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Cell Rep. 2015 Jan 13;10(2):148-61. doi: 10.1016/j.celrep.2014.12.015. Epub 2014 Dec 31.

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

Author information

1
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
2
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
3
Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
4
Department of Pediatrics, King Fahad Medical City, Riyadh 11525, Saudi Arabia.
5
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
6
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
7
Department of Pediatrics, King Fahad General Hospital, Jeddah 23325, Saudi Arabia.
8
Department of Pediatrics, Armed Forces Hospital, Khamis Mushayt 62413, Saudi Arabia.
9
Department of Obstetrics & Gynecology, King Faisal Specialist Hospital, Riyadh 11211, Saudi Arabia.
10
Center of Excellence for Genomics, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
11
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh 11159, Saudi Arabia.
12
Department of Pediatrics, Security Forces Hospital, Riyadh 12625, Saudi Arabia.
13
Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
14
Division of Genetics, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh 14611, Saudi Arabia.
15
Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
16
Department of Psychiatry, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
17
Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo 12345, Egypt.
18
Department of Pediatrics, Johns Hopkins Aramco Healthcare, Dhahran 34465, Saudi Arabia.
19
Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia; Department of Pediatrics, Children's Hospital, Ain Shams University, Cairo 01234, Egypt.
20
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
21
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia.
22
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Internal Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia.
23
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 11442, Saudi Arabia. Electronic address: falkuraya@kfshrc.edu.sa.

Abstract

Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function.

PMID:
25558065
DOI:
10.1016/j.celrep.2014.12.015
[Indexed for MEDLINE]
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