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Abstract
Heterogenetic developmental disorders (DDs) have eluded much of diagnosis. DD is recently re-defined as “a disorder in which the most prominent pathogenetic mechanism occurs during embryogenesis or early brain development”. It is not limited to disorders pertaining to the nervous system, although the majority of persons with DD have abnormalities of the nervous system. This thesis introduces the concept of polygenic contribution to DD, namely proving that the inherited variants in functionally related haploinsufficient genes found using whole-exome sequencing can explain undiagnosed DDs even after failing to find causative de novo or recessive mutations in monogenic Mendelian inheritance models. 29 DD patient-parent trios were recruited and their exomes were analyzed as proof-of-concept. Since overconservativeness in previous exome studies may have led to exclusion of contributing variants, this study broadens the scope of investigation by including semi-rare variants, and includes unreported neurodevelopmental genes for clinical review. With further validation, this novel approach can greatly raise the diagnostic rate of DDs, and is anticipated to change the perspective of clinical diagnosis and management. This thesis also attempts network-based analysis of phenotype similarity between diagnosed DDs and finds that semantic similarity exists between DDs whose causative genes are known to be functionally related, as well as between DDs whose causative genes’ molecular relationships are less characterized.
