IDENTIFICATION OF RARE GENETIC VARIANTS CAUSING PEDIATRIC CRANIOFACIAL DISORDERS USING WHOLE GENOME SEQUENCING

Abstract

Craniofacial disorders represent some of the most common congenital malformations globally. These conditions vary in severity, spanning from mild facial dysmorphism to complex deformities necessitating urgent surgical correction, resulting from a combination of genetic and environmental factors disrupting normal embryonic development. Despite their prevalence, many causative genes remain undiscovered. In Qatar and the region, the high levels of consanguinity and the large family size increase the prevalence of rare inherited recessive diseases that are sometimes challenging to diagnose, leaving a significant portion of patients without a molecular diagnosis. In this study, Whole-Genome Sequencing (WGS) was employed to uncover genetic variants associated with a variety of craniofacial disorders within 30 families, comprising 40 affected individuals, the majority of whom (77%) were under the age of 5 years. In 20 families, candidate disease-causing variants in unique genes were identified, majority of which are known to cause various Mendelian craniofacial disorders. Of all the families, 13 were considered as solved cases offering a solve rate of 43%. Altogether, the ‘diagnostic yield’ from this cohort was approximately 43-67%. In these families, our research findings played a pivotal role in patient diagnosis, either by identifying the syndrome or by confirming the suspected diagnosis. Also, it influenced patient care, by expediting screening for additional associated phenotypes and/or facilitating the provision of appropriate genetic counseling through the genetics clinic. For the 10 unsolved families, further research is planned, alongside an expanded search to include novel genes and variants within non-coding regions. Overall, this study demonstrates the utility of WGS in identifying candidate genes and variants responsible for craniofacial anomalies in patients with suspected genetic etiologies where previous testing techniques could not reach a definitive diagnosis.

Date of Award	2024
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences