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In a single family with autosomal dominant inheritance, whole-exome sequencing identified a heterozygous missense mutation in SOCS4 that cosegregated with an autoimmune phenotype including hypothyroidism, vitiligo, and alopecia (PMID:25639832). One index patient and multiple affected relatives demonstrated full penetrance of the variant, supporting a gene-disease link in this pedigree. No additional unrelated cases have been reported to date.
Functional assays in peripheral blood mononuclear cells revealed dysregulated epidermal growth factor receptor signalling in variant carriers, consistent with impaired SOCS4 inhibitory function on immune activation (PMID:25639832). These data support a pathogenic mechanism of altered immune regulation due to SOCS4 haploinsufficiency. Further case series are needed to expand the variant spectrum and validate prevalence.
Key Take-home: SOCS4 variants may underlie familial autoimmune disease, meriting targeted sequencing in undiagnosed multigenerational autoimmunity.
Gene–Disease AssociationLimitedSingle family with cosegregation and supportive functional data Genetic EvidenceLimitedOne proband and familial segregation in a single pedigree Functional EvidenceModerateCellular assays demonstrate dysregulated EGF receptor signalling consistent with SOCS4 loss of function |