MOCS3

Inheritance Pattern: AR

Disease ID:MONDO:0020480

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0980701

Submitter: ClinGen

*MOCS3 *was first reported in relation to “sulfite oxidase deficiency due to molybdenum cofactor deficiency type B2”, an autosomal recessive disorder of molybdenum cofactor (moco) biosynthesis, in 2017 (Huijmans et al, PMID: 28544736). This is the only known disease entity asserted to be caused by variants in *MOCS3*. Moco deficiency has been shown to be caused by variants in genes involved in moco biosynthesis, including *MOCS1*, *MOCS2*, and *GEPH*. There is a spectrum of clinical severity. The most severe cases present shortly after birth with neonatal-onset severe encephalopathy, refractory seizures, opisthotonos, hypotonia, feeding difficulties, and apnea. Brain MRI changes MRI changes like hypoxic–ischemic lesions. Most patients die in infancy. Individuals with milder, late-onset condition often present with acute neurologic decompensation during illness, with altered mental state, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia (Misko et al, 2021, PMID: 34870926; Johannes et al, 2022, PMID: 36296488). The clinical features are believed to be related to loss of sulfite oxidase (SOX) activity, one of four human proteins that require moco to function. Reduction of SOX activity results in accumulation of sulfite and secondary metabolites, S-sulfocysteine and thiosulfate, that are toxic, as well as a decrease in cysteine and cystine. Three variants (two missense, one nonsense) that have been reported in 2 probands in 2 publications were scored in this curation. The first reported patient was noted to have a mild phenotype with normal or low normal uric acid levels in plasma and urine, normal urine sulfite level, and normal sulfite oxidase activity, unlike patients with severe moco deficiency (Huijmans et al, 2017, PMID: 28544736). The second patient reported had a severe neonatal onset; sulfite oxidase activity was not reported (Tian et al, 2021, PMID: 33897766). In addition to these two cases, molecular analysis of a pregnancy loss with non-immune hydrops fetalis identified homozygosity for a nonsense variant (Shamseldin et al, 2018, PMID: 28749478; SCV001870500.1). A subsequent report indicated that the variant had been found in homozygosity in an individual with “no phenotype”; details of the age of the homozygous individual and evaluation were not provided (Aladbi et al, 2025, PMID: 3950496). This gene-disease relationship supported by experimental evidence including the biochemical function of the gene product and its interaction with MOCS2A, one of the two proteins encoded by *MOCS2*, a gene previously classified as having a definitive relationship with “sulfite oxidase deficiency due to molybdenum cofactor deficiency type B1”. MOCS3 activates MOCS2A by ATP-dependent adenylation and formation of a thiocarboxylate group, required for molybdopterin (MPT) synthesis (Matthies et al, 2004, PMID: 15073332; Chowdhury, 2012, PMID: 22453920; Johannes et al, 2022, PMID: 36296488). In summary, there is limited evidence supporting the relationship between *MOCS3* and autosomal recessive “sulfite oxidase deficiency due to molybdenum cofactor deficiency type B2”. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on April 24, 2026 (SOP v12).