Burden of Mendelian disorders in a large Middle Eastern biobank
Authors: Aamer Waleed , Al-Maraghi Aljazi , Syed Najeeb , Gandhi Geethanjali Devadoss , Aliyev Elbay , Al-Kurbi Alya A. , Al-Saei Omayma , Kohailan Muhammad , Krishnamoorthy Navaneethakrishnan , Palaniswamy Sasirekha , Al-Malki Khulod , Abbasi Saleha , Agrebi Nourhen , Abbaszadeh Fatemeh , Akil Ammira S. Al-Shabeeb , Badii Ramin , Ben-Omran Tawfeg , Lo Bernice ,   The Qatar Genome Program Research Consortium, Ismail Said I. , Al-Muftah Wadha , Badji Radja , Mbarek Hamdi , Darwish Dima , Fadl Tasnim , Yasin Heba , Ennaifar Maryem , Abdellatif Rania , Alkuwari Fatima , Alvi Muhammad , Al-Sarraj Yasser , Saad Chadi , Althani Asmaa , Fethnou Eleni , Qafoud Fatima , Alkhayat Eiman , Afifi Nahla , Tomei Sara , Liu Wei , Wang Kun , Lorenz Stephan , Almabrazi Hakeem , Vempalli Fazulur Rehaman , Temanni Ramzi , Saqri Tariq Abu , Khatib Mohammedhusen , Hamza Mehshad , Zaid Tariq Abu , Khouly Ahmed El , Pathare Tushar , Poolat Shafeeq , Al-Ali Rashid , Albagha Omar , Al-Khodor Souhaila , Alshafai Mashael , Chouchane Lotfi , Estivill Xavier , Mbarek Hamdi , Puthen Jithesh V. , Suhre Karsten , Tatari Zohreh , Mokrab Younes , Fakhro Khalid A. 
Published: April 2024

Abstract
Background
Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.

Methods
Here, we interrogate 6045 whole genomes from Qatar—a Middle Eastern population with high consanguinity and understudied mutational burden—enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.

Results
We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1–3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.

Conclusions
This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.