Genetic Investigation and Transcriptome Profiling in a Nuclear Family With Peutz–Jeghers Syndrome

Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant disorder hallmarked by mucocutaneous melanocytic macules and gastrointestinal hamartomatous polyposis associated with germline/somatic pathogenic variants in the tumor suppressor STK11 . PJS is clinically heterogeneous; however, the relationship between clinical phenotype and genotype remains elusive. Here, we report a family with PJS that harbors a heterozygous STK11 whole gene deletion combined with a heterozygous variant in TP53AIP1 that segregates with mucocutaneous pigmentation in the family. RNA‐seq analysis followed by qRT‐PCR confirmed that the expression of STK11 , TP53 , and TP53AIP1 and a large fraction of p53 signaling pathway components are significantly reduced, while Wnt signaling pathway effectors are upregulated in cells from an affected individual. Our findings shed light on transcriptome‐level pathway dysregulation in PJS with germline deletion of STK11 . Further evaluation of mutational burden across relevant signaling pathways can likely inform disease prognosis.