Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair

Kitty Sherwood, Joseph C. Ward, Ignacio Soriano, Lynn Martin, Archie Campbell, Raheleh Rahbari, Ioannis Kafetzopoulos, Duncan Sproul, Andrew Green, Julian R. Sampson, Alan Donaldson, Kai-Ren Ong, Karl Heinimann, Maartje Nielsen, Huw Thomas, Andrew Latchford, Claire Palles () and Ian Tomlinson ()
Additional contact information
Kitty Sherwood: Institute of Genomics and Cancer
Joseph C. Ward: University of Oxford
Ignacio Soriano: University of Oxford
Lynn Martin: University of Birmingham Medical School
Archie Campbell: Western General Hospital
Raheleh Rahbari: Wellcome Genome Campus
Ioannis Kafetzopoulos: Institute of Genomics and Cancer
Duncan Sproul: Institute of Genomics and Cancer
Andrew Green: Children’s Health Ireland and School of Medicine University College
Julian R. Sampson: Cardiff University School of Medicine
Alan Donaldson: St Michael’s Hospital
Kai-Ren Ong: Birmingham Women’s and Children’s NHS Foundation Trust
Karl Heinimann: University Hospital Basel
Maartje Nielsen: Leiden University Medical Centre
Huw Thomas: St Mark’s Hospital
Andrew Latchford: St Mark’s Hospital
Claire Palles: University of Birmingham Medical School
Ian Tomlinson: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39248-0

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