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Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
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Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
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Journal Article
Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair
2023
Overview
DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline
POLE
or
POLD1
mutation, or biallelic
MUTYH
mutations, had 3-4 fold increased DNMs over sex-matched controls.
POLE
had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of
MUTYH
heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic
MUTYH
mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.
DNA repair defects underlie many cancer syndromes. This study investigates whether parents with inherited problems of DNA repair pass on an increased number of de novo mutations to their children. The authors find that this does occur, but that clinical consequences are unlikely.
