A missense mutation underlies defective SOCS4 function in a family with autoimmunity.

Objective The aim of this study was to determine the genetic and immunological defects underlying familial manifestations of an autoimmune disorder. Methods Whole-exome sequencing was performed on the index patient with various manifestations of autoimmunity, including hypothyroidism, vitiligo and alopecia. Peripheral blood mononuclear cells and DNA of family members were used for functional and genetic testing of the candidate variants obtained by Sanger sequencing. Results Exome sequencing identified 233 rare, coding and nonsynonymous variants in the index patient; five were highly conserved and affect genes that have a possible role in autoimmunity. Only a heterozygous missense mutation in the suppressor of cytokine signalling 4 gene ( SOCS4) cosegregated with the autoimmune disorder in the family. SOCS4 is a known inhibitor of epidermal growth factor ( EGF) receptor signalling, and functional studies demonstrated specific upregulation of EGF-dependent immune stimulation in affected family members. Conclusion We present a family with an autoimmune disorder, probably resulting from dysregulated immune responses due to mutations in SOCS4. [ABSTRACT FROM AUTHOR]