Unraveling The Genomics Landscape of Inherited Bone Marrow Failure Syndromes and Rare Congenital Diseases Through Genome Sequencing in The Middle East and North Africa (MENA) Region

Abstract

Inherited Bone Marrow Failure Syndromes (IBMFS) are a genetically heterogeneous group of disorders associated with bone marrow failure, physical anomalies, and cancer predisposition. These syndromes often present in children with medical complexity (CMC), requiring multidisciplinary care due to their multisystem involvement. Despite their clinical significance, data from the Middle East are limited. This study establishes the first IBMFS registry and integrates findings from Qatar Genome Program (QGP) to contextualize genetic variants within the local population. Methods This multi-center study analyzed clinical and Genome Sequencing (GS) data from 44 families (133 individuals including 46 patients). Disease-causing variants were classified using ClinVar and the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines. Findings were contextualized using the QGP data of 14,060 participants to estimate the cumulative carrier frequency and disease burden across 49 genes associated with 9 IBMFS in the local population. Results Pathogenic and likely pathogenic variants were identified in 20 (43%) patients in FANCA/C D2/F/J, ELANE, RPS26, SBDS, MPL genes, including a de novo 8 Mb deletion in Xp11.3-p11.22 in one family. Notably, two founder variants in FANCC (c.165+1G>T), and MPL (c.317C>T), with a potential novel variant in FANCF (c.538delG) were detected. Variants of uncertain significance (VUS) were identified in 26 (57%) patients in FANCA/E/J/P/W, ACD, SAMD9L, GNE, RPS24 and ITGA2B, including four novel candidate genes: WDR20, NOP56, DDX5, MDM2. Cumulative carrier frequency estimation using QGP data revealed the highest carrier frequencies for congenital amegakaryocytic thrombocytopenia (1 in 62) followed by Fanconi anemia (1 in 156). Conclusion This study identified pathogenic variants, two potential founder variants, novel candidate genes, and carrier frequencies of IBMFS. This underscores the value of GS for rare disease diagnosis and screening, timely detection of predisposition to hematological malignancies, and informed selection of donor compatibility for hematopoietic stem cell transplantation.

Date of Award	2025
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences