UC San Diego

The structural organization and maturation of the brain are the result of a precisely orchestrated series of developmental processes with complex genetic regulation that occur during embryonic gestation and are critical for neuronal identity, wiring and connectivity. Mutations affecting any of the cellular processes involved in proper human brain development can lead to altered neurodevelopment and result in a number of different neurological diseases. Such diseases arising as a consequence of a biallelic mutation in a single gene are much more prevalent among offspring of consanguineous marriages, increasing the odds that a deleterious mutation will be inherited on both chromosomes. The identification of a disease-causing gene in families with inherited brain disorders is one of the most useful methods for gaining insight into human brain development, function, and pathology. This study largely focuses on identifying novel mutations in both known and novel recessive pediatric brain diseases using next-generation sequencing approaches in combination with in vitro and in vivo modeling. By taking advantage of the large number of consanguineous families in our cohort, we are not only able to explore the cause of disease directly in humans, but also able to determine genetic disease risk and identify novel disease-causing variants with a high level of certainty. A total of 88 affected individuals were identified and studied from 46 families displaying a range of SBDs including neurodegeneration (i.e. cortical and cerebellar atrophy), microlissencephaly, PCH, and Joubert syndrome, among other symptoms. A total of six disease-causing genes, ADPRHL2, TMX2, TRAPPC4, HEATR5B, HPDL, and ARMC9 were identified, four of which had never been implicated in disease prior to this study. We were further able to model disease in vivo for three out of the five genes (ADPRHL2, HEATR5B, and HPDL) using either fly or mouse models. Taken together, this study not only provides further knowledge in identifying novel causes of both previously unknown diseases as well as known diseases with unknown cause, but also provides further promise to the application of NGS in revealing the full spectrum of mutations associated with these diseases and in further delineating the relevant molecular pathways involved.