ArticleNature communications2023
Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation.
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Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29citing papers in PubMed
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29 citing papers in PubMed, 36 citations in OpenAlex.
- The Utilisation of Genetic Counselling Services Amongst Prenatal Healthcare Providers in Gauteng, South Africa.Prenatal diagnosis · 2026Article
- Article
- Landscape of parental postzygotic mutations across >11,000 rare disease trios.American journal of human genetics · 2026Article
- A Synonymous DLG4 Variant (c.771G>A) Causes Exon 9 Skipping via Paternal Germline Mosaicism in DLG4-Related Synaptopathy.Molecular genetics & genomic medicine · 2026Article
- Inherited variants in autosomal dominant disease genes are a significant cause of fetal structural anomalies.Journal of medical genetics · 2026Article
- Case Report: First case of paternal mosaicism in Snijders Blok-Fisher syndrome.Frontiers in genetics · 2026Article
- Xp21 contiguous gene deletion syndrome presenting as congenital adrenal hypoplasia: molecular diagnosis and clinical re-evaluation of a pedigree.Frontiers in endocrinology · 2026Article
- Maternal Mosaicism Challenges in Non-Invasive Prenatal Diagnosis.Prenatal diagnosis · 2025Article
- MED13L-related disorder characterized by severe motor speech impairment.Journal of neurodevelopmental disorders · 2025Article
- Gastric-type endocervical adenocarcinoma in situ as the presenting feature in a mosaic STK11 pathogenic variant carrier with a Peutz-Jeghers syndrome child.Familial cancer · 2025Article
- Development of a Clinically Applicable High-Resolution Assay for Sperm Mosaicism.The Journal of molecular diagnostics : JMD · 2025Article
- Impact of a Genetic Diagnosis for a Child's Autism on Parental Perceptions.Journal of autism and developmental disorders · 2025Article
- Direct measurement of the male germline mutation rate in individuals using sequential sperm samples.Nature communications · 2025Article
- Parental germline mosaicism in genome-wide phased de novo variants: Recurrence risk assessment and implications for precision genetic counselling.PLoS genetics · 2025Article
- Parental Somatic Mosaicism Detected During Prenatal Diagnosis.Prenatal diagnosis · 2025Article
- Professionals' views on providing personalized recurrence risks for de novo mutations: Implications for genetic counseling.Journal of genetic counseling · 2025Article
- Expanding the Spectrum of Autosomal DominantGenes · 2024Review
- SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.American journal of human genetics · 2024Article
- Genomic Mosaicism of the Brain: Origin, Impact, and Utility.Neuroscience bulletin · 2024Review
- [Sperm Mosaic Variants and Their Influence on the Offspring].Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition · 2024Review
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Authors and funding
45 authors at 18 institutions in 3 countries.
Marie Bernkopf *Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.ORCID 0000-0001-6650-4592
Ummi B Abdullah *Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Stephen J BushClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.ORCID 0000-0001-9341-2562
Katherine A WoodClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Sahar GhaffariClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Eleni GiannoulatouVictor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
Nils KoellingClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.ORCID 0000-0001-5292-4510
Geoffrey J MaherClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
Loïc M ThibautCentre for Population Genomics, Garvan Institute of Medical Research, UNSW Sydney, Sydney, NSW, Australia.ORCID 0000-0003-3813-682X
Jonathan WilliamsOxford Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.ORCID 0000-0003-2672-2450
Edward M BlairNIHR Oxford Biomedical Research Centre, Oxford, UK.
Fiona Blanco KellyOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Angela BlossOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Emma Burkitt-WrightManchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.
Natalie CanhamDepartment of Clinical Genetics, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Alexander T DengClinical Genetics Department, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.ORCID 0000-0002-8121-817X
Abhijit DixitNottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Jacqueline EasonNottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Frances ElmslieSouth West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
Alice GardhamNorth West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Eleanor HayNorth East Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Muriel HolderClinical Genetics Department, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.
Tessa HomfraySouth West Thames Regional Genetics Service, St George's University Hospitals NHS Foundation Trust, London, UK.
Jane A HurstNorth East Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Diana JohnsonSheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Wendy D JonesNorth East Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Usha KiniNIHR Oxford Biomedical Research Centre, Oxford, UK.
Emma KivuvaClinical Genetics, Royal Devon & Exeter Hospital (Heavitree), Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Ajith KumarNorth East Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.ORCID 0000-0003-3878-2856
Melissa M LeesNorth East Thames Regional Genetics Service, Great Ormond Street Hospital NHS Foundation Trust, London, UK.
Harry G LeitchNottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Jenny E V MortonWest Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's Hospitals NHS Foundation Trust, Birmingham, UK.
Andrea H NémethOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Shwetha RamachandrappaClinical Genetics Department, Guy's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK.ORCID 0000-0003-2639-766X
Katherine SaundersOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Deborah J ShearsOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Lucy SideWessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.
Miranda SplittNorthern Genetics Service, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
Alison StewartSheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK.
Helen StewartOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Mohnish SuriNottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Penny CloustonOxford Genetics Laboratories, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Robert W DaviesDepartment of Statistics, University of Oxford, Oxford, UK.
Andrew O M WilkieClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.ORCID 0000-0002-2972-5481
Anne GorielyClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. anne.goriely@imm.ox.ac.uk.ORCID 0000-0001-9229-7216
University of Oxford · GBNuffield Orthopaedic Centre · GBGreat Ormond Street Hospital for Children NHS Foundation Trust · GBNottingham University Hospitals NHS Trust · GBGuy's Hospital · GBChurchill Hospital · GBSheffield Children's NHS Foundation Trust · GBSt George’s University Hospitals NHS Foundation Trust · GBBirmingham Women’s and Children’s NHS Foundation Trust · GBGarvan Institute of Medical Research · AULondon North West Healthcare NHS Trust · GBMRC Weatherall Institute of Molecular Medicine · GBNewcastle upon Tyne Hospitals NHS Foundation Trust · GBPrincess Anne Hospital · GBRoyal Devon and Exeter Hospital · GBUniversity of Liverpool · GBUniversity of Manchester · GBVictor Chang Cardiac Research Institute · AU
Funding
Medical Research Council G0902418Medical Research Council MC_UP_1605/2Wellcome Trust 102731/Z/13/Z
Abstract
Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.
Indexed as
FathersParturitionChildFemaleGerm CellsGerm-Line MutationHumansMaleMosaicismMutationPedigreePregnancyRisk Assessment
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