2. Academic Validation
  3. Autozygome and high throughput confirmation of disease genes candidacy

Autozygome and high throughput confirmation of disease genes candidacy

  • Genet Med. 2019 Mar;21(3):736-742. doi: 10.1038/s41436-018-0138-x.
Sateesh Maddirevula 1,  Fatema Alzahrani 1,  Mohammed Al-Owain 2 3,  Mohammad A Al Muhaizea 3 4,  Husam R Kayyali 5,  Amal AlHashem 6,  Zuhair Rahbeeni 2,  Maha Al-Otaibi 7,  Hamad I Alzaidan 2 3,  Ameera Balobaid 2,  Heba Y El Khashab 8 9,  Dalal K Bubshait 10,  Maha Faden 7,  Suad Al Yamani 4,  Omar Dabbagh 4,  Mariam Al-Mureikhi 11,  Abdulla Al Jasser 6,  Hessa S Alsaif 1,  Iram Alluhaydan 12,  Mohammed Zain Seidahmed 13,  Bashair Hamza Alabbasi 6,  Ibrahim Almogarri 14,  Wesam Kurdi 15 16,  Hana Akleh 15,  Alya Qari 2,  Saeed M Al Tala 17,  Suzan Alhomaidi 7,  Amal Y Kentab 18,  Mustafa A Salih 18,  Aziza Chedrawi 4,  Seham Alameer 19,  Brahim Tabarki 6,  Hanan E Shamseldin 1,  Nisha Patel 1,  Niema Ibrahim 1,  Firdous Abdulwahab 1,  Menasria Samira 1,  Ewa Goljan 1,  Mohamed Abouelhoda 1 20,  Brian F Meyer 1 20,  Mais Hashem 1,  Ranad Shaheen 1,  Saad AlShahwan 6,  Majid Alfadhel 21,  Tawfeg Ben-Omran 11,  Mohammad M Al-Qattan 22,  Dorota Monies 1 20,  Fowzan S Alkuraya 23 24 25 26
Affiliations

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. [email protected].
  • 24 College of Medicine, Alfaisal University, Riyadh, Saudi Arabia. [email protected].
  • 25 Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia. [email protected].
  • 26 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. [email protected].
PMID: 30237576 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.

Keywords

ACMG guidelines; candidate genes; variant interpretation.

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