The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome

Ruipeng Wei; Lamis Yehia; Ying Ni; Charis Eng

doi:10.1016/j.xhgg.2023.100199

The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome

HGG Adv. 2023 Apr 24;4(3):100199. doi: 10.1016/j.xhgg.2023.100199. eCollection 2023 Jul 13.

Authors

Ruipeng Wei^{1

2}, Lamis Yehia¹, Ying Ni³, Charis Eng^{1

4

5

6}

Affiliations

¹ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
² Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
³ Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁴ Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
⁵ Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
⁶ Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.

Abstract

Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10^-3 in all samples; p = 4.2 × 10^-3 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10^-2); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10^-2). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS.

Keywords: PTEN; autism spectrum disorder; cancer; genomic modifiers; mitochondrial DNA (mtDNA).

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Autism Spectrum Disorder* / genetics
Autistic Disorder* / genetics
DNA Copy Number Variations / genetics
DNA, Mitochondrial / genetics
Genome, Mitochondrial* / genetics
Hamartoma Syndrome, Multiple* / genetics
Humans
PTEN Phosphohydrolase / genetics
Phenotype
Thyroid Neoplasms* / genetics

Substances

DNA, Mitochondrial
PTEN protein, human
PTEN Phosphohydrolase

Grants and funding

R01 HD105049/HD/NICHD NIH HHS/United States