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Analysis of incidental findings in Qatar genome participants reveals novel functional variants in LMNA and DSP

journal contribution
submitted on 2024-04-03, 10:09 and posted on 2024-04-03, 10:10 authored by Amal Elfatih, Sahar I Da’as, Doua Abdelrahman, Hamdi Mbarek, Idris Mohammed, Waseem Hasan, Khalid A Fakhro, Said I Ismail, Wadha Al-Muftah, Radja Badji, Dima Darwish, Tasnim Fadl, Heba Yasin, Maryem Ennaifar, Rania Abdel-latif, Fatima Alkuwari, Muhammad Alvi, Yasser Al Sarraj, Chadi Saad, Asmaa Althani, Eleni Fthenou, Fatima Qafoud, Eiman Alkhayat, Nahla Afifi, Sara Tomei, Wei Liu, Stephan Lorenz, Najeeb Syed, Hakeem Almabrazi, Fazulur Rehaman Vempalli, Ramzi Temanni, Tariq Abu Saqri, Mohammed Husen Khatib, Mehshad Hamza, Tariq Abu Zaid, Ahmed El Khouly, Tushar Pathare, Shafeeq Poolat, Rashid Al-Ali, Omar M E Albagha, Souhaila Al-Khodor, Mashael Alshafai, Ramin Badii, Lotfi Chouchane, Xavier Estivill, Younes Mokrab, Jithesh V Puthen, Karsten Suhre, Zohreh Tatari, Borbala Mifsud, for the The Qatar Genome Program Research Consortium

In order to report clinically actionable incidental findings in genetic testing, the American College of Medical Genetics and Genomics (ACMG) recommended the evaluation of variants in 59 genes associated with highly penetrant mutations. However, there is a lack of epidemiological data on medically actionable rare variants in these genes in Arab populations. We used whole genome sequencing data from 6045 participants from the Qatar Genome Programme and integrated it with phenotypic data collected by the Qatar Biobank. We identified novel putative pathogenic variants in the 59 ACMG genes by filtering previously unrecorded variants based on computational prediction of pathogenicity, variant rarity and segregation evidence. We assessed the phenotypic associations of candidate variants in genes linked to cardiovascular diseases. Finally, we used a zebrafish knockdown and synthetic human mRNA co-injection assay to functionally characterize two of these novel variants. We assessed the zebrafish cardiac function in terms of heart rate, rhythm and hemodynamics, as well as the heart structure. We identified 52 492 novel variants, which have not been reported in global and disease-specific databases. A total of 74 novel variants were selected with potentially pathogenic effect. We prioritized two novel cardiovascular variants, DSP c.1841A > G (p.Asp614Gly) and LMNA c.326 T > G (p.Val109Gly) for functional characterization. Our results showed that both variants resulted in abnormal zebrafish heart rate, rhythm and structure. This study highlights medically actionable variants that are specific to the Middle Eastern Qatari population.

Other Information

Published in: Human Molecular Genetics
License: https://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1093/hmg/ddac073

History

Language

  • English

Publisher

Oxford University Press

Publication Year

  • 2022

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Sidra Medicine
  • Qatar Genome Programme

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