Deletions and duplications in the human genome are a major cause for neurodevelopmental disorders such as autism, epilepsy, and intellectual disability. However, not all individuals carrying these deletions and duplications share similar clinical features with high variability in the extent and severity of presenting signs and symptoms. This suggests that these individuals may have other genetic variations (second hits) modifying the manifestation as well as altering the trajectory of the progression of the disorder. In 2010, we analyzed 2,312 individuals with genomic disorders such as 16p11.2 deletion, 16p13.11 deletion, 15q13.3 deletion, 1q21.1 deletion, and 16p12.2 deletion. We found that individuals carrying additional variants at second sites (second hit) exhibited more clinical features than those with only one hit. Of these, the 16p12.2 deletion showed the highest variation in clinical features. The 16p12.2 deletion (previously 16p12.1 deletion) is a disorder characterized by speech delay, hypotonia, craniofacial and skeletal abnormalities, growth delay, microcephaly, sleep disturbance, and cardiac disease. Because of this wide range of clinical features and the increased frequency of second hits, we intend to use the 16p12.2 deletion to model the variability of neurodevelopmental disease.
Our project aims to search for second hits or genetic modifiers within genomes of affected patients and their family members using high throughput, state-of-the-art molecular genetic techniques. This work will provide a better understanding of the mechanisms behind the manifestation of clinical features associated with the genomic disorders. Using sophisticated computational methods we will be able to map the combination of genetic variants that confer high risk for disease. With the knowledge gained from this project, it is our hope to lay a foundation to provide a better quality of life to those who suffer from genomic disorders such as the 16p12.2 deletion.
Our work would not be possible without the recruitment of patients for study. We invite you to participate in our study if your child or loved one of yours has been affected by the 16p12.2 deletion.