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Mendeliome v1.4625 DOCK2 Zornitza Stark edited their review of gene: DOCK2: Added comment: PMID 41654261: Six individuals from three unrelated families, aged 3 months to 50 years, reported with one of three heterozygous variants in DOCK2 and severe infections with human papilloma virus, respiratory syncytial virus, or SARS-CoV-2. All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-α therapy led to complete resolution of refractory warts in one patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency.

PMID 36836791: Patient with recurrent HLH. Heterozygous c.1334A>G (p.Asn445Ser) variant. Functional studies showing lower CD107a expression and diminished NK degranulation and cytotoxicity. ? partial dominant negative.; Changed publications: 26083206, 29204803, 33928462, 30826364, 30838481, 11518968, 41654261, 36836791; Changed phenotypes: Immunodeficiency 40 MIM# 616433, Inborn error of immunity, MONDO:0003778, DOCK2-related; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.4589 DYNC1H1 Zornitza Stark edited their review of gene: DYNC1H1: Added comment: PMID 38848546 reports 47 individuals from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years). Most individuals presented with divergent neurological and multisystem features such as autonomic features, behavioural disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. Age-dependent biphasic disease course observed with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, in several cases neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health.; Changed publications: 21820100, 32788638, 27549087, 38848546
Mendeliome v1.1922 OAS2 Zornitza Stark gene: OAS2 was added
gene: OAS2 was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: OAS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OAS2 were set to 36538032
Phenotypes for gene: OAS2 were set to Multisystem inflammatory syndrome, MONDO:0035375, OAS2-related
Review for gene: OAS2 was set to GREEN
Added comment: 3x unrelated patients with MIS-C after COVID infection. Patients displayed excessive inflammatory responses to intracellular dsRNA, SARS-CoV-2, SARS-CoV-2–infected cells, and their RNA, providing a plausible mechanism for MIS-C. Similar presentation to OAS1 and RNASEL. Functional data.
Sources: Literature
Mendeliome v1.1696 PTCRA Achchuthan Shanmugasundram gene: PTCRA was added
gene: PTCRA was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: PTCRA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PTCRA were set to 38422122
Phenotypes for gene: PTCRA were set to Autoimmunity, HP:0002960; lymphopenia, MONDO:0003783
Review for gene: PTCRA was set to GREEN
Added comment: PMID:38422122 reported the identification of 10 individuals from seven kindreds from four different ethnicities with biallelic PTCRA variants (homozygous in five kindreds and compound heterozygous in two kindreds).

Six of these 10 patients were clinically asymptomatic at their most recent evaluation, while other four patients displayed infection, lymphoproliferation, and/or autoimmunity with an onset during their teens or in adulthood. One of these patients died from SARS-CoV-2 pneumonia at the age of 24 years. Patient 9 had a small thymus on MRI at the age of 2 years, whereas P5 and P6 had no visible thymus at the ages of 13 and 8 years, respectively. Three of the nine patients with pLOF PTCRA variants tested were found to produce autoantibodies, several of which were associated with clinical manifestations. Anti-thyroid autoantibodies and/or clinically overt thyroiditis were found in three of the nine patients. P7, who suffered from recurrent herpes infections, had autoantibodies against type I interferons.

Two of those identified variants are hypomorphic and are associated with autoimmunity. In addition, there is extensive functional and epidemiological data available.
Sources: Literature
Mendeliome v1.619 SARS Zornitza Stark Phenotypes for gene: SARS were changed from neurodevelopmental disorder MONDO#070009, SARS1-related to neurodevelopmental disorder MONDO#070009, SARS1-related; Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.618 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048; 36041817
Mendeliome v1.617 SARS Zornitza Stark Mode of inheritance for gene: SARS was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Mendeliome v1.361 SARS Ee Ming Wong edited their review of gene: SARS: Added comment: -Two missense variants within the aminoacylation domain identified in 16 affected individuals from 3 distinct CMT families
-Mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation; Changed rating: GREEN; Changed publications: 36088542; Changed phenotypes: Genetic peripheral neuropathy MONDO#0020127, SARS1-related
Mendeliome v1.301 SARS Zornitza Stark Publications for gene: SARS were set to 28236339; 34570399; 35790048
Mendeliome v1.289 SARS Ee Ming Wong reviewed gene: SARS: Rating: RED; Mode of pathogenicity: Other; Publications: 36041817; Phenotypes: neurodevelopmental disorder, MONDO#070009, SARS1-related; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Mendeliome v1.222 SARS Ain Roesley Publications for gene: SARS were set to 28236339; 34570399
Mendeliome v1.222 SARS Ain Roesley Classified gene: SARS as Green List (high evidence)
Mendeliome v1.222 SARS Ain Roesley Gene: sars has been classified as Green List (High Evidence).
Mendeliome v1.222 SARS Ain Roesley Phenotypes for gene: SARS were changed from Intellectual disability to neurodevelopmental disorder MONDO#070009, SARS1-related
Mendeliome v1.220 SARS Ain Roesley reviewed gene: SARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 35790048; Phenotypes: neurodevelopmental disorder MONDO#070009, SARS1-related; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Mendeliome v0.11753 SARS2 Zornitza Stark Marked gene: SARS2 as ready
Mendeliome v0.11753 SARS2 Zornitza Stark Gene: sars2 has been classified as Green List (High Evidence).
Mendeliome v0.11753 SARS2 Zornitza Stark Phenotypes for gene: SARS2 were changed from to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845
Mendeliome v0.11752 SARS2 Zornitza Stark Publications for gene: SARS2 were set to
Mendeliome v0.11751 SARS2 Zornitza Stark Mode of inheritance for gene: SARS2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11750 SARS2 Zornitza Stark reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 33751860; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.11719 SARS2 Samantha Ayres reviewed gene: SARS2: Rating: GREEN; Mode of pathogenicity: None; Publications: 24034276, 21255763; Phenotypes: Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis, MIM#613845; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Mendeliome v0.9297 SARS Bryony Thompson Marked gene: SARS as ready
Mendeliome v0.9297 SARS Bryony Thompson Gene: sars has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9295 SARS Bryony Thompson Classified gene: SARS as Amber List (moderate evidence)
Mendeliome v0.9295 SARS Bryony Thompson Gene: sars has been classified as Amber List (Moderate Evidence).
Mendeliome v0.9294 SARS Bryony Thompson gene: SARS was added
gene: SARS was added to Mendeliome. Sources: Literature
Mode of inheritance for gene: SARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS were set to 28236339; 34570399
Phenotypes for gene: SARS were set to Intellectual disability
Review for gene: SARS was set to AMBER
Added comment: Summary - 2 unrelated families with overlapping ID phenotype, and supporting in vitro and patient cell assays.
PMID: 28236339 - an Iranian family (distantly related) segregating a homozygous missense (c.514G>A, p.Asp172Asn) with moderate ID, microcephaly, ataxia, speech impairment, and aggressive behaviour. Also, supporting in vitro functional assays demonstrating altered protein function.
PMID: 34570399 - a consanguineous Turkish family segregating a homozygous missense (c.638G>T, p.(Arg213Leu)) with developmental delay, central deafness, cardiomyopathy, and metabolic decompensation during fever leading to death. Also, reduced protein level and enzymatic activity in patient cells.
Sources: Literature
Mendeliome v0.0 SARS2 Zornitza Stark gene: SARS2 was added
gene: SARS2 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services
Mode of inheritance for gene: SARS2 was set to Unknown