Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations

摘要: In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and disorders of sex development, through international research collaboration, we identified twelve de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved cell migration, adhesion, morphogenesis. This has not been previously reported association human disease, it intolerance to LoF as illustrated by a very low observed-to-expected ratio gnomAD. Of the individuals, midline brain malformations were found five, urogenital anomalies nine, combination both phenotypes two. Other congenital included omphalocele, jejunal, ileal atresia aberrant mesenteric blood supply, syndactyly. Six had stop gain variants, five deletion or duplication resulting frameshift, one canonical splice acceptor site loss. Murine situ hybridization immunostaining revealed PPP1R12A expression prosencephalic neural folds localization lower urinary tract at critical periods forebrain division development. Based on these clinical molecular findings, propose pathogenic syndrome affecting embryogenesis genitourinary systems including