Clinical and Immunologic Phenotype of Patients with SMAD4 Gain-of-Function Mutations

Abstract

Smad4 is a critical downstream signaling molecule in the transforming growth factor-β (TGF-β) pathway. Germline gain-of-function mutations in SMAD4 (most commonly p. I500V) cause Myhre syndrome (MIM#139210), an autosomal dominant disease with cognitive impairment, hearing loss, and musculoskeletal anomalies. The immunological phenotype has not been previously described, despite the critical role for TGF-β in regulating immune responses.