Date of Award

Winter 12-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Degree Name

Master of Arts (AM/MA)

Degree Type



Chiari Malformation Type 1 (CM1) is a neurodevelopmental disorder that occurs when one of the cerebellar tonsils herniates past the foramen magnum causing headaches, motor or sensory deficits, sleep apnea, and difficulty swallowing. This disorder is estimated to affect 1% of the population but due to the need of neuroimaging for diagnosis and the presence of asymptomatic patients there is still uncertainty about the exact proportion of the population affected. CM1 often presents itself with other neurodevelopmental disorders such as syringomyelia, scoliosis, and known genetic syndromes such as Klippel-Feil and Marfan syndromes. Twin, family, and familial clustering studies have established a genetic component to CM1 etiology, but have failed to ascertain any specific causal gene. The difficulty ascertaining causal genes, its comorbidity with multiple different syndromes, and the complex symptomatology of its patients indicate genetic heterogeneity. Other neurodevelopmental disorders with genetic heterogeneity such as Autism Spectrum Disorder and Epileptic Encephalopathies have had success finding genes of interests by looking for de novo mutants (DNMs) from spontaneous patient trios. With this in mind, we sequenced the exomes of a cohort of 29 offspring-parent trios affected with CM1 in search of candidate causative DNMs. Using previously established methods that predict which variants in the exome are DNMs, we found 44 variants that passed multiple filtering steps for quality, likelihood of being real DNMs, and potential to be causative. Three of these variants were classified as stopgain which made them likelier to be detrimental. These three were validated and analyzed for their potential role in CM1 risk. From thousands of possible variants, we successfully obtained a shortlist of genes to further study in future studies.


English (en)

Chair and Committee

Christina Gurnett

Committee Members

Nancy Saccone, James Skeath, John Rice


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