@article{3087744,
    title = "Diagnostic Exome Sequencing to Elucidate the Genetic Basis of Likely Recessive Disorders in Consanguineous Families",
    author = "Makrythanasis, P. and Nelis, M. and Santoni, F.A. and Guipponi, M. and Vannier, A. and Béna, F. and Gimelli, S. and Stathaki, E. and Temtamy, S. and Mégarbané, A. and Masri, A. and Aglan, M.S. and Zaki, M.S. and Bottani, A. and Fokstuen, S. and Gwanmesia, L. and Aliferis, K. and Bustamante Eduardo, M. and Stamoulis, G. and Psoni, S. and Kitsiou-Tzeli, S. and Fryssira, H. and Kanavakis, E. and Al-Allawi, N. and Sefiani, A. and Al Hait, S. and Elalaoui, S.C. and Jalkh, N. and Al-Gazali, L. and Al-Jasmi, F. and Bouhamed, H.C. and Abdalla, E. and Cooper, D.N. and Hamamy, H. and Antonarakis, S.E.",
    journal = "Human Mutation",
    year = "2014",
    volume = "35",
    number = "10",
    pages = "1203-1210",
    publisher = "John Wiley and Sons Inc",
    issn = "1059-7794, 1098-1004",
    doi = "10.1002/humu.22617",
    keywords = "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",
    abstract = "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."
}