2. Academic Validation
  3. Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders

Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders

  • Genet Med. 2021 Aug;23(8):1551-1568. doi: 10.1038/s41436-021-01159-0.
Aida M Bertoli-Avella 1,  Krishna K Kandaswamy 2,  Suliman Khan 2,  Natalia Ordonez-Herrera 2,  Kornelia Tripolszki 2,  Christian Beetz 2,  Maria Eugenia Rocha 2,  Alize Urzi 2,  Ronja Hotakainen 2,  Anika Leubauer 2,  Ruslan Al-Ali 2,  Vasiliki Karageorgou 2,  Oana Moldovan 3,  Patrícia Dias 3,  Amal Alhashem 4,  Brahim Tabarki 4,  Mohammed A Albalwi 5 6 7,  Abdulrahman Faiz Alswaid 7 8,  Zuhair N Al-Hassnan 9,  Malak Ali Alghamdi 10,  Zahra Hadipour 11,  Fatemeh Hadipour 11,  Nadia Al Hashmi 12,  Lihadh Al-Gazali 13,  Huma Cheema 14,  Maha S Zaki 15,  Irina Hüning 16,  Ahmed Alfares 5 17,  Wafaa Eyaid 6 8,  Fuad Al Mutairi 6 8,  Majid Alfadhel 6 8,  Fowzan S Alkuraya 18,  Nouriya Abbas Al-Sannaa 19,  Aisha M AlShamsi 13,  Najim Ameziane 2,  Arndt Rolfs 2 20,  Peter Bauer 2
Affiliations

Affiliations

  • 1 CENTOGENE GmbH, Rostock, Germany. [email protected].
  • 2 CENTOGENE GmbH, Rostock, Germany.
  • 3 Serviço de Genética Médica. Hospital de Santa Maria. Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal.
  • 4 Division of Pediatric Genetics, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
  • 5 Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 6 King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, MNGHA, Riyadh, Saudi Arabia.
  • 7 College of Medicine, King Saud bin Abdulaziz University for Health Sciences. King Abdulaziz Medical City, Riyadh, Saudi Arabia.
  • 8 Division of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, MNGHA, Riyadh, Saudi Arabia.
  • 9 Department of Medical Genetics, King Faisal Specialist Hospital & Research Center, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • 10 Medical Genetic Division, Pediatric Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • 11 Medical Genetics Department, Atieh Research Center & Hospital, Tehran, Iran.
  • 12 National Genetic Center, Royal Hospital Muscat. Sultanate of Oman, Muscat, Oman.
  • 13 Department of Pediatrics, Tawan Hospital, Al-Ain, United Arab Emirates.
  • 14 Pediatric Department of Gastroenterology, Children's Hospital of Lahore Hospital, Lahore, Pakistan.
  • 15 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
  • 16 Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
  • 17 Department of Pediatrics, College of Medicine, Qassim University, Riyadh, Saudi Arabia.
  • 18 Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 19 John Hopkins Aramco Health Care, Pediatric Services, Dhahran, Saudi Arabia.
  • 20 University of Rostock, Rostock, Germany.
PMID: 33875846 DOI: 10.1038/s41436-021-01159-0
Abstract

Purpose: Within this study, we aimed to discover novel gene-disease associations in patients with no genetic diagnosis after exome/genome sequencing (ES/GS).

Methods: We followed two approaches: (1) a patient-centered approach, which after routine diagnostic analysis systematically interrogates variants in genes not yet associated to human diseases; and (2) a gene variant centered approach. For the latter, we focused on de novo variants in patients that presented with neurodevelopmental delay (NDD) and/or intellectual disability (ID), which are the most common reasons for genetic testing referrals. Gene-disease association was assessed using our data repository that combines ES/GS data and Human Phenotype Ontology terms from over 33,000 patients.

Results: We propose six novel gene-disease associations based on 38 patients with variants in the BLOC1S1, IPO8, MMP15, PLK1, RAP1GDS1, and ZNF699 genes. Furthermore, our results support causality of 31 additional candidate genes that had little published evidence and no registered OMIM phenotype (56 patients). The phenotypes included syndromic/nonsyndromic NDD/ID, oral-facial-digital syndrome, cardiomyopathies, malformation syndrome, short stature, skeletal dysplasia, and ciliary dyskinesia.

Conclusion: Our results demonstrate the value of data repositories which combine clinical and genetic data for discovering and confirming gene-disease associations. Genetic laboratories should be encouraged to pursue such analyses for the benefit of undiagnosed patients and their families.

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