High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.
Mehdi BenkiraneCecilia MarelliClaire GuissartAgathe RoubertieElizabeth OllagnonAriane ChoumertFrédérique FluchèreFabienne Ory MagneYosra HallebMathilde RenaudLise LarrieuDavid BauxOlivier PatatIdriss BousquetJean-Marie RavelDanielle Cuntz-ShadfarCatherine SarretXavier AyrignacAnne RollandRaoul MoralesMorgane PointauxCathy Lieutard-HaagBrice LaurensCaroline TilliketeEmilien BernardMartial MallaretClarisse Carra-DallièreChristine TranchantPierre MeyerLena DamajLaurent PasquierCecile AcquavivaAnnabelle ChaussenotBertrand IsidorKarine NguyenWilliam CamuAlexandre EusebioNicolas CarrièreAudrey RiquetEric ThouvenotVictoria GonzalesEmilie CarmeShahram AttarianSylvie OdentAnna CastriotoClaire EwenczykPerrine CharlesLaurent KremerSamira SissaouiNadia Bahi-BuissonElsa KaphanAdrian DegardinBérénice DoraySophie JuliaGanaëlle RemerandValerie FraixLydia Abou HaidarLeila LazaroVincent LaugelFrederic VillegaCyril CharlinSolène FrismandMarinha Costa MoreiraTatiana WitjasChristine FrancannetUlrike Walther-LouvierMélanie FradinBrigitte ChabrolJoel FlussEric BiethGiovanni CastelnovoSylvain VergnetIsabelle MeunierAlain VerloesElise Brischoux-BoucherChristine CoubesDavid GenevièveNicolas LeboucJean Phillipe AzulayMathieu AnheimCyril GoizetFrançois RivierPierre LabaugePatrick CalvasMichel KoenigPublished in: Genetics in medicine : official journal of the American College of Medical Genetics (2021)
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.