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Hum Genet. 2017 Nov;136(11-12):1419-1429. doi: 10.1007/s00439-017-1843-2. Epub 2017 Sep 22.

Expanding the genetic heterogeneity of intellectual disability.

Author information

1
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
2
Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
3
Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
4
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
5
Department of Genetics, College of Medicine, Sultan Qaboos University, Muscat, Sultanate of Oman.
6
Pediatric Neurology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
7
King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
8
Neurology Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
9
Department of Pediatrics and Genetic Unit, Armed Forces Hospital, Khamis Mushayt, Saudi Arabia.
10
Department of Obstetrics and Gynecology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.
11
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
12
Department of Pediatric Neurology, ICH and SSF Hospital Mirpur, Dhaka, 1216, Bangladesh.
13
Department of Pediatric Neurology, Institute of Child Health and The Children's Hospital Lahore, 381-D/2, Lahore, Pakistan.
14
Department of Ophthalmology, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.
15
Division of Pediatric Neurology, Department of Pediatrics, King Khalid University Hospital and College of Medicine, King Saud University, Riyadh, Saudi Arabia.
16
Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
17
Division of Neurology, Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates.
18
Division of Clinical Genetics and Metabolic Disorders, Department of Pediatrics, Tawam Hospital, Al-Ain, United Arab Emirates.
19
Spectrum Health Genetics, Grand Rapids, MI, USA.
20
Genetics Division, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
21
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
22
Division of Biological and Environmental Sciences and Engineering (BESE), Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
23
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
24
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
25
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.
26
Spectrum Health Genetics, Grand Rapids, MI, USA. falkuraya@kfshrc.edu.sa.
27
Division of Biological and Environmental Sciences and Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia. falkuraya@kfshrc.edu.sa.

Abstract

Intellectual disability (ID) is a common morbid condition with a wide range of etiologies. The list of monogenic forms of ID has increased rapidly in recent years thanks to the implementation of genomic sequencing techniques. In this study, we describe the phenotypic and genetic findings of 68 families (105 patients) all with novel ID-related variants. In addition to established ID genes, including ones for which we describe unusual mutational mechanism, some of these variants represent the first confirmatory disease-gene links following previous reports (TRAK1, GTF3C3, SPTBN4 and NKX6-2), some of which were based on single families. Furthermore, we describe novel variants in 14 genes that we propose as novel candidates (ANKHD1, ASTN2, ATP13A1, FMO4, MADD, MFSD11, NCKAP1, NFASC, PCDHGA10, PPP1R21, SLC12A2, SLK, STK32C and ZFAT). We highlight MADD and PCDHGA10 as particularly compelling candidates in which we identified biallelic likely deleterious variants in two independent ID families each. We also highlight NCKAP1 as another compelling candidate in a large family with autosomal dominant mild intellectual disability that fully segregates with a heterozygous truncating variant. The candidacy of NCKAP1 is further supported by its biological function, and our demonstration of relevant expression in human brain. Our study expands the locus and allelic heterogeneity of ID and demonstrates the power of positional mapping to reveal unusual mutational mechanisms.

PMID:
28940097
DOI:
10.1007/s00439-017-1843-2
[Indexed for MEDLINE]

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