Quantification of transmission risk in a male patient with a FLNB mosaic mutation causing Larsen syndrome: Implications for genetic counseling in postzygotic mosaicism cases |
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| Authors: | Marie Bernkopf David Hunt Nils Koelling Tim Morgan Amanda L. Collins Joanna Fairhurst Stephen P. Robertson Andrew G. L. Douglas Anne Goriely |
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| Affiliation: | 1. Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;2. Nuffield Department of Clinical Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom;3. Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom;4. Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand;5. Paediatric Radiology, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom;6. Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom |
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| Abstract: | We report the case of a male patient with Larsen syndrome found to be mosaic for a novel point mutation in FLNB in whom it was possible to provide evidence‐based personalized counseling on transmission risk to future offspring. Using dideoxy sequencing, a low‐level FLNB c.698A>G, encoding p.(Tyr233Cys) mutation was detected in buccal mucosa and fibroblast DNA. Mutation quantification was performed by deep next‐generation sequencing (NGS) of DNA extracted from three somatic tissues (blood, fibroblasts, saliva) and a sperm sample. The mutation was detectable in all tissues tested, at levels ranging from 7% to 10% (mutation present in ～20% of diploid somatic cells and 7% of haploid sperm), demonstrating the involvement of both somatic and gonadal lineages in this patient. This report illustrates the clinical utility of performing targeted NGS analysis on sperm from males with a mosaic condition in order to provide personalized transmission risk and offer evidence‐based counseling on reproductive safety. |
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| Keywords: | FLNB genetic counseling Larsen syndrome mosaicism next‐generation sequencing sperm |
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