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Dahlia F Davidoff Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Camperdown, New South Wales, Australia
Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

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Eugénie S Lim Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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Diana E Benn Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Camperdown, New South Wales, Australia

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Yuvanaa Subramaniam Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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Eleanor Dorman Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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John R Burgess Department of Diabetes and Endocrinology, Royal Hobart Hospital, Hobart, Tasmania, Australia
School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

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Scott A Akker Department of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK

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Roderick J Clifton-Bligh Cancer Genetics, Kolling Institute, Royal North Shore Hospital, St Leonards, New South Wales, Australia
University of Sydney, Camperdown, New South Wales, Australia
Department of Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia

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Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs’s cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew’s Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.

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