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Hum Genet. 2017 Aug;136(8):921-939. doi: 10.1007/s00439-017-1821-8. Epub 2017 Jun 9.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

Author information

1
Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
2
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
3
Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
4
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
5
Children's Hospital, King Saud Medical City, Riyadh, Saudi Arabia.
6
Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
7
Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
8
Department of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
9
Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
10
Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
11
Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
12
Pediatric Department, Al-Jahra Hospital, Ministry of Health, Kuwait, Kuwait.
13
Department of Pediatrics, Children's Hospital, Ain Shams University, Cairo, Egypt.
14
Department of Pediatrics, Dr. Suliman Al Habib Medical Group, Riyadh, Saudi Arabia.
15
Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
16
Department of Liver Transplantation, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
17
Genetics Department, Sultan Qaboos University Hospital, Muscat, Oman.
18
Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
19
Pediatric Neurology Department, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia.
20
Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
21
Global Eye Care, Specialized Medical Center Hospital, Riyadh, Saudi Arabia.
22
Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia.
23
Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
24
Department of Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.
25
Medical Genetic 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.
26
Maternity and Children's Hospital, Mecca, Saudi Arabia.
27
Saudi German Hospital, Aseer, Saudi Arabia.
28
Clinical Genetic Division of Human Genetics & Genome Research, National Research Center, Dokki, Giza, Egypt.
29
Taif Children's Hospital, Taif, Saudi Arabia.
30
Neonatology, Al Hammadi Hospital, Riyadh, Saudi Arabia.
31
Department of Obstetrics and Gynaecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
32
Medical Diagnostic Laboratory, Riyadh, Saudi Arabia.
33
Department of Pediatrics, King Fahd Hospital of the University, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
34
Deparment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa].
35
College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa].
36
Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa].

Abstract

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

PMID:
28600779
PMCID:
PMC5502059
DOI:
10.1007/s00439-017-1821-8
[Indexed for MEDLINE]
Free PMC Article

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