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

Aida M. Bertoli-Avella*, Krishna K. Kandaswamy, Suliman Khan, Natalia Ordonez-Herrera, Kornelia Tripolszki, Christian Beetz, Maria Eugenia Rocha, Alize Urzi, Ronja Hotakainen, Anika Leubauer, Ruslan Al-Ali, Vasiliki Karageorgou, Oana Moldovan, Patrícia Dias, Amal Alhashem, Brahim Tabarki, Mohammed A. Albalwi, Abdulrahman Faiz Alswaid, Zuhair N. Al-Hassnan, Malak Ali AlghamdiZahra Hadipour, Fatemeh Hadipour, Nadia Al Hashmi, Lihadh Al-Gazali, Huma Cheema, Maha S. Zaki, Irina Hüning, Ahmed Alfares, Wafaa Eyaid, Fuad Al Mutairi, Majid Alfadhel, Fowzan S. Alkuraya, Nouriya Abbas Al-Sannaa, Aisha M. AlShamsi, Najim Ameziane, Arndt Rolfs, Peter Bauer

*Corresponding author for this work


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.

Original languageEnglish
JournalGenetics in Medicine
Issue number8
Pages (from-to)1551-1568
Number of pages18
Publication statusPublished - 08.2021

Research Areas and Centers

  • Research Area: Medical Genetics
  • Centers: Center for Rare Diseases (ZSE)

DFG Research Classification Scheme

  • 205-03 Human Genetics


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