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Journal Articles Genetics in Medicine Year : 2021

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

Mehdi Benkirane (1, 2) , Cecilia Marelli (2, 3) , Claire Guissart (2, 1) , Agathe Roubertie (2, 4) , Elizabeth Ollagnon (5) , Ariane Choumert (6) , Frédérique Fluchère (7) , Fabienne Ory Magne (8) , Yosra Halleb (2, 1) , Mathilde Renaud (9) , Lise Larrieu (2, 1) , David Baux (2, 1) , Olivier Patat (8) , Idriss Bousquet (5) , Jean-Marie Ravel (9) , Danielle Cuntz-Shadfar (2) , Catherine Sarret (10) , Xavier Ayrignac (2, 11) , Anne Rolland (2) , Raoul Morales (2) , Morgane Pointaux (2, 1) , Cathy Lieutard-Haag (2, 1) , Brice Laurens (12) , Caroline Tillikete (5) , Emilien Bernard (5, 13) , Martial Mallaret (14) , Clarisse Carra-Dallière (2) , Christine Tranchant (15) , Pierre Meyer (1, 2) , Lena Damaj (16) , Laurent Pasquier (16) , Cecile Acquaviva (17) , Annabelle Chaussenot (18) , Bertrand Isidor (19) , Karine Nguyen (7) , William Camu (2, 4) , Alexandre Eusebio (7) , Nicolas Carrière (20) , Audrey Riquet (20) , Eric Thouvenot (21, 22) , Victoria Gonzales (2) , Emilie Carme (2) , Shahram Attarian (7) , Sylvie Odent (16) , Anna Castrioto (14) , Claire Ewenczyk (23) , Perrine Charles (23) , Laurent Kremer (7) , Samira Sissaoui (24) , Nadia Bahi-Buisson (24) , Elsa Kaphan (7) , Adrian Degardin (20) , Bérénice Doray (6) , Sophie Julia (8, 25) , Ganaëlle Remerand (10) , Valerie Fraix (14) , Lydia Abou Haidar (2) , Leila Lazaro , Vincent Laugel (15) , Frederic Villega (26) , Cyril Charlin (6) , Solène Frismand (9) , Marinha Costa Moreira (2) , Tatiana Witjas (7) , Christine Francannet (7) , Ulrike Walther-Louvier (2) , Mélanie Fradin (16) , Brigitte Chabrol (7) , Joel Fluss (27) , Eric Bieth (8) , Giovanni Castelnovo (21) , Sylvain Vergnet (12) , Isabelle Meunier (2, 4) , Alain Verloes (28) , Elise Brischoux-Boucher (29) , Christine Coubes (2) , David Geneviève (2, 11) , Nicolas Lebouc (2) , Jean Phillipe Azulay (7) , Mathieu Anheim (15) , Cyril Goizet (12) , Francois Rivier (1, 2) , Pierre Labauge (2) , Patrick Calvas (8) , Michel Koenig (1, 2)
1 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
2 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
3 MMDN - Mécanismes moléculaires dans les démences neurodégénératives
4 INM - Institut des Neurosciences de Montpellier
5 HCL - Hospices Civils de Lyon
6 CHU La Réunion - Centre Hospitalier Universitaire de La Réunion
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
9 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
10 CHU Clermont-Ferrand
11 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
12 CHU Bordeaux
13 INMG - Institut NeuroMyoGène
14 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
15 CHU Strasbourg - Centre Hospitalier Universitaire [Strasbourg]
16 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
17 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
18 CHU Nice - Centre Hospitalier Universitaire de Nice
19 CHU Nantes - Centre Hospitalier Universitaire de Nantes = Nantes University Hospital
20 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
21 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
22 IGF - Institut de Génomique Fonctionnelle
23 CHU Pitié-Salpêtrière [AP-HP]
24 Hôpital Necker - Enfants Malades [AP-HP]
25 Equipe BIOETHICS (CERPOP)
26 IINS - Interdisciplinary Institute for Neuroscience [Bordeaux]
27 Geneva University Hospitals and Geneva University
28 Hôpital Robert Debré
29 CHRU Besançon - Centre Hospitalier Régional Universitaire de Besançon
Brice Laurens
  • Function : Author
Karine Nguyen
Shahram Attarian
  • Function : Author
  • PersonId : 1042088
Claire Ewenczyk
Elsa Kaphan
Leila Lazaro
  • Function : Author
Sylvain Vergnet
  • Function : Author
Alain Verloes
Cyril Goizet
  • Function : Author

Abstract

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.
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hal-03282716 , version 1 (09-06-2022)

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Mehdi Benkirane, Cecilia Marelli, Claire Guissart, Agathe Roubertie, Elizabeth Ollagnon, et al.. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families. Genetics in Medicine, 2021, ⟨10.1038/s41436-021-01250-6⟩. ⟨hal-03282716⟩
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