Disease | |
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Inheritance | Autosomal dominant |
Prevalence | unknown Source: |
Rapid or full curation? | |
ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen - none. GenCC - only 1 strong curation by US based lab (Invitae). HGMD below |
Clinical Validity Scoring Notes and points | PMID: 29455859 (2018) WES performed in a family with infantile onset pulmonary alveolar proteinosis with hypogammaglobulinemia. Based on the main text it sounds like parents were included for variant filtering so assuming this is trio. c.227C>T p.A76V (absent gnomAD) in family A - they say this variant was de novo in the three affected family members, but was not found in the two unaffected parents or the unaffected sib. Biological parentage was confirmed based on microsatellite markers, and deep sequencing of the mom showed that the mutant allele was present in 3.81% of reads. 1 VARIANT POINT, 2 AD SEGREGATIONS c.326G>A Cys109Tyr (absent gnomad) in family B - identified as de novo 1 VARIANT POINT c.592C>G in p.Leu98Val (absent gnomad) in family C - identified as de novo 1 VARIANT POINT
PMID: 34145065 (2021) Previously unreported patients with recurrent fever, ulcerative skin rash, viral like airway infection, diarrhea, mild interstitial lung disease and PAP, dermatitis with mononuclear infammation, nonspecific gastrointestinal inflammation and hypogammaglobulinemia, respiratory insufficiency, poor weight gain or FTT, tested via exome sequencing, described as de novo. Variants per fig 1 c.227C>T p.A76V (same variant as above), functional evidence below 1.5 VARIANT POINT c.326G>A Cys109Tyr (same variant as above), functional evidence below 1.5 VARIANT POINT c.326G>A Cys109Tyr (same variant as above) 1 VARIANT POINT C.362T>G VAL121GLY absent gnomad 1 VARIANT POINT c.592C>G in p.Leu98Val (same variant as above) 1 VARIANT POINT c.326G>A Cys109Tyr (same variant as above) 1 VARIANT POINT
Gene function - initiates an antiviral immune response upon recognition of cytoplasmic foreign nucleoic acid (double stranded RNA). It is a template-independent nucleotidyltransferase and produces the second messenger 2'-5' oligoadenylate (2-5A). 2-5A activates RNase L which degrades viral RNA. Functional evidence A76V and C109Y B-cell proliferation and differentiation into non-class-switched memory B-cell, class-switched memory B-cells, and plasmablasts were impaired (fig 2A-B). A76V and C109Y T-cells had impaired activation and proliferation and activation as indicated by CD25 up-regulation and CFSE-dilution, especially after CD3- and to a lesser extent after CD3/CD28- stimulation Fig S3 Increased apoptosis in A76V and C109Y monocytes Found A76V allele expression in 50% of T-cells, 43% of B-cells and 17% of monocytes (Fig. S9) thereby excluding nonsense mediated decay. Compared to OAS1-WT, A76V monocytes, B-cells, and T-cells differentially expressed 2,455, 1,179, and 1,135 genes, respectively (Fig. 2E, Tab. S5) Unstimulated primary L198V iPSC, and L198V and C109Y KI iPSC-MΦ showed decreased adhesion, cell clustering, and increased floating single cells (FSC) as compared to OAS1-WT iPSC MΦ (Fig. 3C) Evidence of GOF: To understand the molecular mechanisms of monocyte/macrophage and B-cell dysfunction and apoptosis, we FACS-sorted unstimulated primary OAS1-WT, A76V and C109Y cells (Fig. S8), isolated cellular RNA from monocytes, B-cells, and T-cells, and analyzed RNA degradation to calculate the RNA integrity number (RIN) (18). While OAS1-WT cells uniformly had intact cellular RNA, A76V and C109Y monocytes and B-cells, but not T-cells, displayed RNA degradation (Fig. 4A–B) that resembled RNase L-mediated degradation (19). CELL CULTURE MODEL Inspected basal activity of each mutant enzyme in absence of dsRNA. As compared to OAS1-WT, the mutant enzyme activity was consistently above background. 1 POINT EXPRESSION Transient transfection of HEK293T cells - OAS1-MUT cells had increased 2-5A production that furthered after poly(rI:rC)-dsRNA treatment (Fig 4E). CELL CULTURE MODEL Thus, OAS1-MUT proteins displayed dsRNA-independent GOF 2–5A synthetase activity that led to RNase L-dependent RNA degradation, translational arrest, and cellular apoptosis. CELL CULTURE MODEL (2 POINTS)
PMID: 34647697 appears to be same patient as reported in 34145065 AUTOSOMAL RECESSIVE EVIDENCE - not scoring now, but noting for future potential AR cases. PMID: 36538032 This paper is for autosomal RECESSIVE OAS1 deficiency. Patients with multisystem inflammatory disease in children (MIS-C), which is a severe, unexplained complicaiton of SARS-CoV-2. Phenotype is 4 weeks after infection, present with fever, rash, abdominal pain, myocarditis, and other clinical features reminiscent of Kawasaki disease, including lymphadenopathy, coronary aneurysm, and high levels of biological markers of acute inflammation. WGS/WES performed on 558 patients w/ MIS-C. Variant - HOM Arg47* in patient 1 - variant present in many individuals from “Remaining” group in gnomAD, grpmax of 41/44890 in East Asian. Additional variants in table S1; however these are just variants that have homozygotes in gnomAD - Asp75Glu, Gln105His, Glu143Gly, Val117Met, Gly72Ser, Gly254Arg, Gln91Glu, Arg242Gln, Gly162Ser. Functional evidence: Decreased synthesis of 2-5A in OAS1 mutant (Fig 1E) Monocytic cell lines w/ genetic deficiency of OAS1 displayed excessive inflammatory cytokine production in response to intracellular double stranded RNA (Fig 1G, fig3) Exogenous 2-5A suppressed inflammatory responses by stimuli in control and OAS1 deficient cells
Source: |
Clinical Validity Points Total | 13 Source: |
Clinical Validity Classification Classifications (pts) Definitive (12pts) Strong (12pts) Moderate (7-11pts) Limited (0.1-6pts) No genetic evidence Refuted Disputed | Definitive |
Molecular Mechanism Mechanisms Loss of function Gain of function Dominant negative Unknown Other | Proposed Gain of function PMID: 34145065 |
Penetrance options Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) | Source: |
Age of Onset options Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Congenital / Infantile PMID 34145065 |
Severity Options Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers. | |
Clinical Features | recurrent fever, ulcerative skin rash, viral like airway infection, diarrhea, mild interstitial lung disease and pulmonary alveolar proteinosis, dermatitis with mononuclear inflammation, nonspecific gastrointestinal inflammation and hypogammaglobulinemia, respiratory insufficiency, poor weight gain or FTT - 34145065, 29455859 One case report describes treatment - monthly immunoglobulin injections, at 15 months needed supplemental oxygen at night, and at 18mos also during the day. At 2 years, whole lung lavages were started and stabilized the patient for 2 years, then the patient was treated with hematopoeitic stem cell transplantation (ie bone marrow transplant) 34647697
Sources: 34145065, 29455859, 34647697 |
HPO Terms https://hpo.jax.org/app/ | |
Gene SOPs & Notes | |
Curation Summary Examples - The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs). - Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited | The OAS1 gene is associated with OAS1-related autoinflammatory immunodeficiency. Clinical features include recurrent fever recurrent fever, ulcerative skin rash, viral like airway infection, diarrhea, mild interstitial lung disease and pulmonary alveolar proteinosis, dermatitis with mononuclear inflammation, nonspecific gastrointestinal inflammation and hypogammaglobulinemia, respiratory insufficiency, and poor weight gain or failure to thrive (PMID: 34145065, 29455859, 34647697) |
Case ID, Curator name, Date, Jira ticket link | Andrea Oza 01.30.2025, 2106077001 |