Whole exome sequencing and transcript analysis of a PTEN splice-site variant in a child with PTEN hamartoma tumor syndrome: a case report

Introduction PTEN hamartoma tumor syndrome (PHTS) is a hereditary tumor syndrome characterized by macrocephaly, neurodevelopmental disorders, mucocutaneous lesions, and predisposition to tumors. In childhood, the characteristic mucocutaneous and tumor-related manifestations may not yet be apparent; hence, diagnosis is often difficult. Therefore, genetic tools, such as whole-exome sequencing (WES) and transcript analysis may be useful for accurate diagnosis. We report a child presenting with macrocephaly and developmental delay who was diagnosed with PHTS using WES and transcript analysis. Case report A three-year-old girl presented with macrocephaly and a mild developmental delay. NSD1 testing and chromosomal microarray analysis were unremarkable. However, WES revealed a heterozygous splice-site variant of PTEN (NM_000314.8:c.802-1G>A). Further transcript analysis using reverse transcription-polymerase chain reaction, TA cloning, and Sanger sequencing revealed an aberrant transcript lacking the first nucleotide at the 5′ end of exon 8. Based on these molecular findings, the patient was diagnosed with PHTS. Subsequently, genetic counseling was provided, and tumor surveillance was planned. Discussion The aberrant splicing identified in this patient supports the loss-of-function effect of PTEN . This splicing pattern differs from that previously observed for variants at the same splice acceptor site (c.802-2A>G and c.802-2A>T). Thus, transcript analysis may be useful for evaluating variant-specific effects. In addition, early diagnosis of PHTS in this patient was crucial for planning tumor surveillance and providing genetic counseling. This case highlights the utility of comprehensive genetic analysis in children with macrocephaly and neurodevelopmental disorders and emphasizes the value of transcript analysis for interpreting splice-site variants.