Scientific article

High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

ContributorsBenkirane, Mehdiorcid; Marelli, Cecilia; Guissart, Claire; Roubertie, Agathe; Ollagnon, Elizabeth; Choumert, Ariane; Fluchère, Frédérique; Magne, Fabienne Ory; Halleb, Yosra; Renaud, Mathilde; Larrieu, Lise; Baux, David; Patat, Olivier; Bousquet, Idriss; Ravel, Jean-Marie; Cuntz-Shadfar, Danielle; Sarret, Catherine; Ayrignac, Xavier; Rolland, Anne; Morales, Raoul; Pointaux, Morgane; Lieutard-Haag, Cathy; Laurens, Brice; Tillikete, Caroline; Bernard, Emilien; Mallaret, Martial; Carra-Dallière, Clarisse; Tranchant, Christine; Meyer, Pierre; Damaj, Lena; Pasquier, Laurent; Acquaviva, Cecile; Chaussenot, Annabelle; Isidor, Bertrand; Nguyen, Karine; Camu, William; Eusebio, Alexandre; Carrière, Nicolas; Riquet, Audrey; Thouvenot, Eric; Gonzales, Victoria; Carme, Emilie; Attarian, Shahram; Odent, Sylvie; Castrioto, Anna; Ewenczyk, Claire; Charles, Perrine; Kremer, Laurent; Sissaoui, Samira; Bahi-Buisson, Nadia; Kaphan, Elsa; Degardin, Adrian; Doray, Bérénice; Julia, Sophie; Remerand, Ganaëlle; Fraix, Valerie; Haidar, Lydia Abou; Lazaro, Leila; Laugel, Vincent; Villega, Frederic; Charlin, Cyril; Frismand, Solène; Moreira, Marinha Costa; Witjas, Tatiana; Francannet, Christine; Walther-Louvier, Ulrike; Fradin, Mélanie; Chabrol, Brigitte; Fluss, Joel Victor; Bieth, Eric; Castelnovo, Giovanni; Vergnet, Sylvain; Meunier, Isabelle; Verloes, Alain; Brischoux-Boucher, Elise; Coubes, Christine; Geneviève, David; Lebouc, Nicolas; Azulay, Jean Phillipe; Anheim, Mathieu; Goizet, Cyril; Rivier, François; Labauge, Pierre; Calvas, Patrick; Koenig, Michel
Published inGenetics in medicine, vol. 23, no. 11, p. 2160-2170
First online date2021-07-07

Purpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.

Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.

Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.

Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.

  • Cerebellar Ataxia
  • Cohort Studies
  • DNA Copy Number Variations / genetics
  • Genomics
  • Humans
  • Peroxins
  • Receptors, Cytoplasmic and Nuclear
  • United States
  • Exome Sequencing
Citation (ISO format)
BENKIRANE, Mehdi et al. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. In: Genetics in medicine, 2021, vol. 23, n° 11, p. 2160–2170. doi: 10.1038/s41436-021-01250-6
Main files (1)
Article (Accepted version)
Secondary files (2)
ISSN of the journal1098-3600

Technical informations

Creation10/03/2022 2:38:12 PM
First validation08/25/2023 8:47:45 AM
Update time08/25/2023 8:47:45 AM
Status update08/25/2023 8:47:45 AM
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