Περίληψη:
Rare, atypical, and undiagnosed autosomal-recessive disorders frequently occur in the offspring of consanguineous couples. Current routine diagnostic genetic tests fail to establish a diagnosis in many cases. We employed exome sequencing to identify the underlying molecular defects in patients with unresolved but putatively autosomal-recessive disorders in consanguineous families and postulated that the pathogenic variants would reside within homozygous regions. Fifty consanguineous families participated in the study, with a wide spectrum of clinical phenotypes suggestive of autosomal-recessive inheritance, but with no definitive molecular diagnosis. DNA samples from the patient(s), unaffected sibling(s), and the parents were genotyped with a 720K SNP array. Exome sequencing and array CGH (comparative genomic hybridization) were then performed on one affected individual per family. High-confidence pathogenic variants were found in homozygosity in known disease-causing genes in 18 families (36%) (one by array CGH and 17 by exome sequencing), accounting for the clinical phenotype in whole or in part. In the remainder of the families, no causative variant in a known pathogenic gene was identified. Our study shows that exome sequencing, in addition to being a powerful diagnostic tool, promises to rapidly expand our knowledge of rare genetic Mendelian disorders and can be used to establish more detailed causative links between mutant genotypes and clinical phenotypes. © 2014 WILEY PERIODICALS, INC.
Συγγραφείς:
Makrythanasis, P.
Nelis, M.
Santoni, F.A.
Guipponi, M.
Vannier, A.
Béna, F.
Gimelli, S.
Stathaki, E.
Temtamy, S.
Mégarbané, A.
Masri, A.
Aglan, M.S.
Zaki, M.S.
Bottani, A.
Fokstuen, S.
Gwanmesia, L.
Aliferis, K.
Bustamante Eduardo, M.
Stamoulis, G.
Psoni, S.
Kitsiou-Tzeli, S.
Fryssira, H.
Kanavakis, E.
Al-Allawi, N.
Sefiani, A.
Al Hait, S.
Elalaoui, S.C.
Jalkh, N.
Al-Gazali, L.
Al-Jasmi, F.
Bouhamed, H.C.
Abdalla, E.
Cooper, D.N.
Hamamy, H.
Antonarakis, S.E.
Λέξεις-κλειδιά:
dentin matrix protein 1; fukutin; glycogen phosphorylase, adolescent; adult; Article; autosomal recessive disorder; autosomal recessive inheritance; child; comparative genomic hybridization; consanguineous marriage; consanguinity; copy number variation; developmental delay; DMP1 gene; Emery Dreifuss muscular dystrophy; female; FKTN gene; Fukuyama congenital muscular dystrophy; gene; genotyping technique; hereditary motor sensory neuropathy; homozygosity; human; hypophosphatemic rickets; intellectual impairment; major clinical study; MAN1B1I gene; molecular diagnosis; MTFMT gene; preschool child; PRX gene; PYGM gene; school child; single nucleotide polymorphism; spinocerebellar degeneration; SYNE1 gene; whole exome sequencing; young adult; Arab; DNA sequence; exome; genetics; infant; male; pedigree; Rare Diseases; recessive gene, Adolescent; Adult; Arabs; Child; Child, Preschool; Consanguinity; Exome; Female; Genes, Recessive; Humans; Infant; Male; Pedigree; Rare Diseases; Sequence Analysis, DNA; Young Adult
