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

De novo intronic PPP1R12A variant generating an out-of-frame transcript with premature stop codon, revealed by RNA sequencing on trio genome sequencing

A 12-year-old with global developmental delay, semi-lobar holoprosencephaly, microcephaly, spastic quadriplegia, bilateral polydactyly, and ambiguous genitalia was found by trio genome + RNA sequencing to carry a de novo intronic PPP1R12A variant generating an out-of-frame transcript with a premature stop codon. This presentation broadens the phenotypic spectrum of PPP1R12A-related syndrome (22 previously described cases) and illustrates the value of RNA sequencing for splicing variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This case illustrates two key points: 1) RNA sequencing transforms a likely intronic VUS into a classifiable pathogenic variant — without RNA-seq, this case would have remained unsolved; 2) the extension toward holoprosencephaly broadens the differential diagnosis of this little-known gene. Worth noting for holoprosencephaly and multi-systemic neurodevelopmental panels.

Clinical impact: 1/3 · Evidence strength: 1/3 · Novelty: 2/2 · Sample size: 0/1 · Journal quality: 1/1 → Total: 5/10