Autosomal recessive mutations in THOC6 cause intellectual disability: syndrome delineation requiring forward and reverse phenotyping.
Fiche publication
Date publication
janvier 2017
Journal
Clinical genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
Tous les auteurs :
Amos JS, Huang L, Thevenon J, Kariminedjad A, Beaulieu CL, Masurel-Paulet A, Najmabadi H, Fattahi Z, Beheshtian M, Tonekaboni SH, Tang S, Helbig KL, Alcaraz W, Rivière JB, Faivre L, Innes AM, Lebel RR, Boycott KM,
Lien Pubmed
Résumé
THOC6 is a part of the THO complex, which is involved in coordinating mRNA processing with export. The THO complex interacts with additional components to form the larger TREX complex (transcription export complex). Previously, a homozygous missense mutation in THOC6 in the Hutterite population was reported in association with syndromic intellectual disability. Using exome sequencing, we identified three unrelated patients with bi-allelic mutations in THOC6 associated with intellectual disability and additional clinical features. Two of the patients were compound heterozygous for a stop and a missense mutation, and the third was homozygous for a missense mutation; the missense mutations were predicted to be pathogenic by in silico analysis and modeling. Clinical features of the three newly identified patients and those previously reported are reviewed; intellectual disability is moderate to severe, and malformations are variable including renal and heart defects, cleft palate, microcephaly, and corpus callosum dysgenesis. Facial features are variable and include tall forehead, short upslanting palpebral fissures +/- deep set eyes, and a long nose with overhanging columella. These subtle facial features render the diagnosis difficult to make in isolation with certainty. Our results expand the mutational and clinical spectrum of this rare disease, confirm that THOC6 is an intellectual disability causing gene, while providing insight into the importance of the THO complex in neurodevelopment.
Mots clés
Adolescent, Child, Exome, genetics, Female, Genes, Recessive, Genetic Predisposition to Disease, genetics, Genotype, Humans, Intellectual Disability, genetics, Male, Models, Molecular, Mutation, Missense, Phenotype, Protein Domains, RNA-Binding Proteins, chemistry, Sequence Analysis, DNA, methods, Severity of Illness Index, Syndrome
Référence
Clin. Genet.. 2017 Jan;91(1):92-99