Segregation of ATP10B variants in families with autosomal recessive parkinsonism
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Segregation of ATP10B variants in families with autosomal recessive parkinsonism Christelle Tesson1 · Ebba Lohmann2 · David Devos3 · Hélène Bertrand1 · Suzanne Lesage1 · Alexis Brice1,4 Received: 15 July 2020 / Revised: 14 August 2020 / Accepted: 27 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Martin et al. [2] recently reported that biallelic missense and stop-gain variants in ATP10B are associated with Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They identified double-heterozygous variants demonstrated to be located in trans in three of seven isolated cases (six with PD and one with DLB). These variants had a minor allele frequency (MAF) 2%), and the presence of healthy carriers homozygous for these variants in GnomAD raised questions about their pathogenicity. In a large case–control study, Real et al. [3] also questioned the implication of ATP10B variants as risk factors in the pathogenesis of PD. However, in their reply Smolders and Van Broeckhoven [4] pointed out that Real Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00401-020-02219-6) contains supplementary material, which is available to authorized users. * Alexis Brice alexis.brice@icm‑institute.org 1
Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Hôpital de la Salpêtrière, Inserm U 1127, CNRS UMR 7225, 75013 Paris, France
2
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
3
Department of Medical Pharmacology, Department of Neurology, University Hospital, University of Lille, Neuroscience and Cognition, Inserm, UMR-S1172, Lille, France
4
Département de Génétique, APHP, Hôpital de la Pitié Salpêtrière, 75013 Paris, France
et al. [3] did not assess the phasing and therefore could not conclude that ATP10B was involved in their cohort but agreed that analyses of large number of trios are necessary to estimate the frequency of PD carriers of homozygous or compound heterozygous ATP10B variants. We assessed the presence of biallelic ATP10B variants in families with PD and their segregation with the disease, by analyzing whole-exome sequencing (WES) data from 17 PD families with autosomal recessive (AR) inheritance including at least two affected siblings (Supplementary information for patients and methods). Setting the MAF threshold at 5%, as used in Martin et al.’s paper, we identified six rare ATP10B missense variants, including three previously reported [2], in two of the 17 families. In the consanguineous Algerian FDP-167 family, the reported p.L1421F and p.I540T variants were both present in the three affected siblings, with ages at onset ranging from 30 to 35 years (Fig. 1a). Segregation analysis provided evidence for a cis location of the two variants, both inherited from the mother, who was unaffected at age 58, suggesting that they cannot be causal for PD, given the AR transmission of the disease. In the consanguineou
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