Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies.
Adolescent
Ataxia
/ genetics
Cerebellar Ataxia
/ genetics
Child
Child, Preschool
Cohort Studies
Exome
/ genetics
Female
France
Genetic Heterogeneity
Genetic Predisposition to Disease
/ genetics
Genotype
Humans
Male
Mutation
/ genetics
Phenotype
Spasms, Infantile
/ genetics
Exome Sequencing
/ methods
Young Adult
Cerebellar atrophy
Congenital ataxia
Early infantile epileptic encephalopathies
Pathophysiology
exome sequencing,
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
21
01
2018
accepted:
04
06
2018
pubmed:
13
7
2018
medline:
16
7
2019
entrez:
13
7
2018
Statut:
ppublish
Résumé
To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).
Identifiants
pubmed: 29997391
doi: 10.1038/s41436-018-0089-2
pii: S1098-3600(21)01019-4
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
553-563Références
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