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<p>PTEN hamartoma tumor syndrome (PHTS), caused by germline <i>PTEN</i> variants, exhibits marked phenotypic heterogeneity, most notably cancer, neurodevelopmental disorders (NDD), or both. The basis for this divergence, even among carriers of identical <i>PTEN</i> variants, remains poorly defined. We performed whole-genome sequencing of 599 individuals with PHTS and family members, complemented by analyses of <i>PTEN</i> variant carriers from the All of Us Research Program. Analyses included both targeted evaluation of genes previously implicated in cancer and NDD and agnostic genome-wide single-variant and rare-variant burden testing. The analytic cohort comprised 543 PHTS probands, including individuals with NDD (<i>n</i> = 171), cancer (<i>n</i> = 221), both phenotypes (<i>n</i> = 21), or neither (<i>n</i> = 130) at the time of enrollment. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 (6.8%), most frequently in <i>MITF</i>, <i>DICER1</i>, and <i>BRCA2</i>, while 43 (7.9%) harbored variants in NDD-related genes, including <i>DHCR7</i>, <i>POLG</i>, and <i>ARSA</i>. Such secondary variants were less common in <i>PTEN</i> variant carriers in All of Us. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in <i>ZNF713</i>, <i>TPTE2P1</i>, and <i>PDPK1</i>. These findings demonstrate that PHTS phenotypes are shaped by complex gene–gene interactions beyond <i>PTEN</i> alone, informing mechanisms underlying the cancer–NDD dichotomy and advancing precision risk stratification.</p>

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Genomic modifiers of malignant and neurodevelopmental phenotypes in individuals with PTEN hamartoma tumor syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Lamis Yehia,
  • Lin Li,
  • Gideon Idumah,
  • Thomas W. Frazier,
  • Vladimir Makarov,
  • Aritra Bose,
  • Laxmi Parida,
  • Antonio Hardan,
  • Julian A. Martinez-Agosto,
  • David M. Ritter,
  • Mustafa Sahin,
  • Charis Eng,
  • Ying Ni,
  • Robyn Busch,
  • Kristn D. Currans,
  • Kira Dies,
  • Rajna Filip-Dhima,
  • Amanda Gulsrud,
  • Ellen Hanson,
  • Bridget Kent,
  • Patricia Klaas,
  • Jennifer M. Phillips

摘要

PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN variants, exhibits marked phenotypic heterogeneity, most notably cancer, neurodevelopmental disorders (NDD), or both. The basis for this divergence, even among carriers of identical PTEN variants, remains poorly defined. We performed whole-genome sequencing of 599 individuals with PHTS and family members, complemented by analyses of PTEN variant carriers from the All of Us Research Program. Analyses included both targeted evaluation of genes previously implicated in cancer and NDD and agnostic genome-wide single-variant and rare-variant burden testing. The analytic cohort comprised 543 PHTS probands, including individuals with NDD (n = 171), cancer (n = 221), both phenotypes (n = 21), or neither (n = 130) at the time of enrollment. Pathogenic or likely pathogenic variants in cancer-associated genes were identified in 37 (6.8%), most frequently in MITF, DICER1, and BRCA2, while 43 (7.9%) harbored variants in NDD-related genes, including DHCR7, POLG, and ARSA. Such secondary variants were less common in PTEN variant carriers in All of Us. Genome-wide analyses identified candidate modifier loci functionally linked to PTEN, including in ZNF713, TPTE2P1, and PDPK1. These findings demonstrate that PHTS phenotypes are shaped by complex gene–gene interactions beyond PTEN alone, informing mechanisms underlying the cancer–NDD dichotomy and advancing precision risk stratification.