Phenotypes: Ehlers-Danlos syndrome, musculocontractural type 1 601776; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 ZNF469 James Eden reviewed gene: ZNF469: Rating: RED; Mode of pathogenicity: None; Publications: 24895405; Phenotypes: Brittle cornea syndrome 1 229200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 TNXB James Eden reviewed gene: TNXB: Rating: RED; Mode of pathogenicity: None; Publications: 23830591; Phenotypes: Ehlers-Danlos syndrome, classic-like, 1 606408, Vesicoureteral reflux 8 615963; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 PKD2 James Eden reviewed gene: PKD2: Rating: RED; Mode of pathogenicity: None; Publications: 10615132, 12874107; Phenotypes: Polycystic kidney disease 2 613095; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 PKD1 James Eden reviewed gene: PKD1: Rating: RED; Mode of pathogenicity: None; Publications: 17656674, 18679710; Phenotypes: Polycystic kidney disease 1 173900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 LTBP2 James Eden reviewed gene: LTBP2: Rating: RED; Mode of pathogenicity: None; Publications: 20179738; Phenotypes: ?Weill-Marchesani syndrome 3, recessive 614819, Glaucoma 3, primary congenital, D 613086, Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma 251750; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 KCNN1 James Eden reviewed gene: KCNN1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: Unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 HNRNPK James Eden reviewed gene: HNRNPK: Rating: RED; Mode of pathogenicity: None; Publications: 29904177; Phenotypes: Au-Kline syndrome 616580; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 SLC39A13 James Eden reviewed gene: SLC39A13: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Ehlers-Danlos syndrome, spondylodysplastic type, 3 612350; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 B4GALT7 James Eden commented on gene: B4GALT7: Not significantly associated with aortopathy.
Thoracic aortic aneurysm or dissection (GMS) v0.32 B4GALT7 James Eden reviewed gene: B4GALT7: Rating: RED; Mode of pathogenicity: None; Publications: 26940150, 28882145; Phenotypes: Ehlers-Danlos syndrome, spondylodysplastic type, 1 130070; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Structural eye disease v0.92 FKRP Ivone Leong Classified gene: FKRP as Amber List (moderate evidence)
Structural eye disease v0.92 FKRP Ivone Leong Gene: fkrp has been classified as Amber List (Moderate Evidence).
Thoracic aortic aneurysm or dissection (GMS) v0.32 ATP7A James Eden reviewed gene: ATP7A: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Menkes disease 309400, Occipital horn syndrome 304150, Spinal muscular atrophy, distal, X-linked 3 300489; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Structural eye disease v0.91 MYRF Nicola Ragge reviewed gene: MYRF: Rating: GREEN; Mode of pathogenicity: ; Publications: 31266062; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 CSPP1 Nicola Ragge reviewed gene: CSPP1: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 WNT3 Nicola Ragge reviewed gene: WNT3: Rating: RED; Mode of pathogenicity: ; Publications: 14872406; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 TUBB Nicola Ragge reviewed gene: TUBB: Rating: AMBER; Mode of pathogenicity: ; Publications: 26637975; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 SNX3 Nicola Ragge reviewed gene: SNX3: Rating: RED; Mode of pathogenicity: ; Publications: 12471201; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 SMO Nicola Ragge edited their review of gene: SMO: Added comment: Twigg 2016: 8 individuals with somatic mosaicism for a nonsynonymous variant in SMO (c.1234C>T [p.Leu412Phe]). 4 of the individuals present coloboma and/microphthalmia. ; Set current diagnostic: yes
Structural eye disease v0.91 SMG9 Nicola Ragge reviewed gene: SMG9: Rating: AMBER; Mode of pathogenicity: ; Publications: 27018474; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 SLC25A24 Nicola Ragge reviewed gene: SLC25A24: Rating: AMBER; Mode of pathogenicity: ; Publications: 29100093; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 TMEM5 Nicola Ragge reviewed gene: TMEM5: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 RIPK4 Nicola Ragge reviewed gene: RIPK4: Rating: GREEN; Mode of pathogenicity: ; Publications: 23074676, 22197488, 22197489 ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 RERE Nicola Ragge reviewed gene: RERE: Rating: GREEN; Mode of pathogenicity: ; Publications: 27087320, 29330883 ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 POMT2 Nicola Ragge edited their review of gene: POMT2: Added comment: Van Reeuwijk, three families with Walker-Warburg syndrome, one case with Peter's anomaly, congenital cataract and microphthalmia and homozygous nonsense variant. The other cases had congenital cataract (homozygous splice site variant) and cataract/buphthalmos (homozygous frameshift). Nabhan family of four diseased siblings with Walker/Warburg syndrome, oldest sibling had microphthalmia, all siblings have homozygous missense. ; Changed rating: GREEN; Changed publications: 15894594, 28815891; Set current diagnostic: yes
Structural eye disease v0.91 POMT1 Nicola Ragge edited their review of gene: POMT1: Added comment: Bernabe 3 families with microphthalmia among 7 families with Walker-Warburg syndrome, one with homozygous missense, one with homozygous nonsense, one with compound het missense/frameshift. Three other families described have buphthalmos, lens opacities and/or cataracts. All variants segregate. Kim one case with microphthalmia with homozygous in-frame deletion.; Changed publications: 12369018, 15037715; Set current diagnostic: yes
Structural eye disease v0.91 POMGNT2 Nicola Ragge reviewed gene: POMGNT2: Rating: AMBER; Mode of pathogenicity: ; Publications: 22958903; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 POMGNT1 Nicola Ragge reviewed gene: POMGNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 19679478, 19452620, 28765568, 11709191, 0961548; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCL Nicola Ragge reviewed gene: FANCL: Rating: AMBER; Mode of pathogenicity: ; Publications: 25754594; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 OLFM2 Nicola Ragge edited their review of gene: OLFM2: Added comment: Holt reports two cases, one with a de novo CNV involving an additional gene and one with a 5' UTR variant which is inherited from an unaffected parent.; Changed publications: 27844144, 17122126; Set current diagnostic: yes
Structural eye disease v0.91 NDUFB11 Nicola Ragge reviewed gene: NDUFB11: Rating: RED; Mode of pathogenicity: ; Publications: 25772934; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 MITF Nicola Ragge edited their review of gene: MITF: Added comment: Dominant variants are associated with Waardenburg syndrome, however George et al reported two cases with compound het changes and a new syndrome including microphthalmia (COMMAD syndrome): one case with compound heterozygous changes for missense/in-frame deletion segregating in parents - inframe deletion was previously shown to lack DNA binding or regulate target-gene promotors in mice (Grill paper), another unrelated case with missense and splice site variant segregating in parents plus convincing evidence in mouse and cell models that these variants are pathogenic. Steingrimsson published first paper on MITF variants causing microphthalmia in mice ; Changed publications: 27889061, 23787126, 7874168; Set current diagnostic: yes
Structural eye disease v0.91 MAPRE2 Nicola Ragge reviewed gene: MAPRE2: Rating: GREEN; Mode of pathogenicity: ; Publications: 26637975; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 KIF11 Nicola Ragge reviewed gene: KIF11: Rating: AMBER; Mode of pathogenicity: ; Publications: 27212378; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 KDM6A Nicola Ragge reviewed gene: KDM6A: Rating: AMBER; Mode of pathogenicity: ; Publications: 29617172, 29300383; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 ISPD Nicola Ragge edited their review of gene: ISPD: Added comment: Roscioli: six Walker-Warburg cases with microphthalmia and one with Peter's anomaly, full segregation of homozygous or compound heterozygous variants. Morpholino treated zebrafish have significantly smaller eyes.; Set current diagnostic: yes
Structural eye disease v0.91 IKBKG Nicola Ragge reviewed gene: IKBKG: Rating: RED; Mode of pathogenicity: ; Publications: 31119873, 20499493, 30905793 ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 GLI2 Nicola Ragge edited their review of gene: GLI2: Added comment: Rahimov one family with anophthalmia,segregation unknown; Bertolacini one case with anophthalmia with de novo missense now benign in Clinvar ; Changed publications: 17096318, 21204792; Set current diagnostic: yes
Structural eye disease v0.91 FKTN Nicola Ragge reviewed gene: FKTN: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 FKRP Nicola Ragge edited their review of gene: FKRP: Added comment: Van reeuwijk: one family with Walker -Warburg syndrome and microphthalmia with homozygous variant in start codon segregating in parents; Bernabe one case with microphthalmia and coloboma with homozygous missense, segregation unknown; Kawahara zebrafish model; Chan: mouse model. ; Changed rating: AMBER; Changed publications: 20236121, 15121789, 19955119, 20675713 ; Set current diagnostic: yes
Structural eye disease v0.91 FANCI Nicola Ragge reviewed gene: FANCI: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCE Nicola Ragge reviewed gene: FANCE: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCD2 Nicola Ragge reviewed gene: FANCD2: Rating: RED; Mode of pathogenicity: ; Publications: 12893777; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 FANCA Nicola Ragge reviewed gene: FANCA: Rating: RED; Mode of pathogenicity: ; Publications: 12913077, 8502512; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 ESCO2 Nicola Ragge reviewed gene: ESCO2: Rating: GREEN; Mode of pathogenicity: ; Publications: 16380922, 19574259; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 DOCK6 Nicola Ragge reviewed gene: DOCK6: Rating: GREEN; Mode of pathogenicity: ; Publications: 25824905; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 DAG1 Nicola Ragge reviewed gene: DAG1: Rating: AMBER; Mode of pathogenicity: ; Publications: 24052401, 25934851; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 C5orf42 Nicola Ragge edited their review of gene: C5orf42: Added comment: Lopez: one case with microphthalmia among 11 families, compound het for missense and frameshift, parents not available; Set current diagnostic: yes
Structural eye disease v0.91 COX7B Nicola Ragge reviewed gene: COX7B: Rating: AMBER; Mode of pathogenicity: ; Publications: 23122588; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 B3GALNT2 Nicola Ragge reviewed gene: B3GALNT2: Rating: GREEN; Mode of pathogenicity: ; Publications: 23453667; Phenotypes: ; Mode of inheritance: ; Current diagnostic: yes
Structural eye disease v0.91 ALX3 Nicola Ragge reviewed gene: ALX3: Rating: RED; Mode of pathogenicity: ; Publications: 19409524; Phenotypes: ; Mode of inheritance:
Structural eye disease v0.91 ALX1 Nicola Ragge reviewed gene: ALX1: Rating: AMBER; Mode of pathogenicity: ; Publications: 20451171, 23059813; Phenotypes: ; Mode of inheritance:
Thoracic aortic aneurysm or dissection (GMS) v0.32 ATP6V0A2 James Eden commented on gene: ATP6V0A2: No significant association with aortopathy.
Thoracic aortic aneurysm or dissection (GMS) v0.32 ATP6V0A2 James Eden reviewed gene: ATP6V0A2: Rating: RED; Mode of pathogenicity: None; Publications: 19321599; Phenotypes: Cutis laxa, autosomal recessive, type IIA 219200, Wrinkly skin syndrome 278250; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 ALDH18A1 James Eden reviewed gene: ALDH18A1: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cutis laxa, autosomal dominant 3 616603, Cutis laxa, autosomal recessive, type IIIA 219150, Spastic paraplegia 9A, autosomal dominant 601162, Spastic paraplegia 9B, autosomal recessive 616586; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 ADAMTS2 James Eden reviewed gene: ADAMTS2: Rating: RED; Mode of pathogenicity: None; Publications: 26765342; Phenotypes: Ehlers-Danlos syndrome, dermatosparaxis typen 225410; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 ACVR1 James Eden reviewed gene: ACVR1: Rating: RED; Mode of pathogenicity: None; Publications: 22536403; Phenotypes: Fibrodysplasia ossificans progressiva 135100; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 EMILIN1 James Eden reviewed gene: EMILIN1: Rating: RED; Mode of pathogenicity: None; Publications: 26462740; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 SMAD6 James Eden reviewed gene: SMAD6: Rating: AMBER; Mode of pathogenicity: None; Publications: 30796334, 28659821, 30963242; Phenotypes: Aortic valve disease 2 614823; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 COL1A1 James Eden reviewed gene: COL1A1: Rating: RED; Mode of pathogenicity: None; Publications: 14630726; Phenotypes: Caffey disease 114000, Ehlers-Danlos syndrome, arthrochalasia type, 1 130060, Osteogenesis imperfecta, types I-IV; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.32 MYLK2 James Eden reviewed gene: MYLK2: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Cardiomyopathy, hypertrophic, 1, digenic 192600; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Bilateral congenital or childhood onset cataracts v2.0 Ivone Leong promoted panel to version 2.0
Bilateral congenital or childhood onset cataracts v1.37 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Bardet Biedl syndrome v1.0 Ivone Leong promoted panel to version 1.0
Bardet Biedl syndrome v0.25 Ivone Leong Panel types changed to GMS Rare Disease; GMS signed-off
Bardet Biedl syndrome v0.24 IFT27 Ivone Leong reviewed gene: IFT27: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bardet Biedl syndrome v0.24 MKS1 Ivone Leong reviewed gene: MKS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Bardet Biedl syndrome v0.24 LZTFL1 Ivone Leong reviewed gene: LZTFL1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Optic neuropathy v2.0 Ivone Leong promoted panel to version 2.0
Optic neuropathy v1.121 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease; GMS signed-off
Primary lymphoedema v2.0 Ivone Leong promoted panel to version 2.0
Primary lymphoedema v1.123 Ivone Leong Panel types changed to Rare Disease 100K; GMS Rare Disease Virtual; GMS signed-off
Bilateral congenital or childhood onset cataracts v1.36 KIAA1109 Ivone Leong Classified gene: KIAA1109 as Red List (low evidence)
Bilateral congenital or childhood onset cataracts v1.36 KIAA1109 Ivone Leong Added comment: Comment on list classification: Demoted from Green to Red. KIAA1109 is associated with Alkuraya-Kucinskas syndrome and cataracts are a minor feature. As we are not aware of any cases of variants in this gene associated with isolated cataracts, it has been demoted to Red.
Bilateral congenital or childhood onset cataracts v1.36 KIAA1109 Ivone Leong Gene: kiaa1109 has been classified as Red List (Low Evidence).
Bilateral congenital or childhood onset cataracts v1.35 LONP1 Ivone Leong Classified gene: LONP1 as Green List (high evidence)
Bilateral congenital or childhood onset cataracts v1.35 LONP1 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on previous review.
Bilateral congenital or childhood onset cataracts v1.35 LONP1 Ivone Leong Gene: lonp1 has been classified as Green List (High Evidence).
Bilateral congenital or childhood onset cataracts v1.34 GEMIN4 Ivone Leong Classified gene: GEMIN4 as Green List (high evidence)
Bilateral congenital or childhood onset cataracts v1.34 GEMIN4 Ivone Leong Added comment: Comment on list classification: Promoted from Red to Green based on previous review.
Bilateral congenital or childhood onset cataracts v1.34 GEMIN4 Ivone Leong Gene: gemin4 has been classified as Green List (High Evidence).
Hypertrophic cardiomyopathy v1.77 MYH6 Ellen McDonagh Publications for gene: MYH6 were set to 27532257; 22194935
Thoracic aortic aneurysm or dissection (GMS) v0.32 FKBP14 James Eden reviewed gene: FKBP14: Rating: AMBER; Mode of pathogenicity: None; Publications: 22265013; Phenotypes: Ehlers-Danlos syndrome, kyphoscoliotic type, 2 614557; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 FBLN5 James Eden changed review comment from: Gene is associated with cutis laxa, which includes aortic symptoms.; to: Gene is associated with cutis laxa, which includes aortic symptoms. Also associated with age-related macular degeneration and autistic spectrum disorder in HGMD.
Thoracic aortic aneurysm or dissection (GMS) v0.32 FBLN5 James Eden reviewed gene: FBLN5: Rating: AMBER; Mode of pathogenicity: None; Publications: 12189163, 27089918; Phenotypes: ?Cutis laxa, autosomal dominant 2 614434, Cutis laxa, autosomal recessive, type IA 219100, Macular degeneration, age-related, 3 608895, Neuropathy, hereditary, with or without age-related macular degeneration 608895; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 ABCC6 James Eden reviewed gene: ABCC6: Rating: RED; Mode of pathogenicity: None; Publications: 28102862; Phenotypes: Pseudoxanthoma elasticum 264800, Pseudoxanthoma elasticum, forme fruste 177850, Arterial calcification, generalized, of infancy, 2 614473; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.32 FLNA Ivone Leong Added comment: Comment on mode of inheritance: MOI has been corrected.
Thoracic aortic aneurysm or dissection (GMS) v0.32 FLNA Ivone Leong Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm or dissection (GMS) v0.31 BGN Ivone Leong Added comment: Comment on mode of inheritance: MOI has been corrected.
Thoracic aortic aneurysm or dissection (GMS) v0.31 BGN Ivone Leong Mode of inheritance for gene: BGN was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm or dissection (GMS) v0.30 SMAD4 James Eden reviewed gene: SMAD4: Rating: AMBER; Mode of pathogenicity: None; Publications: 29392890; Phenotypes: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 175050, Myhre syndrome 139210, Pancreatic cancer, somatic 260350, Polyposis, juvenile intestinal 174900; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 PRKG1 James Eden reviewed gene: PRKG1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23910461, 30577811; Phenotypes: Aortic aneurysm, familial thoracic 8 615436; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 NOTCH1 James Eden reviewed gene: NOTCH1: Rating: GREEN; Mode of pathogenicity: None; Publications: 29907982, 18593716; Phenotypes: Aortic valve disease 1 109730, Adams-Oliver syndrome 5 616028; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 MFAP5 James Eden reviewed gene: MFAP5: Rating: AMBER; Mode of pathogenicity: None; Publications: 25434006; Phenotypes: Aortic aneurysm, familial thoracic 9 616166; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 MED12 James Eden reviewed gene: MED12: Rating: RED; Mode of pathogenicity: None; Publications: 28724790; Phenotypes: Lujan-Fryns syndrome 309520, Ohdo syndrome, X-linked 300895, Opitz-Kaveggia syndrome 305450; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Catecholaminergic polymorphic VT v1.25 CALM3 Ellen McDonagh Publications for gene: CALM3 were set to
Thoracic aortic aneurysm or dissection (GMS) v0.30 LOX James Eden reviewed gene: LOX: Rating: GREEN; Mode of pathogenicity: None; Publications: 26838787, 27432961; Phenotypes: Aortic aneurysm, familial thoracic 10 617168; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 FOXE3 James Eden reviewed gene: FOXE3: Rating: AMBER; Mode of pathogenicity: None; Publications: 26854927; Phenotypes: Aortic aneurysm, familial thoracic 11, (susceptibility to) 617349; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 EFEMP2 James Eden reviewed gene: EFEMP2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868310, 22440127; Phenotypes: Cutis laxa, autosomal recessive, type IB 614437; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.30 COL5A2 James Eden reviewed gene: COL5A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868310; Phenotypes: Ehlers-Danlos syndrome, classic type, 2 130010; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 COL5A1 James Eden reviewed gene: COL5A1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28868310; Phenotypes: Ehlers-Danlos syndrome, classic type, 1 130000; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection (GMS) v0.30 SLC2A10 James Eden reviewed gene: SLC2A10: Rating: GREEN; Mode of pathogenicity: None; Publications: 16550171, 17935213; Phenotypes: Arterial tortuosity syndrome 208050; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Thoracic aortic aneurysm or dissection (GMS) v0.30 FBN2 James Eden reviewed gene: FBN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 25944730, 29907982; Phenotypes: Contractural arachnodactyly, congenital 121050, Macular degeneration, early-onset 616118; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection v1.103 ADAMTS2 Ellen McDonagh Phenotypes for gene: ADAMTS2 were changed from to 225410 Ehlers-Danlos syndrome, type VIIC
Thoracic aortic aneurysm or dissection v1.102 ADAMTS2 Ellen McDonagh Publications for gene: ADAMTS2 were set to
Thoracic aortic aneurysm or dissection v1.101 ADAMTS2 Ellen McDonagh Mode of inheritance for gene: ADAMTS2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Thoracic aortic aneurysm or dissection v1.100 ABCC6 Ellen McDonagh Phenotypes for gene: ABCC6 were changed from to #614473- Arterial calcification, generalized, of infancy, 2; #264800- Pseudoxanthoma elasticum; #177850- Pseudoxanthoma elasticum, forme fruste
Thoracic aortic aneurysm or dissection v1.99 ABCC6 Ellen McDonagh Publications for gene: ABCC6 were set to
Paediatric or syndromic cardiomyopathy v0.13 ABCC9 Matthew Edwards reviewed gene: ABCC9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: OMIM#239850:Cantu Syndrome; Mode of inheritance: None; Current diagnostic: yes
Thoracic aortic aneurysm or dissection v1.98 SLC2A10 Ellen McDonagh edited their review of gene: SLC2A10: Added comment: Biallelic mode of inheritance is correct.; Changed publications: 22001912, doi:10.​1007/​s12265-016-9673-5; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Progressive cardiac conduction disease v0.28 KCNK17 James Eden reviewed gene: KCNK17: Rating: RED; Mode of pathogenicity: None; Publications: 24972929; Phenotypes: ; Mode of inheritance: Unknown
Thoracic aortic aneurysm or dissection v1.98 MYH11 Ellen McDonagh Publications for gene: MYH11 were set to 27081537
Progressive cardiac conduction disease v0.28 ANK2 James Eden edited their review of gene: ANK2: Changed rating: RED; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 ANK2 James Eden changed review comment from: Little literature associating this gene with conduction disease in particular.; to: Little literature associating this gene with conduction disease in particular.
Progressive cardiac conduction disease v0.28 ANK2 James Eden reviewed gene: ANK2: Rating: ; Mode of pathogenicity: None; Publications: 30929919; Phenotypes: Cardiac arrhythmia, ankyrin-B-related 600919, Long QT syndrome 4 600919; Mode of inheritance: None
Progressive cardiac conduction disease v0.28 GJA5 James Eden reviewed gene: GJA5: Rating: RED; Mode of pathogenicity: None; Publications: 22247482; Phenotypes: Atrial fibrillation, familial, 11 614049, Atrial standstill, digenic (GJA5/SCN5A) 108770; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 TBX3 James Eden reviewed gene: TBX3: Rating: RED; Mode of pathogenicity: None; Publications: 30820409; Phenotypes: Ulnar-mammary syndrome 181450; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Progressive cardiac conduction disease v0.28 PRKAG2 James Eden reviewed gene: PRKAG2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26729852, 12015471; Phenotypes: Cardiomyopathy, hypertrophic 6 600858, Glycogen storage disease of heart, lethal congenital 261740, Wolff-Parkinson-White syndrome 194200; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown; Current diagnostic: yes
Progressive cardiac conduction disease v0.28 TNNI3K James Eden reviewed gene: TNNI3K: Rating: GREEN; Mode of pathogenicity: None; Publications: 25791106, 24925317, 30010057; Phenotypes: Cardiac conduction disease with or without dilated cardiomyopathy 616117; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Neurological ciliopathies v0.7 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Neurological ciliopathies v0.7 FAM149B1 Eleanor Williams Added comment: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Neurological ciliopathies v0.7 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Neurological ciliopathies v0.6 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Neurological ciliopathies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Ophthalmological ciliopathies v0.11 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Ophthalmological ciliopathies v0.11 FAM149B1 Eleanor Williams Added comment: Comment on list classification: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Ophthalmological ciliopathies v0.11 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Ophthalmological ciliopathies v0.10 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Ophthalmological ciliopathies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Likely inborn error of metabolism v1.336 ISCA2 Sarah Leigh Classified gene: ISCA2 as Green List (high evidence)
Likely inborn error of metabolism v1.336 ISCA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two different ethinicities.
Rated green based on review of Anna de Burca (Clinical Fellow, Genomic England).
Likely inborn error of metabolism v1.336 ISCA2 Sarah Leigh Gene: isca2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.335 ISCA2 Sarah Leigh Added comment: Comment on phenotypes: infantile neurodegenerative mitochondrial disorder
Likely inborn error of metabolism v1.335 ISCA2 Sarah Leigh Phenotypes for gene: ISCA2 were changed from infantile neurodegenerative mitochondrial disorder to Multiple mitochondrial dysfunctions syndrome 4 616370
Likely inborn error of metabolism v1.334 ISCA2 Sarah Leigh Publications for gene: ISCA2 were set to PMID: 25539947
Mitochondrial disorders v2.1 ISCA2 Sarah Leigh Publications for gene: ISCA2 were set to PMID: 25539947
Likely inborn error of metabolism v1.333 DNM2 Sarah Leigh Publications for gene: DNM2 were set to 18560793; 17932957; 17636067; 17008356; 16227997; 15731758
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Classified gene: DNM2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Added comment: Comment on list classification: This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 1 case with multiple deletions and COX negative fibres; 5 cases presented in a poster with dominant DMN2 variants (had COX deficient muscle fibres, one case with the p.Arg369Trp revealed disruption of the dynamic mitochondrial network, https://doi.org/10.1016/j.nmd.2012.06.124). From panels: Possible mitochondrial disorder - nuclear genes (Version 0.187) and Mitochondrial DNA maintenance disorder (Version 0.8).
Undiagnosed metabolic disorders v1.364 DNM2 Sarah Leigh Gene: dnm2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.332 DNM2 Sarah Leigh Added comment: Comment on phenotypes: Disorders of mitochondrial DNA maintenance and integrity
Likely inborn error of metabolism v1.332 DNM2 Sarah Leigh Phenotypes for gene: DNM2 were changed from Disorders of mitochondrial DNA maintenance and integrity to Centronuclear myopathy 1 160150; Charcot-Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.363 DNM2 Sarah Leigh Publications for gene: DNM2 were set to
Undiagnosed metabolic disorders v1.362 DNM2 Sarah Leigh Phenotypes for gene: DNM2 were changed from Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482 to Centronuclear myopathy 1 160150; Charcot-Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams changed review comment from: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.; to: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported. However, the skeletal phenotypes are polydactyly/clinodactyly only.
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams Classified gene: FAM149B1 as Amber List (moderate evidence)
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams Added comment: Comment on list classification: 3 founder variant cases reported plus one other. Some functional data. Changing rating from red to amber based on the 2 independent cases reported.
Skeletal ciliopathies v0.15 FAM149B1 Eleanor Williams Gene: fam149b1 has been classified as Amber List (Moderate Evidence).
Skeletal ciliopathies v0.14 FAM149B1 Eleanor Williams gene: FAM149B1 was added
gene: FAM149B1 was added to Skeletal ciliopathies. Sources: Literature
Mode of inheritance for gene: FAM149B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAM149B1 were set to 30905400
Phenotypes for gene: FAM149B1 were set to Joubert syndrome; oral-facial-digital syndrome; OFD VI
Review for gene: FAM149B1 was set to AMBER
Added comment: PMID: 30905400 - Shaheen et al 2019 - report 4 cases in which homozygous variants in the FAM149B1 gene are found in patients with a ciliopathy phenotype that most closely matches Joubert syndrome or Joubert syndrome/oral-facial-digital syndrome (OFD VI) . 3 of the cases in Consanguinity families of Arab origin have the same c.356_357del (p.Lys119Ilefs∗18) variant and haplotype analysis suggests a founder mutation. The fourth case in a Turkish family with Joubert syndrome was found to have a different homozygous truncating variant in the same gene (c.439C>T [p.Gln147∗])). Both variants are predicted to result in truncated proteins.
Functional studies - FAM149B1 encodes a protein of unknown function and mutant fibroblasts were found to have normal ciliogenesis potential. But some cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling.
Sources: Literature
Clefting v1.59 ALX1 Eleanor Williams commented on gene: ALX1: Amber rating confirmed by Genomics England clinical team.
Paroxysmal central nervous system disorders v0.168 NKX2-1 Rebecca Foulger Publications for gene: NKX2-1 were set to 24555207
Paroxysmal central nervous system disorders v0.167 ISCA-37468-Loss Rebecca Foulger Classified Region: ISCA-37468-Loss as Red List (low evidence)
Paroxysmal central nervous system disorders v0.167 ISCA-37468-Loss Rebecca Foulger Added comment: Comment on list classification: Demoted CNV from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.167 ISCA-37468-Loss Rebecca Foulger Region: isca-37468-loss has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.166 TBP_CAG Rebecca Foulger Classified STR: TBP_CAG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.166 TBP_CAG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.166 TBP_CAG Rebecca Foulger Str: tbp_cag has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.165 DMPK_CTG Rebecca Foulger Classified STR: DMPK_CTG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.165 DMPK_CTG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.165 DMPK_CTG Rebecca Foulger Str: dmpk_ctg has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.164 CSTB_CCCCGCCCCGCG Rebecca Foulger Classified STR: CSTB_CCCCGCCCCGCG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.164 CSTB_CCCCGCCCCGCG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.164 CSTB_CCCCGCCCCGCG Rebecca Foulger Str: cstb_ccccgccccgcg has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.163 CACNA1A_CAG Rebecca Foulger Classified STR: CACNA1A_CAG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.163 CACNA1A_CAG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.163 CACNA1A_CAG Rebecca Foulger Str: cacna1a_cag has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.162 ATN1_CAG Rebecca Foulger Classified STR: ATN1_CAG as Red List (low evidence)
Paroxysmal central nervous system disorders v0.162 ATN1_CAG Rebecca Foulger Added comment: Comment on list classification: Demoted STR from Green to Red based on GLH review and a recent comment (September 30th 2019) from Robyn Labrum (University College London Hospitals) collated on behalf of London North GLH for the GMS Neurology specialist test group: Inappropriate phenotype. Better suited to ataxia panels, epilepsy or muscular dystrophy panel.
Paroxysmal central nervous system disorders v0.162 ATN1_CAG Rebecca Foulger Str: atn1_cag has been classified as Red List (Low Evidence).
Paroxysmal central nervous system disorders v0.161 ATAD1 Rebecca Foulger Classified gene: ATAD1 as Green List (high evidence)
Paroxysmal central nervous system disorders v0.161 ATAD1 Rebecca Foulger Added comment: Comment on list classification: Upgraded ATAD1 from Amber to Green to match Green rating of other Hyperkeplexia genes (GLRA1, GLRB, SLC6A5). A comment from Robyn Labrum (University College London Hospitals) on behalf of London North GLH for the GMS Neurology specialist test group (received via email, September 30th 2019) notes that Hyperkeplexia genes should be included on the panel if the clinicians agree.
Paroxysmal central nervous system disorders v0.161 ATAD1 Rebecca Foulger Gene: atad1 has been classified as Green List (High Evidence).
Paroxysmal central nervous system disorders v0.160 VAMP2 Rebecca Foulger commented on gene: VAMP2: Review from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. This is a gene that was re-reviewed to reach a consensus- The comment by Robyn Labrum was expanded from previous comment. No new rating was submitted so the suggested rating remains as Green.
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Marked gene: KCNK18 as ready
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Gene: kcnk18 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Classified gene: KCNK18 as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber based on consensus of GLH review.
Paroxysmal central nervous system disorders v0.160 KCNK18 Rebecca Foulger Gene: kcnk18 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.159 KCNK18 Rebecca Foulger commented on gene: KCNK18: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Suggested rating: Amber. This is a gene that was re-reviewed to reach a consensus, and therefore the rating by Robyn Labrum has changed from Red to Amber.
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Marked gene: MOG as ready
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Gene: mog has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Classified gene: MOG as Amber List (moderate evidence)
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Added comment: Comment on list classification: Kept rating as Amber based on consensus GLH review- insufficient evidence for Green rating.
Paroxysmal central nervous system disorders v0.159 MOG Rebecca Foulger Gene: mog has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.158 MOG Rebecca Foulger commented on gene: MOG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Suggested rating: None submitted but comment suggests Amber. This is a gene that was re-reviewed to reach a consensus, and therefore the rating by Robyn Labrum has changed from Green to Amber in PanelApp.
Paroxysmal central nervous system disorders v0.158 CACNB4 Rebecca Foulger Marked gene: CACNB4 as ready
Paroxysmal central nervous system disorders v0.158 CACNB4 Rebecca Foulger Gene: cacnb4 has been classified as Amber List (Moderate Evidence).
Paroxysmal central nervous system disorders v0.158 CACNB4 Rebecca Foulger commented on gene: CACNB4: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 30th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Suggested rating: ? Amber. This review agrees with the recent downgrading of CACNB4 to Amber.
Paroxysmal central nervous system disorders v0.158 VAMP2 Robyn Labrum commented on gene: VAMP2: Recent publication (Salpietro et al. Am J Hum Genet. 2019 Apr 4;104(4):721-730) de novo mutations in 5 unrelated individuals phenotype neurodevelopmental disorder characterized by axial hypotonia (which had been present since birth), intellectual disability, and autistic features. More severe phenotype includes additional neurological features, including central visual impairment, hyperkinetic movement disorder, and epilepsy or electroencephalography abnormalities. ?Better on intellectual disability or neurodevelopmental panel. Needs clinical input.
Paroxysmal central nervous system disorders v0.158 KCNK18 Robyn Labrum edited their review of gene: KCNK18: Added comment: Phenotype is migraine with aura in one family - amber.; Changed rating: AMBER
Paroxysmal central nervous system disorders v0.158 MOG Robyn Labrum edited their review of gene: MOG: Added comment: In a single large Spanish family across 4 generations. All 11 affected members studied and 1 who did not completely fulfill the diagnostic criteria for narcolepsy carried the mutation, whereas all 14 unaffected family members studied did not have the mutation. Is this sufficient evidence? If not then it should be amber.; Changed rating: AMBER
Paroxysmal central nervous system disorders v0.158 CACNB4 Robyn Labrum reviewed gene: CACNB4: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Catecholaminergic polymorphic VT v1.24 TECRL Ivone Leong Phenotypes for gene: TECRL were changed from to Ventricular tachycardia, catecholaminergic polymorphic, 3 614021
Catecholaminergic polymorphic VT v1.23 TECRL Ivone Leong Publications for gene: TECRL were set to
Paroxysmal central nervous system disorders v0.157 TBP_CAG Rebecca Foulger commented on STR: TBP_CAG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: TBP_CAG. Suggested rating: ?; Comments provided: Triplet repeat.
Paroxysmal central nervous system disorders v0.157 DMPK_CTG Rebecca Foulger commented on STR: DMPK_CTG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: DMPK_CTG. Suggested rating: ?; Comments provided: Triplet repeat.
Paroxysmal central nervous system disorders v0.157 CSTB_CCCCGCCCCGCG Rebecca Foulger commented on STR: CSTB_CCCCGCCCCGCG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: CSTB_CCCCGCCCCGCG. Suggested rating: ?; Comments provided: STR.
Paroxysmal central nervous system disorders v0.157 CACNA1A_CAG Rebecca Foulger commented on STR: CACNA1A_CAG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: CACNA1A_CAG. Suggested rating: ?; Comments provided: Triplet repeat. Primarily an ataxia gene.
Paroxysmal central nervous system disorders v0.157 ATN1_CAG Rebecca Foulger commented on STR: ATN1_CAG: Review and rating from Robyn Labrum (University College London Hospitals) was collated (September 19th 2019) on behalf of London North GLH for the GMS Neurology specialist test group for clinical indication R66: Paroxysmal central nervous system disorders. Symbol submitted: ATN1_CAG. Suggested rating: ?; Comments provided: Triplet repeat. Primarily an ataxia gene. Also ataxia is not episodic/paroxysmal in nature.
Differences in sex development v2.1 MYRF Ivone Leong Classified gene: MYRF as Red List (low evidence)
Differences in sex development v2.1 MYRF Ivone Leong Added comment: Comment on list classification: New gene added by reviewer. I have given this gene a Red rating as this was added after the panel has been signed-off by the GMS specialist group.
Differences in sex development v2.1 MYRF Ivone Leong Gene: myrf has been classified as Red List (Low Evidence).
Structural eye disease v0.90 MYRF Ivone Leong Phenotypes for gene: MYRF were changed from to Nanophthalmos
Structural eye disease v0.89 MYRF Ivone Leong gene: MYRF was added
gene: MYRF was added to Structural eye disease. Sources: Expert Review Green,NHS GMS
Mode of inheritance for gene: MYRF was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: MYRF were set to 31266062
Structural eye disease v0.89 CSPP1 Ivone Leong Source NHS GMS was added to CSPP1.
Source Expert Review Red was added to CSPP1.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 WNT3 Ivone Leong Source NHS GMS was added to WNT3.
Source Expert Review Red was added to WNT3.
Publications for gene WNT3 were changed from to 14872406
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 TUBB Ivone Leong Source NHS GMS was added to TUBB.
Publications for gene TUBB were changed from to 26637975
Structural eye disease v0.89 SNX3 Ivone Leong Source NHS GMS was added to SNX3.
Source Expert Review Red was added to SNX3.
Publications for gene SNX3 were changed from to 12471201
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 SMG9 Ivone Leong Source NHS GMS was added to SMG9.
Publications for gene SMG9 were changed from to 27018474
Structural eye disease v0.89 SLC25A24 Ivone Leong Source NHS GMS was added to SLC25A24.
Publications for gene SLC25A24 were changed from to 29100093
Structural eye disease v0.89 TMEM5 Ivone Leong Source NHS GMS was added to TMEM5.
Source Expert Review Red was added to TMEM5.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 RIPK4 Ivone Leong Source Expert Review Green was added to RIPK4.
Source NHS GMS was added to RIPK4.
Publications for gene RIPK4 were changed from to 22197489; 23074676; 22197488
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 RERE Ivone Leong Source Expert Review Green was added to RERE.
Source NHS GMS was added to RERE.
Publications for gene RERE were changed from to 27087320; 29330883
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 POMT2 Ivone Leong Source Expert Review Green was added to POMT2.
Publications for gene POMT2 were changed from 28815891; 15894594 to 15894594; 28815891
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 POMT1 Ivone Leong Publications for gene POMT1 were changed from 15037715; 12369018 to 12369018; 15037715
Structural eye disease v0.89 POMGNT2 Ivone Leong Source NHS GMS was added to POMGNT2.
Publications for gene POMGNT2 were changed from to 22958903
Structural eye disease v0.89 POMGNT1 Ivone Leong Source Expert Review Green was added to POMGNT1.
Source NHS GMS was added to POMGNT1.
Publications for gene POMGNT1 were changed from to 0961548; 19452620; 28765568; 11709191; 19679478
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 FANCL Ivone Leong Source NHS GMS was added to FANCL.
Publications for gene FANCL were changed from to 25754594
Structural eye disease v0.89 OLFM2 Ivone Leong Publications for gene OLFM2 were changed from 27844144 to 27844144; 17122126
Structural eye disease v0.89 NDUFB11 Ivone Leong Source NHS GMS was added to NDUFB11.
Source Expert Review Red was added to NDUFB11.
Publications for gene NDUFB11 were changed from to 25772934
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 MITF Ivone Leong Publications for gene MITF were changed from 27889061 to 7874168; 27889061; 23787126
Structural eye disease v0.89 MAPRE2 Ivone Leong Source Expert Review Green was added to MAPRE2.
Source NHS GMS was added to MAPRE2.
Publications for gene MAPRE2 were changed from to 26637975
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 KIF11 Ivone Leong Source NHS GMS was added to KIF11.
Publications for gene KIF11 were changed from to 27212378
Structural eye disease v0.89 KDM6A Ivone Leong Source NHS GMS was added to KDM6A.
Publications for gene KDM6A were changed from to 29617172; 29300383
Structural eye disease v0.89 IKBKG Ivone Leong Source NHS GMS was added to IKBKG.
Source Expert Review Red was added to IKBKG.
Publications for gene IKBKG were changed from to 31119873; 20499493; 30905793
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 GLI2 Ivone Leong Publications for gene GLI2 were changed from 17096318; 21204792 to 21204792; 17096318
Structural eye disease v0.89 FKTN Ivone Leong Source Expert Review Green was added to FKTN.
Source NHS GMS was added to FKTN.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 FKRP Ivone Leong Publications for gene FKRP were changed from 20675713; 19955119; 20236121; 15121789 to 15121789; 20675713; 19955119; 20236121
Structural eye disease v0.89 FANCI Ivone Leong Source NHS GMS was added to FANCI.
Source Expert Review Red was added to FANCI.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 FANCE Ivone Leong Source NHS GMS was added to FANCE.
Source Expert Review Red was added to FANCE.
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 FANCD2 Ivone Leong Source NHS GMS was added to FANCD2.
Source Expert Review Red was added to FANCD2.
Publications for gene FANCD2 were changed from to 12893777
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 FANCA Ivone Leong Source NHS GMS was added to FANCA.
Source Expert Review Red was added to FANCA.
Publications for gene FANCA were changed from to 8502512; 12913077
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 ESCO2 Ivone Leong Source Expert Review Green was added to ESCO2.
Source NHS GMS was added to ESCO2.
Publications for gene ESCO2 were changed from to 16380922; 19574259
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 DOCK6 Ivone Leong Source Expert Review Green was added to DOCK6.
Source NHS GMS was added to DOCK6.
Publications for gene DOCK6 were changed from to 25824905
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 DAG1 Ivone Leong Source NHS GMS was added to DAG1.
Publications for gene DAG1 were changed from to 25934851; 24052401
Structural eye disease v0.89 COX7B Ivone Leong Source NHS GMS was added to COX7B.
Publications for gene COX7B were changed from to 23122588
Structural eye disease v0.89 B3GALNT2 Ivone Leong Source Expert Review Green was added to B3GALNT2.
Source NHS GMS was added to B3GALNT2.
Publications for gene B3GALNT2 were changed from to 23453667
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Structural eye disease v0.89 ALX3 Ivone Leong Source NHS GMS was added to ALX3.
Source Expert Review Red was added to ALX3.
Publications for gene ALX3 were changed from to 19409524
Rating Changed from Amber List (moderate evidence) to Red List (low evidence)
Structural eye disease v0.89 ALX1 Ivone Leong Source NHS GMS was added to ALX1.
Publications for gene ALX1 were changed from to 20451171; 23059813
Familial hypercholesterolaemia v1.25 APOB Sarah Leigh commented on gene: APOB
Additional findings health related v0.55 APOB Sarah Leigh edited their review of gene: APOB: Added comment: Familial Hypercholesterolemia 2, Familial ligand-defective apolipoprotein B-100 (FDB)
• Monoallelic
• Mostly missense variants
• Terminating variants unlikely to be involved
• Prevents the LDL particle from binding with cell surface receptors (LDLR)
• Increased levels of cholesterol in blood; Changed rating: GREEN
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Classified gene: ALKBH8 as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Added comment: Comment on list classification: Demoted ALKBH8 from Green to Amber following review from Helen Lord on behalf of West Midlands, Oxford and Wessex GLH, and agreement from Richard Scott (Genomics England clinical team).
Early onset or syndromic epilepsy v1.347 ALKBH8 Rebecca Foulger Gene: alkbh8 has been classified as Amber List (Moderate Evidence).
Early onset or syndromic epilepsy v1.346 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Early onset or syndromic epilepsy v1.345 POLG2 Rebecca Foulger Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
Early onset or syndromic epilepsy v1.344 POLG2 Rebecca Foulger Added comment: Comment on mode of inheritance: Kept rating as Amber to match Helen Lord's review, but changed MOI from biallelic to 'BOTH biallelic and monoallelic' since (as Helen Lord notes) Young et al 2011 (PMID:21555342) report 4/11 patients with seizures as part of their phenotype and heterozygous variants in POLG2.
Early onset or syndromic epilepsy v1.344 POLG2 Rebecca Foulger Mode of inheritance for gene: POLG2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Classified gene: SLC2A1 as Green List (high evidence)
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Added comment: Comment on list classification: Promoted from Amber to Green. SLC2A1 is associated with GLUT1 deficiency syndrome 1 and GLUT1 deficiency syndrome 2 on OMIM and Gene2Phenotype. There are >3 unrelated cases reported on OMIM. Therefore, there is enough evidence for this gene to be promoted to Green status.
Undiagnosed metabolic disorders v1.361 SLC2A1 Ivone Leong Gene: slc2a1 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.331 SLC2A1 Ivone Leong Classified gene: SLC2A1 as Green List (high evidence)
Likely inborn error of metabolism v1.331 SLC2A1 Ivone Leong Added comment: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.

Promoted from Amber to Green. SLC2A1 is associated with GLUT1 deficiency syndrome 1 and GLUT1 deficiency syndrome 2 on OMIM and Gene2Phenotype. There are >3 unrelated cases reported on OMIM. Therefore, there is enough evidence for this gene to be promoted to Green status.
Likely inborn error of metabolism v1.331 SLC2A1 Ivone Leong Gene: slc2a1 has been classified as Green List (High Evidence).
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Tag watchlist tag was added to gene: PIGP.
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Classified gene: PIGP as Amber List (moderate evidence)
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Added comment: Comment on list classification: PIGP was added to the panel and rated Green by Konstantinos Varvagiannis. Upgraded rating from Grey to Amber, and added watchlist tag, following review of literature and GLH-review by Helen Lord. Not yet associated with a disorder in Gene2Phenotype. 2 unrelated cases from the literature plus a third case from LOVD. Therefore Amber rating is appropriate.
Early onset or syndromic epilepsy v1.343 PIGP Rebecca Foulger Gene: pigp has been classified as Amber List (Moderate Evidence).
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Classified gene: TIMM50 as Green List (high evidence)
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Added comment: Comment on list classification: TIMM50 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Not yet associated with a disorder in Gene2Phenotype but upgraded rating from Grey to Green following review of literature evidence. PMID:27573165 and PMID:31058414 report 5 patients from 3 families with a consistent ID and epilepsy phenotype accompanied by 3-methylglutaconic aciduria. In addition, PMID:30190335 report pyschomotor regression in their patient, and a conference abstract (Serajee et al. 2015) adds an additional case of developmental delay. Therefore ID appears a consistent phenotype of 3-methylglutaconic aciduria and with sufficient reported cases, a Green rating is appropriate.
Intellectual disability v2.1054 TIMM50 Rebecca Foulger Gene: timm50 has been classified as Green List (High Evidence).
Intellectual disability v2.1053 TIMM50 Rebecca Foulger commented on gene: TIMM50
Additional findings health related v0.55 RET Ellen McDonagh Source Additional Findings was removed from RET.
Source ACMG was removed from RET.
Source Other was added to RET.
Mode of pathogenicity for gene RET 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
Additional findings health related v0.51 APOB Ellen McDonagh Source Additional Findings was removed from APOB.
Source ACMG was removed from APOB.
Source Other was added to APOB.
Mode of pathogenicity for gene APOB 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
Undiagnosed metabolic disorders v1.360 HSPA9 Sarah Leigh Classified gene: HSPA9 as Amber List (moderate evidence)
Undiagnosed metabolic disorders v1.360 HSPA9 Sarah Leigh Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.359 HSPA9 Sarah Leigh Added comment: Comment on phenotypes: Monoallelic variants reported in Anemia, sideroblastic, 4 182170.
Undiagnosed metabolic disorders v1.359 HSPA9 Sarah Leigh Phenotypes for gene: HSPA9 were changed from Even-plus syndrome 616854 to Even-plus syndrome 616854
Undiagnosed metabolic disorders v1.358 HSPA9 Sarah Leigh gene: HSPA9 was added
gene: HSPA9 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: HSPA9 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HSPA9 were set to 26598328
Phenotypes for gene: HSPA9 were set to Even-plus syndrome 616854
Review for gene: HSPA9 was set to AMBER
Added comment: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated cases.
Sources: Literature
Intellectual disability v2.1053 TIMM50 Rebecca Foulger Phenotypes for gene: TIMM50 were changed from 3-methylglutaconic aciduria, type IX (MIM 617698) to 3-methylglutaconic aciduria, type IX, 617698
Likely inborn error of metabolism v1.330 HSPA9 Sarah Leigh Added comment: Comment on phenotypes: EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia;Epiphyseal, Vertebral, Ear, Nose, plus associated findings.
Monoallelic variants reported in Anemia, sideroblastic, 4 182170.
Likely inborn error of metabolism v1.330 HSPA9 Sarah Leigh Phenotypes for gene: HSPA9 were changed from EVEN-PLUS syndrome of congenital malformations and skeletal dysplasia; Epiphyseal, Vertebral, Ear, Nose, plus associated findings to Even-plus syndrome 616854
Likely inborn error of metabolism v1.329 HSPA9 Sarah Leigh Classified gene: HSPA9 as Amber List (moderate evidence)
Likely inborn error of metabolism v1.329 HSPA9 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two unrelated cases.
Likely inborn error of metabolism v1.329 HSPA9 Sarah Leigh Gene: hspa9 has been classified as Amber List (Moderate Evidence).
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Classified gene: FDX2 as Green List (high evidence)
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Added comment: Comment on list classification: Based on reviews from Carl Fratter and Zornitza Stark (below).
This gene was added as Green due to the overall review and evidence assessment from the GMS mitochondrial specialist test group, submitted by Carl Fratter (May 2019) on behalf of GMS mitochondrial specialist test group: 3 unrelated familties; iron sulfur pathway. From panel: Possible mitochondrial disorder - nuclear genes (Version 0.187).
Promoted from red to amber, based on the expert review by Zornitza Stark (Australian Genomics) and the literature. FDX2 is associated with a phenotype in OMIM and not Gene2Phenotype. PMID: 24281368 describes a patient born of consanguineous Jewish Moroccan patents with episodic mitochondrial myopathy without optic atrophy or reversible leukoencephalopathy. The authors identified a homozygous missense variant in this gene (M1L). PMID: 30010796 describes 6 patients from 2 apparently unrelated Brazilian familes from the same geographical region with episodic mitochondrial myopathy. All affected individuals had the same homozygous variant (P144L). No haplotype analysis was performed. As there are only 2 different variants reported in this gene and no haplotype analysis was performed in PMID: 30010796 it was decided that there is currently not enough evidence to promote this gene to green status.
Undiagnosed metabolic disorders v1.357 FDX2 Sarah Leigh Gene: fdx2 has been classified as Green List (High Evidence).
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Classified gene: GABRA5 as Green List (high evidence)
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Added comment: Comment on list classification: Upgraded from Amber to Green following advice from Genomics England clinical team. The case reported in PMID:29961870 (Butler et al 2018) had delayed milestones and is reported to be non-verbal, which is a relevant phenotype for this panel. Overall 3 unrelated cases from 2 papers.
Intellectual disability v2.1052 GABRA5 Rebecca Foulger Gene: gabra5 has been classified as Green List (High Evidence).
Undiagnosed metabolic disorders v1.356 FDX2 Sarah Leigh gene: FDX2 was added
gene: FDX2 was added to Undiagnosed metabolic disorders. Sources: Literature
Mode of inheritance for gene: FDX2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDX2 were set to 24281368; 28803783; 30010796
Phenotypes for gene: FDX2 were set to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy 251900
Review for gene: FDX2 was set to GREEN
Added comment: Sources: Literature
Likely inborn error of metabolism v1.328 FDX2 Sarah Leigh Classified gene: FDX2 as Green List (high evidence)
Likely inborn error of metabolism v1.328 FDX2 Sarah Leigh Added comment: Comment on list classification: Based on reviews from Carl Fratter and Zornitza Stark.
Likely inborn error of metabolism v1.328 FDX2 Sarah Leigh Gene: fdx2 has been classified as Green List (High Evidence).
Likely inborn error of metabolism v1.327 FDX2 Sarah Leigh Phenotypes for gene: FDX2 were changed from No OMIM phenotype?Mitochondrial myopathy with lactic acidosis, association with, 255125 to Mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy 251900
Long QT syndrome v1.42 SCN5A Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Long QT syndrome v1.42 SCN5A Ivone Leong Mode of inheritance for gene: SCN5A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Long QT syndrome v1.41 KCNQ1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Long QT syndrome v1.41 KCNQ1 Ivone Leong Mode of inheritance for gene: KCNQ1 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
Long QT syndrome v1.40 KCNE1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Long QT syndrome v1.40 KCNE1 Ivone Leong Mode of inheritance for gene: KCNE1 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
Likely inborn error of metabolism v1.326 FDX2 Sarah Leigh Publications for gene: FDX2 were set to
Likely inborn error of metabolism v1.325 FDX2 Sarah Leigh Mode of inheritance for gene: FDX2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Hereditary spastic paraplegia, childhood onset v1.179 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia to Childhood onset hereditary spastic paraplegia;R61
Hereditary spastic paraplegia, adult onset v0.156 Louise Daugherty List of related panels changed from to R60
Hydrocephalus v1.38 Louise Daugherty List of related panels changed from Hydrocephalus to Hydrocephalus;R86
Holoprosencephaly v1.23 Louise Daugherty List of related panels changed from Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal to Rhombencephalosynapsis; Holoprosencephaly - NOT chromosomal; R85
Hypertrophic cardiomyopathy v1.76 TNNI3 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Hypertrophic cardiomyopathy v1.76 TNNI3 Ivone Leong Mode of inheritance for gene: TNNI3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hypertrophic cardiomyopathy v1.75 GLA Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Hypertrophic cardiomyopathy v1.75 GLA Ivone Leong Mode of inheritance for gene: GLA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Short QT syndrome v1.23 CACNB2 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Short QT syndrome v1.23 CACNB2 Ivone Leong Mode of inheritance for gene: CACNB2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.22 CACNA2D1 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Short QT syndrome v1.22 CACNA2D1 Ivone Leong Mode of inheritance for gene: CACNA2D1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Short QT syndrome v1.21 SLC22A5 Ivone Leong Added comment: Comment on mode of inheritance: Phenotype changed due to expert reviews.
Short QT syndrome v1.21 SLC22A5 Ivone Leong Mode of inheritance for gene: SLC22A5 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Catecholaminergic polymorphic VT v1.22 RYR2 Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Catecholaminergic polymorphic VT v1.22 RYR2 Ivone Leong Mode of inheritance for gene: RYR2 was changed from BIALLELIC, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.63 TTN Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.63 TTN Ivone Leong Mode of inheritance for gene: TTN was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.62 TCAP Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.62 TCAP Ivone Leong Mode of inheritance for gene: TCAP was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.61 SCN5A Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.61 SCN5A Ivone Leong Mode of inheritance for gene: SCN5A was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.60 MYH7 Ivone Leong commented on gene: MYH7
Dilated Cardiomyopathy and conduction defects v1.60 MYH7 Ivone Leong Mode of inheritance for gene: MYH7 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.59 LMNA Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Dilated Cardiomyopathy and conduction defects v1.59 LMNA Ivone Leong Mode of inheritance for gene: LMNA was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Dilated Cardiomyopathy and conduction defects v1.58 DES Ivone Leong commented on gene: DES
Additional findings health related v0.50 Ellen McDonagh Panel name changed from Genomics England Secondary Findings to Genomics England Additional Findings
Dilated Cardiomyopathy and conduction defects v1.58 DES Ivone Leong Mode of inheritance for gene: DES was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Likely inborn error of metabolism v1.324 DNM2 Sarah Leigh Publications for gene: DNM2 were set to
Undiagnosed metabolic disorders v1.351 DNM2 Sarah Leigh gene: DNM2 was added
gene: DNM2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DNM2 were set to Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Undiagnosed metabolic disorders v1.351 DNM2 Sarah Leigh gene: DNM2 was added
gene: DNM2 was added to Undiagnosed metabolic disorders. Sources: Other
Mode of inheritance for gene: DNM2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DNM2 were set to Centronuclear myopathy 1 160150; -Marie-Tooth disease, axonal type 2M 606482; Charcot-Marie-Tooth disease, dominant intermediate B 606482
Hereditary ataxia and cerebellar anomalies, childhood onset v3.390 Louise Daugherty Changed child panels to: Congenital disorders of glycosylation; Ataxia and cerebellar anomalies - narrow panel
Thoracic aortic aneurysm or dissection v1.97 FLNA Ivone Leong Added comment: Comment on mode of inheritance: MOI was corrected.
Thoracic aortic aneurysm or dissection v1.97 FLNA Ivone Leong Mode of inheritance for gene: FLNA was changed from X-LINKED: hemizygous mutation in males, biallelic mutations in females to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Thoracic aortic aneurysm or dissection v1.96 COL3A1 Ivone Leong commented on gene: COL3A1
Thoracic aortic aneurysm or dissection v1.96 COL1A2 Ivone Leong commented on gene: COL1A2
Thoracic aortic aneurysm or dissection v1.96 BGN Ivone Leong commented on gene: BGN
Thoracic aortic aneurysm or dissection v1.96 COL3A1 Ivone Leong Mode of inheritance for gene: COL3A1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic, autosomal or pseudoautosomal