title: First steps in exploring prospective exome sequencing of consanguineous couples.
abstract: Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non-exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples.
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Teeuw
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. Electronic address: q.waisfisz@vumc.nl.
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Petra J G
authors.initials: PJ
authors.lastname: Zwijnenburg
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Sistermans
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Lidewij
authors.initials: L
authors.lastname: Henneman
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Leo P
authors.initials: LP
authors.lastname: ten Kate
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands; EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Martina C
authors.initials: MC
authors.lastname: Cornel
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Hanne
authors.initials: H
authors.lastname: Meijers-Heijboer
mesh_terms: D003241:Consanguinity; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D011446:Prospective Studies; D017422:Sequence Analysis, DNA
keywords: Autosomal recessive disorders; Consanguinity; Exome sequencing; Preconception carrier screening