Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience.
Adolescent
Adult
Alleles
Child
Child, Preschool
Consanguinity
DNA Mutational Analysis
Family
Female
Genetic Association Studies
/ methods
Genetic Diseases, Inborn
/ diagnosis
Genetic Predisposition to Disease
Genotype
Humans
Infant
Infant, Newborn
Male
Mutation
Pathology, Molecular
Phenotype
Qatar
/ epidemiology
Exome Sequencing
Young Adult
Arab
Mendelian diseases
Middle East
Qatar
clinical exome sequencing
consanguinity
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
20
10
2018
revised:
22
01
2019
accepted:
25
02
2019
pubmed:
29
3
2019
medline:
11
6
2020
entrez:
29
3
2019
Statut:
ppublish
Résumé
Clinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically-oriented data sharing. This is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first-tier) test from April 2014 to December 2016 for various clinical indications. The CES diagnostic yield for the overall cohort was 48.3% (n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex-WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001). Middle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.
Sections du résumé
BACKGROUND
Clinical exome sequencing (CES) is rapidly becoming the diagnostic test of choice in patients with suspected Mendelian diseases especially those that are heterogeneous in etiology and clinical presentation. Reporting large CES series can inform guidelines on best practices for test utilization, and improves accuracy of variant interpretation through clinically-oriented data sharing.
METHODS
This is a retrospective series of 509 probands from Qatar who underwent singleton or trio CES either as a reflex or naïve (first-tier) test from April 2014 to December 2016 for various clinical indications.
RESULTS
The CES diagnostic yield for the overall cohort was 48.3% (n = 246). Dual molecular diagnoses were observed in 2.1% of cases; nearly all of whom (91%) were consanguineous. We report compelling variants in 11 genes with no established Mendelian phenotypes. Unlike reflex-WES, naïve WES was associated with a significantly shorter diagnostic time (3 months vs. 18 months, p < 0.0001).
CONCLUSION
Middle Eastern patients tend to have a higher yield from CES than outbred populations, which has important implications in test choice especially early in the diagnostic process. The relatively high diagnostic rate is likely related to the predominance of recessive diagnoses (60%) since consanguinity and positive family history were strong predictors of a positive CES.
Identifiants
pubmed: 30919572
doi: 10.1002/ajmg.a.61126
pmc: PMC6916397
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
927-935Informations de copyright
© 2019 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals, Inc.
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