Exome sequencing in congenital ataxia identifies two new candidate genes and highlights a pathophysiological link between some congenital ataxias and early infantile epileptic encephalopathies

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Stéphanie ValenceLydie Burglen

Abstract

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 r...Continue Reading

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Citations

Aug 14, 2019·Annals of Clinical and Translational Neurology·Jaya PunethaJames R Lupski
Nov 20, 2019·Neurology. Genetics·Areej MahjoubUNKNOWN Care4Rare Canada Consortium
May 28, 2020·Pflügers Archiv : European journal of physiology·Mercè Izquierdo-SerraMercedes Serrano
Jul 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Nicolás Sarute, Susan R Ross
Jul 9, 2020·Neurology. Genetics·Erika IgnatiusChristopher J Carroll
Jul 2, 2020·Pflügers Archiv : European journal of physiology·Cornelia AblingerGerald J Obermair
Aug 2, 2020·Journal of Neurochemistry·Abinayah JohnKate Baker
Mar 13, 2020·G3 : Genes - Genomes - Genetics·Agapi DimitriadouStuart J Newfeld
Jan 12, 2021·Frontiers in Pediatrics·Linxia ZhangXinhua Bao
Jul 6, 2021·Neurogenetics·Magdalena Krygier, Maria Mazurkiewicz-Bełdzińska

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Methods Mentioned

BETA
exome sequencing
flow cytometry

Software Mentioned

Alamut
PolyPhen
MaxEntScan
ClinVar
MutationTaster

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