Date of Award

8-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Healthcare Genetics

Committee Chair/Advisor

Luigi Boccuto

Committee Member

Kathleen Valentine

Committee Member

Linda D. Ward

Committee Member

Sara M. Sarasua

Committee Member

Diana Ivankovic

Abstract

Phelan-McDermid Syndrome (PMS) is a rare neurodevelopmental disorder that involves chromosomal abnormalities on 22q13.3 and pathogenic variants with the SHANK3 gene. SHANK3 encodes for a critical scaffolding protein that is important in post-synaptic density, function, and maintenance of excitatory synapses. Haploinsufficiency of SHANK3 is considered the major cause of the neurological phenotype of PMS. These studies focused on further characterizing the neurologic phenotype of sleep disturbances in individuals with PMS.

Sleep disturbances are a common feature of PMS, however there is little research available on the subject matter. We reviewed the literature on sleep disturbances and used the Phelan-McDermid Syndrome International Registry (PMS-IR) to accurately characterize the prevalence of sleep disturbances in individuals with PMS. We concluded that 3 out of 4 individuals with PMS experience sleep disturbances. SHANK3 is the main candidate gene for sleep disturbances in PMS.

We then characterized sleep disturbances in a cohort of 56 individuals with PMS using genetic, metabolic, and clinical data. We found that most individuals with PMS who experienced sleep disturbances had a pathogenic variant in SHANK3 compared to 22q13.3 deletions. There were differences in the metabolism of carboxylic acids and external signaling molecules.

Next, we investigated potential biomarkers to stratify a cohort of 48 individuals with PMS and metabolic data based on their response to Insulin-like Growth Factor 1 (IGF-1) and human Growth Hormone (hGH). We were able to stratify the cohort into low and high responder groups based on the response to IGF-1 and hGH. We found that the same individuals were selected for high and low responder groups across the two hormones. This has the potential to allow for better patient selection for clinical trials, identify candidates that are predisposed to better response to IGF-1 or hGH, and minimize adverse reactions.

Lastly, we discussed the author’s laboratory expertise and skills developed unrelated to the projects of the dissertation. This included conducting cancer and rare disease research utilizing specific cell lines.

These studies determined sleep disturbances are extremely common in individuals with PMS. Sleep is a major feature of PMS, as it does affect the quality of life of patients and their families. Therefore, sleep disturbances should be considered an outcome measure of clinical trials that are targeting SHANK3.

Author ORCID Identifier

https://orcid.org/0000-0002-5906-2391

Available for download on Thursday, August 31, 2023

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