Investigation of associated gene variants in intellectual disability accompanied by microcephaly

Syndromic intellectual disability with accompanying microcephaly is an important group of rare neurodevelopmental disorders. The affected individuals have limited cognitive and communicative skills due to microcephaly and reduced brain volume. Additional phenotypic features include developmental delay, hypotonia and various dysmorphic disorders. The recent increase in the incidence of Zika virus-induced microcephaly in recent years has drawn attention to primary microcephaly, which is actually present in hundreds of different syndromes. More than half of these cases lack genetic diagnosis. Disease-related variant detection may not be possible with conventional gene analysis in disorders with extremely genetic and clinical heterogeneity. Whole exome sequencing (WES), one of the next generation sequencing methods, is an up-to-date technique that facilitates the discovery of pathogenic variants in all inheritance models by high-throughput data analysis in such disorders. The risk of rare and recessive congenital anomalies increases due to increased high rate of consanguinity in certain populations including ours.In this studythesis, we aimed to determine the rare and potentially recessive pathogenic variations in 9 patients from consanguineous families that have been diagnosed with primary microcephaly in prenatal term or birth. Another focus of this study is de novo variants associated with this phenotype. As a result of this study, a novel loss-of–function WDR62 pathogenic variant related to MCPH2 was detected in two different families possibly having a common founder. In a different patient, the known variant reported with SPG50 was found. De novo and new mutations were detected in SOX11 and TRIO genes in two different families. These proteins encoded by these genes are involved in key cellular processes including NPC differentiation and cell division. Finally, out study draws attention to de novo variants that may be overlooked in consanguineous families.