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Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families

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Published in Human Mutation. 2014, vol. 35, no. 10, p. 1203-10
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.
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PMID: 25044680
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Research group Pathologie Moléculaire de la Trisomie 21 et le Génome Humain (248)
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MAKRYTHANASIS, Periklis et al. Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families. In: Human Mutation, 2014, vol. 35, n° 10, p. 1203-10. https://archive-ouverte.unige.ch/unige:42302

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Deposited on : 2014-12-01

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