High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.
Genetics in Medicine. 2021-11-01; 23(11): 2160-2170
DOI: 10.1038/s41436-021-01250-6
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1. Genet Med. 2021 Nov;23(11):2160-2170. doi: 10.1038/s41436-021-01250-6. Epub 2021
Jul 7.
High rate of hypomorphic variants as the cause of inherited ataxia and related
diseases: study of a cohort of 366 families.
Benkirane M(1), Marelli C(2), Guissart C(1), Roubertie A(3)(4), Ollagnon E(5),
Choumert A(6), Fluchère F(7), Magne FO(8), Halleb Y(1), Renaud M(9), Larrieu
L(1), Baux D(1), Patat O(10), Bousquet I(5), Ravel JM(9), Cuntz-Shadfar D(3),
Sarret C(11), Ayrignac X(12), Rolland A(3), Morales R(12), Pointaux M(1),
Lieutard-Haag C(1), Laurens B(13), Tillikete C(14), Bernard E(14)(15), Mallaret
M(16), Carra-Dallière C(12), Tranchant C(17), Meyer P(3)(18), Damaj L(19),
Pasquier L(19), Acquaviva C(20), Chaussenot A(21), Isidor B(22), Nguyen K(7),
Camu W(12), Eusebio A(7), Carrière N(23), Riquet A(24), Thouvenot E(25), Gonzales
V(12), Carme E(3), Attarian S(7), Odent S(19), Castrioto A(16), Ewenczyk C(26),
Charles P(26), Kremer L(7), Sissaoui S(27), Bahi-Buisson N(27), Kaphan E(7),
Degardin A(23), Doray B(28), Julia S(10), Remerand G(29), Fraix V(16), Haidar
LA(3), Lazaro L(30), Laugel V(31), Villega F(32), Charlin C(6), Frismand S(9),
Moreira MC(3), Witjas T(7), Francannet C(11), Walther-Louvier U(3), Fradin M(19),
Chabrol B(33), Fluss J(34), Bieth E(10), Castelnovo G(25), Vergnet S(13), Meunier
I(4)(35), Verloes A(36), Brischoux-Boucher E(37), Coubes C(38), Geneviève D(38),
Lebouc N(39), Azulay JP(7), Anheim M(17), Goizet C(40), Rivier F(3)(18), Labauge
P(12), Calvas P(10), Koenig M(41).
Author information:
(1)PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université
de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
(2)Expert Centre for Neurogenetic Diseases and Adult Mitochondrial and Metabolic
Diseases, Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier;
Molecular Mechanisms of Neurodegenerative Dementia (MMDN), EPHE, INSERM,
Université de Montpellier, Montpellier, France.
(3)Department of Pediatrics, Gui de Chauliac Hospital, CHU de Montpellier,
Montpellier, France.
(4)INSERM, Institut des Neurosciences de Montpellier, Montpellier, France.
(5)Department of Medical Genetics and Reference Centre for Neurological and
Neuromuscular Diseases, Croix-Rousse Hospital, Lyon, France.
(6)Department of Rare Neurological Diseases, CHU de la Réunion, Saint-Pierre,
France.
(7)Department of Neurology, La Timone Hospital, CHU de Marseille, Marseille,
France.
(8)Department of Neurology, Purpan Hospital, CHU de Toulouse, Toulouse, France.
(9)Departments of Genetics and of Neurology, CHU de Nancy, Nancy, France.
(10)Department of Clinical Genetics, Purpan Hospital, CHU de Toulouse, Toulouse,
France.
(11)Department of Medical Genetics, Estaing Hospital, CHU de Clermont-Ferrand,
Clermont-Ferrand, France.
(12)Department of Neurology, Gui de Chauliac Hospital, CHU de Montpellier,
Montpellier, France.
(13)Departement of Neurology, Groupe Hospitalier Pellegrin, CHU de Bordeaux,
Institute for Neurodegenerative Diseases, CNRS-UMR, Université de Bordeaux,
Bordeaux, France.
(14)Department of Neurology, Hôpital Neurologique Pierre Wertheimer, Hospices
Civils de Lyon, Bron, France.
(15)Institut NeuroMyoGène, INSERM-CNRS-UMR, Université Claude Bernard, Lyon,
France.
(16)Department of Functional Explorations of the Nervous System, CHU de Grenoble,
Grenoble, France.
(17)Department of Neurology, Hautepierre Hospital, CHU de Strasbourg, Strasbourg,
France.
(18)PhyMedExp, INSERM, University of Montpellier, CNRS, Montpellier, France.
(19)Department of Clinical Genetics, Centre de Référence Maladies Rares Anomalies
du Développement, CHU de Rennes, Rennes, France.
(20)Department of Hereditary Metabolic Diseases, Centre de Biologie et Pathologie
Est, CHU de Lyon et UMR, Bron, France.
(21)Department of Medical Genetics, National Centre for Mitochondrial Diseases,
CHU de Nice, Nice, France.
(22)Department of Medical Genetics, CHU de Nantes, Nantes, France.
(23)Department of Neurology, Roger Salengro Hospital, CHU de Lille, Lille,
France.
(24)Department of Pediatrics Neurology, Roger Salengro Hospital, CHU de Lille,
Lille, France.
(25)Department of Neurology, CHU de Nîmes, Nîmes, France.
(26)Neurogenetics Reference Centre, Hôpital de la Pitié-Salpêtrière, Assistance
Publique- Hôpitaux de Paris (AP-HP), Paris, France.
(27)Department of Pediatrics, Hôpital Necker-Enfant Malades, Assistance
Publique-Hôpitaux de Paris (AP-HP), Paris, France.
(28)Department of Medical Genetics, CHU de la Réunion, Saint-Denis, France.
(29)Department of Neonatology, Estaing Hospital, CHU de Clermont-Ferrand,
Clermont-Ferrand, France.
(30)Department of Pediatrics, CH de la Côte Basque-Bayonne, Bayonne, France.
(31)Department of Pediatrics, Hautepierre Hospital, CHU de Strasbourg,
Strasbourg, France.
(32)Department of Pediatrics, Groupe Hospitalier Pellegrin, CHU de Bordeaux;
Institute for Interdisciplinary Neurosciences (IINS), CNRS -UMR, Université de
Bordeaux, Bordeaux, France.
(33)Departement of Pediatrics, La Timone Hospital, CHU de Marseille, Marseille,
France.
(34)Pediatric Neurology Unit, Geneva Children’s Hospital, Genève, Switzerland.
(35)Genetics of Sensory Diseases, Gui de Chauliac Hospital, CHU de Montpellier,
Montpellier, France.
(36)Federation of Genetics, Hôpital Robert Debré, Assistance Publique-Hôpitaux de
Paris (AP-HP), Paris, France.
(37)Department of Medical Genetics, Hôpital Saint-Jacques, CHU de Besançon,
Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
(38)Department of Medical Genetics, Arnaud de Villeneuve, CHU de Montpellier,
Montpellier, France.
(39)Department of Neuroradiology, Gui de Chauliac Hospital, CHU de Montpellier,
Montpellier, France.
(40)Department of Medical Genetics, Pellegrin Hospital, CHU de Bordeaux,
Bordeaux, France.
(41)PhyMedExp, Institut Universitaire de Recherche Clinique, UMR_CNRS-Université
de Montpellier, INSERM, CHU de Montpellier, Montpellier, France.
.
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.
© 2021. The Author(s), under exclusive licence to the American College of Medical
Genetics and Genomics.
DOI: 10.1038/s41436-021-01250-6
PMID: 34234304 [Indexed for MEDLINE]