Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.
Bottom Line: We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information.Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4).We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2).
Affiliation: Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France Chaire de Génétique Humaine, Collège de France, Illkirch, France.Show MeSH
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Mentions: The identification of non-segregating truncating variants (ie, detected both in patients and healthy relatives) can also challenge the implication of genes in X-linked and autosomal-dominant forms of ID. In one family, we identified a frameshift variant in SRPX2 in a male proband. It is most likely inherited from the deceased asymptomatic maternal grandfather since it was also detected in the mother and in three maternal aunts yet absent from the maternal grandmother. Despite recent functional evidences regarding the role of SRPX2 in brain development,5859 its definitive implication in cognitive disorders has already been questioned following the presence of the initially proposed mutations in EVS14 and in control individuals,60 and subsequently to the identification of a missense mutation in GRIN2A co-segregating with the epileptic status in the initial SRPX2 family.61 In another family, we identified a nonsense variant in SHROOM4 in a male proband yet also in his unaffected brothers, a finding that further challenges the implication of SHROOM4 in X-linked cognitive disorders (see online supplementary table S5, figure 2).14
Affiliation: Département de Médicine translationnelle et Neurogénétique, IGBMC, CNRS UMR 7104/INSERM U964/Université de Strasbourg, Illkirch, France Chaire de Génétique Humaine, Collège de France, Illkirch, France.