title: Diagnostic exome sequencing to elucidate the genetic basis of likely recessive disorders in consanguineous families.
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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.forename: Mari
authors.initials: M
authors.lastname: Nelis
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Anne
authors.initials: A
authors.lastname: Vannier
authors.forename: Frédérique
authors.initials: F
authors.lastname: Béna
authors.forename: Stefania
authors.initials: S
authors.lastname: Gimelli
authors.forename: Elisavet
authors.initials: E
authors.lastname: Stathaki
authors.forename: Samia
authors.initials: S
authors.lastname: Temtamy
authors.forename: André
authors.initials: A
authors.lastname: Mégarbané
authors.forename: Amira
authors.initials: A
authors.lastname: Masri
authors.forename: Mona S
authors.initials: MS
authors.lastname: Aglan
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.forename: Siv
authors.initials: S
authors.lastname: Fokstuen
authors.forename: Lorraine
authors.initials: L
authors.lastname: Gwanmesia
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Aliferis
authors.forename: Mariana
authors.initials: M
authors.lastname: Bustamante Eduardo
authors.forename: Georgios
authors.initials: G
authors.lastname: Stamoulis
authors.forename: Stavroula
authors.initials: S
authors.lastname: Psoni
authors.forename: Sofia
authors.initials: S
authors.lastname: Kitsiou-Tzeli
authors.forename: Helen
authors.initials: H
authors.lastname: Fryssira
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Kanavakis
authors.forename: Nasir
authors.initials: N
authors.lastname: Al-Allawi
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Sefiani
authors.forename: Sana'
authors.initials: S
authors.lastname: Al Hait
authors.forename: Siham C
authors.initials: SC
authors.lastname: Elalaoui
authors.forename: Nadine
authors.initials: N
authors.lastname: Jalkh
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: Fatma
authors.initials: F
authors.lastname: Al-Jasmi
authors.forename: Habiba Chaabouni
authors.initials: HC
authors.lastname: Bouhamed
authors.forename: Ebtesam
authors.initials: E
authors.lastname: Abdalla
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
mesh_terms: D000293:Adolescent; D000328:Adult; D018912:Arabs; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D059472:Exome; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D035583:Rare Diseases / Q000175:diagnosis* / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
keywords: consanguinity; exome sequencing; high-throughput sequencing; homozygosity mapping