Expanded Phenotype Associated With an Intronic PPP1R12A Variant: A Case Report and Literature Review

Autosomal dominant PPP1R12A-related genitourinary and/or brain malformation syndrome is a recently described multisystem disorder caused by loss-of-function variants in the protein phosphatase 1 regulatory subunit 12a (PPP1R12A) gene. To date, 22 affected individuals have been reported with variable brain malformations and genitourinary anomalies, including differences of sexual development. Of these cases, four probands had anomalies involving both organ systems. Here, we report a 12-year-old individual with global developmental delay, semi-lobar holoprosencephaly, microcephaly, spastic quadriplegia, bilateral polydactyly, and ambiguous genitalia. The proband was found to have a 46,XY chromosome complement. Trio genome sequencing with sequential RNA sequencing revealed a novel intronic variant that generates an out-of-frame transcript with a premature stop codon, supporting a loss-of-function mechanism. We review previously reported cases of PPP1R12A-related disease and summarize genotypes and frequency of reported clinical features, further illustrating the variable expressivity associated with this condition. Our findings broaden the phenotypic and genotypic spectrum of PPP1R12A and reinforce the role of transcript-level analysis in the evaluation of suspected splicing variants.