TOWARDS UNDERSTANDING THE GENETIC BASIS OF PHENOTYPIC HETEROGENEITY IN NEURODEVELOPMENTAL DISORDERS
Open Access
- Author:
- Pizzo Suarez, Lucilla
- Graduate Program:
- Molecular Medicine
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- February 25, 2019
- Committee Members:
- Santhosh Girirajan, Dissertation Advisor/Co-Advisor
Santhosh Girirajan, Committee Chair/Co-Chair
Ross Cameron Hardison, Committee Member
Zhi-Chun Lai, Committee Member
Qunhua Li, Outside Member
Scott Brian Selleck, Committee Member - Keywords:
- copy number variant
autism
modifier gene
genetic background
phenotypic variability
neurodevelopmental disorders - Abstract:
- Great advances have been recently made in understanding the genetic basis of neurodevelopmental disorders, which comprise a spectrum of phenotypes including autism, intellectual disability, epilepsy and schizophrenia. These studies pinpointed a role of large (>500kbp) rare (<1%) deletions and duplications, known as copy-number variants (CNVs). The association of rare recurrent CNVs with neurodevelopmental disorders contributed in the molecular diagnosis of affected individuals. However, the same genetic alteration was later found associated with multiple neurodevelopmental phenotypes, leading to challenges in establishing prognosis and management among carriers of rare recurrent CNVs. In this work, we explored the global contribution of rare variants in the genetic background towards variable clinical features among carriers of CNVs. We studied 16p12.1 deletion, a rare CNV associated with severe developmental delay but characterized by extreme phenotypic heterogeneity. We analyzed clinical and genomic data of families carrying 16p12.1 deletion, and found that a high number of functionally constraint genes affected by rare likely pathogenic variants (“other hits”) led to more severe clinical outcome in probands compared with their parents or siblings who also carried the deletion. The burden of “other hits” was also higher in probands with a positive family history of neuropsychiatric disease, who also exhibited more heterogeneous clinical phenotypes, compared with probands with negative family history. Moreover, we extended these analyses to other CNVs and found that the burden of “other-hits” correlated with quantitative cognitive and developmental phenotypes. These results support an oligogenic basis of disease, and highlight the importance of evaluating additional variants in the genetic background among carriers of disease-associated mutations. To functionally explore the complex genetic basis of neurodevelopmental phenotypes, we analyzed how genes within 16p12.1 deletion contribute to molecular, cellular and neurodevelopmental phenotypes in Drosophila melanogaster, and how these phenotypes are modulated by other developmental genes. Phenotypic and transcriptomic analyses of 16p12.1 homologs in Drosophila showed early lethality, decreased brain size, and alteration of housekeeping cellular functions after decreasing the expression of MOSMO and POLR3E in the nervous system. These results suggest a strong role of MOSMO and POLR3E towards neuronal development. Our results also showed that 16p12.1 genes contribute to distinct phenotypes, such as MOSMO to decreased complexity of dendritic arbors, POLR3E to developmental delay, and UQCRC2 to seizures, and that genes in the region do not interact towards eye phenotypes. To explore how other developmental genes modify 16p12.1 phenotypes, we tested 314 pair-wise interactions between 16p12.1 homologs with developmental genes, using the fly eye as a model. We observed that additive, suppressive and synergistic interactions modify neurodevelopmental phenotypes caused by 16p12.1 deletion genes. More precisely, we observed that homologs of the disease-associated genes SETD5 and ARID1B modified neurodevelopmental phenotypes in MOSMO by affecting cellular proliferation and apoptosis processes. Overall, these results suggest that genes within 16p12.1 region individually sensitize to neurodevelopmental phenotypes, which are further modified by interactions with other developmental genes. Our results support an oligogenic basis of neurodevelopmental disorders. We propose that the contribution of the genetic background towards phenotypic heterogeneity is phenotypespecific and also depends on the impact of the primary variant towards a specific phenotypic domain.