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BMC Med Genomics. 2016 Jul 19;9(1):42. doi: 10.1186/s12920-016-0208-3.

Exome sequencing in mostly consanguineous Arab families with neurologic disease provides a high potential molecular diagnosis rate.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
2
The Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, 77030, USA.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
4
Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
5
Exome Laboratory, Baylor Miraca Genetics Laboratories, Houston, TX, 77030, USA.
6
Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, 43205, USA.
7
Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia.
8
Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
9
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA. jlupski@bcm.edu.
10
The Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, 77030, USA. jlupski@bcm.edu.
11
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA. jlupski@bcm.edu.
12
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA. jlupski@bcm.edu.
13
Department of Pediatrics, Texas Children's Hospital, Houston, TX, 77030, USA. jlupski@bcm.edu.

Abstract

BACKGROUND:

Neurodevelopment is orchestrated by a wide range of genes, and the genetic causes of neurodevelopmental disorders are thus heterogeneous. We applied whole exome sequencing (WES) for molecular diagnosis and in silico analysis to identify novel disease gene candidates in a cohort from Saudi Arabia with primarily Mendelian neurologic diseases.

METHODS:

We performed WES in 31 mostly consanguineous Arab families and analyzed both single nucleotide and copy number variants (CNVs) from WES data. Interaction/expression network and pathway analyses, as well as paralog studies were utilized to investigate potential pathogenicity and disease association of novel candidate genes. Additional cases for candidate genes were identified through the clinical WES database at Baylor Miraca Genetics Laboratories and GeneMatcher.

RESULTS:

We found known pathogenic or novel variants in known disease genes with phenotypic expansion in 6 families, disease-associated CNVs in 2 families, and 12 novel disease gene candidates in 11 families, including KIF5B, GRM7, FOXP4, MLLT1, and KDM2B. Overall, a potential molecular diagnosis was provided by variants in known disease genes in 17 families (54.8 %) and by novel candidate disease genes in an additional 11 families, making the potential molecular diagnostic rate ~90 %.

CONCLUSIONS:

Molecular diagnostic rate from WES is improved by exome-predicted CNVs. Novel candidate disease gene discovery is facilitated by paralog studies and through the use of informatics tools and available databases to identify additional evidence for pathogenicity.

TRIAL REGISTRATION:

Not applicable.

KEYWORDS:

Copy Number Variants (CNV); Developmental Delay/Intellectual Disability (DD/ID); GRM7; Neurodevelopment; Whole exome sequencing (WES)

PMID:
27435318
PMCID:
PMC4950750
DOI:
10.1186/s12920-016-0208-3
[Indexed for MEDLINE]
Free PMC Article

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