TY - JOUR
TI - Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families
AU - Makrythanasis, P.
AU - Nelis, M.
AU - Santoni, F.A.
AU - Guipponi, M.
AU - Vannier, A.
AU - Béna, F.
AU - Gimelli, S.
AU - Stathaki, E.
AU - Temtamy, S.
AU - Mégarbané, A.
AU - Masri, A.
AU - Aglan, M.S.
AU - Zaki, M.S.
AU - Bottani, A.
AU - Fokstuen, S.
AU - Gwanmesia, L.
AU - Aliferis, K.
AU - Bustamante Eduardo, M.
AU - Stamoulis, G.
AU - Psoni, S.
AU - Kitsiou-Tzeli, S.
AU - Fryssira, H.
AU - Kanavakis, E.
AU - Al-Allawi, N.
AU - Sefiani, A.
AU - Al Hait, S.
AU - Elalaoui, S.C.
AU - Jalkh, N.
AU - Al-Gazali, L.
AU - Al-Jasmi, F.
AU - Bouhamed, H.C.
AU - Abdalla, E.
AU - Cooper, D.N.
AU - Hamamy, H.
AU - Antonarakis, S.E.
JO - Human Mutation
PY - 2014
VL - 35
TODO - 10
SP - 1203-1210
PB - John Wiley and Sons Inc
SN - 1059-7794, 1098-1004
TODO - 10.1002/humu.22617
TODO - 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
TODO - 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.
ER -