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Publication Details

Title :

Autozygome and high throughput confirmation of disease genes candidacy

Journal:

Genet Med.

Impact Factor:

9.937

Authors:

Maddirevula S1, Alzahrani F1, Al-Owain M2,3, Al Muhaizea MA3,4, Kayyali HR5, AlHashem A6, Rahbeeni Z2, Al-Otaibi M7, Alzaidan HI2,3, Balobaid A2, El Khashab HY8,9, Bubshait DK10, Faden M7, Yamani SA4, Dabbagh O4, Al-Mureikhi M11, Jasser AA6, Alsaif HS1, Alluhaydan I12, Seidahmed MZ13, Alabbasi BH6, Almogarri I14, Kurdi W15,16, Akleh H15, Qari A2, Al Tala SM17, Alhomaidi S7, Kentab AY18, Salih MA18, Chedrawi A4, Alameer S19, Tabarki B6, Shamseldin HE1, Patel N1, Ibrahim N1, Abdulwahab F1, Samira M1, Goljan E1, Abouelhoda M1,20, Meyer BF1,20, Hashem M1, Shaheen R1, AlShahwan S6, Alfadhel M21, Ben-Omran T11, Al-Qattan MM22, Monies D1,20, Alkuraya FS23,24,25,26.

Affiliations:

1 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

2 Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

3 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.

4 Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

5 Department of Pediatrics, King Faisal Specialist hospital and Research Center, Jeddah, Saudi Arabia.

6 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

7 Genetic Unit, Children’s Hospital, King Saud Medical City, Riyadh, Saudi Arabia.

8 Department of Pediatrics, Children’s Hospital, Ain Shams University, Cairo, Egypt.

9 Department of Pediatrics, Dr. Suliman Al Habib Medical Group, Riyadh, Saudi Arabia.

10 Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.

11 Section of Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, Doha, Doha, Qatar.

12 Genetics Division, Department of Pediatrics, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia.

13 Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.

14 Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

15 Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

16 Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

17 Department of Pediatrics, Armed Forces Hospital SR, Khamis Mushayt, Saudi Arabia.

18 Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

19 Department of pediatrics, King Abdulaziz Medical City, Jeddah, Saudi Arabia.

20 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.

21 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.

22 Department of Surgery, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

23 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.

24 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.

25 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.

26 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. falkuraya@kfshrc.edu.sa.

Year of Publication:

2018

DOI:

10.1038/s41436-018-0138-x

Abstract:

PURPOSE:

Establishing links between Mendelian phenotypes and genes enables the proper interpretation of variants therein. Autozygome, a rich source of homozygous variants, has been successfully utilized for the high throughput identification of novel autosomal recessive disease genes. Here, we highlight the utility of the autozygome for the high throughput confirmation of previously published tentative links to diseases.

METHODS:

Autozygome and exome analysis of patients with suspected Mendelian phenotypes. All variants were classified according to the American College of Medical Genetics and Genomics guidelines.

RESULTS:

We highlight 30 published candidate genes (ACTL6B, ADAM22, AGTPBP1, APC, C12orf4, C3orf17 (NEPRO), CENPF, CNPY3, COL27A1, DMBX1, FUT8, GOLGA2, KIAA0556, LENG8, MCIDAS, MTMR9, MYH11, QRSL1, RUBCN, SLC25A42, SLC9A1, TBXT, TFG, THUMPD1, TRAF3IP2, UFC1, UFM1, WDR81, XRCC2, ZAK) in which we identified homozygous likely deleterious variants in patients with compatible phenotypes. We also identified homozygous likely deleterious variants in 18 published candidate genes (ABCA2, ARL6IP1, ATP8A2, CDK9, CNKSR1, DGAT1, DMXL2, GEMIN4, HCN2, HCRT, MYO9A, PARS2, PLOD3, PREPL, SCLT1, STX3, TXNRD2, WIPI2) although the associated phenotypes are sufficiently different from the original reports that they represent phenotypic expansion or potentially distinct allelic disorders.

CONCLUSIONS:

Our results should facilitate the timely relabeling of these candidate disease genes in relevant databases to improve the yield of clinical genomic sequencing.