Identification of Genes Causing Pediatric Craniofacial Disorders Using Whole Genome Sequencing

Craniofacial disorders are among the most highly prevalent congenital malformations worldwide and include a wide spectrum of abnormalities of the face and/or skull which range in severity from mild facial dysmorphism to complex deformities requiring immediate surgical intervention. Craniofacial disorders are considered multifactorial, where both genetic and environmental influences are reported to play a role in the disease etiology by interfering with the normal early embryonic development. Moreover, many craniofacial anomalies can either present in association with other clinical phenotypes, as part of a syndrome, or as isolated phenotypes where the underlying genetic determinant remains elusive. In Qatar, high levels of consanguinity increase the prevalence of rare inherited recessive diseases/conditions that are sometimes challenging to diagnose. In this study, we apply Whole-Genome Sequencing (WGS) to identify genetic variants that cause a range of craniofacial disorders in 11 families, comprising 15 affected individuals. We successfully identify 10 rare candidate variants in 8 disease-causing genes in 6 families (54.5%) with different craniofacial anomalies. In the remaining 5 unsolved families, we will further investigate structural variants and expand the search to include novel genes and variants in the non-coding region. Overall, we demonstrate the effectiveness of WGS in identifying disease-causing genes in patients with suspected genetic etiologies where previous testing techniques could not reach a definitive diagnosis.