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: As for MED13L, the mode of inheritance associated to some genes is ambiguously described in literature. We identified an heterozygous variant affecting splicing in DEAF1 inherited from the asymptomatic mother in a patient presenting with severe ID, developmental delay, poor speech, pain resistance, dysmorphic features and aggressive behaviour (figure 1), while the gene had been proposed as associated to autosomal-dominant forms of ID.78 The recent report of two additional individuals carrying de novo missense mutations narrowed the associated phenotype to moderate/severe ID, speech impairment, behavioural problems, high pain threshold, dysmorphic features and abnormal walking pattern, hence highly similar to the one of our proband.54 Although in vitro validation studies suggest that the reported missense variants lead to an impaired function of DEAF1, the authors concluded that they presumably act as dominant-negatives incapacitating both normal and mutant proteins since truncating variants had been observed in asymptomatic individuals.54 In parallel, a homozygous missense mutation clustering in the same SAND-domain with all three de novo missense mutations was reported in members of a consanguineous family presenting with ID, microcephaly and white matter abnormalities, therefore suggesting a possible autosomal-recessive mode of inheritance.55 The pathogenic mechanism associated to DEAF1 mutations is therefore unclear. Due to the highly similar clinical features of the herein reported proband and of probands carrying de novo missense mutations, the splice variant detected here may contribute to the phenotype of our patient, possibly through a recessive mode of inheritance (ie, acting in trans with another heterozygous variant) since haploinsufficiency appears tolerated in healthy individuals. Altogether those findings either suppose a similar phenotype for autosomal-dominant and autosomal-recessive mode of inheritance associated to DEAF1 mutations, or a universal autosomal-recessive mode of inheritance with a second variant that has not been yet identified, alike what was finally proven for Thrombocytopenia-absent radius (TAR) syndrome for instance.56
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.