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Genome Sequencing of Individuals with PTEN Hamartoma Tumor Syndrome

This study investigated genomic modifiers of cancer and neurodevelopmental outcomes among individuals with PTEN hamartoma tumor syndrome (PHTS), a rare hereditary disorder caused by germline PTEN variants and associated with broad clinical variability, including cancer predisposition, autism spectrum disorder, developmental delay, and intellectual disability. The primary aim was to determine whether additional inherited genomic variation beyond PTEN contributes to divergent clinical manifestations, particularly the development of cancer versus neurodevelopmental disorders.

The main analytic cohort consisted of 543 probands with germline PTEN variants, including participants with cancer, neurodevelopmental disorders, both cancer and neurodevelopmental disorders, or neither phenotype at the time of consent.

Molecular data were generated from germline DNA extracted from peripheral blood leukocytes using PCR-free whole-genome sequencing at approximately 30× coverage. Sequence reads were aligned to the hg38 human reference genome, followed by standard variant calling, quality control, annotation, and downstream genomic analyses. The study evaluated pathogenic or likely pathogenic variants in established cancer predisposition genes and neurodevelopmental disorder genes, and also performed genome-wide common-variant and rare-variant association analyses to identify candidate modifier loci.

Principal findings showed that a subset of individuals with PHTS carried additional germline variants in known cancer- or neurodevelopment-related genes. Specifically, additional cancer-associated variants were identified in 37 of 543 probands, most commonly involving MITF, DICER1, and BRCA2, while neurodevelopment-associated variants were identified in 43 of 543 probands, including variants in DHCR7, POLG, ARSA, and other genes. Genome-wide analyses further identified candidate modifier loci with potential biological relevance to PTEN signaling and phenotype divergence, including ZNF713, TPTE2P1, and PDPK1. These findings support the hypothesis that PHTS clinical outcomes are influenced not only by germline PTEN variation, but also by additional inherited genomic modifiers.

Data to be made available through dbGaP will include de-identified individual-level germline whole-genome sequencing data and associated phenotype information relevant to PHTS, cancer status, neurodevelopmental status, demographic variables, and PTEN variant classification, consistent with participant consent and institutional certification. The individual-level data are intended for controlled access.