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

Article Article scientifique Article Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families eng 2014 author Makrythanasis Periklis 638085 author Nelis Mari 735840 author Santoni Federico 681638 author Guipponi Michel 118157 author Vannier Anne 751929 author Sloan Bena Frédérique 629243 author Gimelli Stefania 663673 author Stathaki Elissavet 691247 author Temtamy Samia author Mégarbané André author Masri Amira author Aglan Mona S author Zaki Maha S author Bottani Armand 513397 author Fokstuen Siv 133715 author Gwanmesia Lorraine Mukud 554387 author Aliferis Konstantinos 600740 author Bustamante Eduardo Mariana 741012 author Stamoulis Georgios 764907 author Psoni Stavroula author Kitsiou-Tzeli Sofia author Fryssira Helen author Kanavakis Emmanouil author Al-Allawi Nasir author Sefiani Abdelaziz author Al Hait Sana' author Elalaoui Siham C author Jalkh Nadine author Al-Gazali Lihadh author Al-Jasmi Fatma author Bouhamed Habiba Chaabouni author Abdalla Ebtesam author Cooper David N author Antonarakis Stylianos 22813 author Hamamy Hanan 1203-1210 10.1002/humu.22617 25044680 1059-7794 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. Dewey 576.5 135 Département de médecine génétique et développement 21D false 196 Pathologie Moléculaire de la Trisomie 21 et le Génome Humain 248 Human mutation 35 10 74af40e2-d4dd-4601-9343-4de60898197d Article (Published version) Restricted humu22617.pdf 174579 application/pdf restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

Title	Published in	Year	Views	Downloads

Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families	Human mutation	2014	704	4
High Throughput Sequencing in Genetic Disorders		2013	330	26

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