Expanded Phenotype Associated With an Intronic PPP1R12A Variant: A Case Report and Literature Review.
Emily M Bland, Amber Nakar Weinstein, Eric C Kao et al.
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Case in brief
A 12-year-old individual presented with global developmental delay, microcephaly, spastic quadriplegia, bilateral polydactyly, ambiguous genitalia, and semi-lobar holoprosencephaly. Chromosome analysis showed a 46,XY complement. Trio genome sequencing identified a novel intronic PPP1R12A variant; sequential RNA sequencing showed that it produced an out-of-frame transcript with a premature stop codon, supporting loss of function. The findings were consistent with PPP1R12A-related genitourinary and/or brain malformation syndrome and expanded the reported clinical and genetic spectrum.
What made this case unusual
The individual had both brain and genitourinary anomalies, alongside polydactyly, and the disease-associated variant was intronic rather than identified solely through genomic sequencing.
Diagnostic / clinical pearl
When an intronic variant is suspected to affect splicing, transcript-level analysis can demonstrate an abnormal out-of-frame transcript and help support a loss-of-function interpretation.