Investigating rare genetic disorders to gain insight into human biology Open Access

Mosley, Trenell (Summer 2021)

Permanent URL:


Discerning how genetic variation contributes to phenotypes is a critical part of understanding biology. Historically, scientists have contributed to our comprehension of variation by observing exceptional phenotypes. In humans, this can translate to the investigation of rare genetic diseases (RGDs), which offer unique insights into human biology. There are over 7,000 defined rare genetic diseases that affect more than 350 million people worldwide. By studying RGDs diseases, we have gained insights into essential biological mechanisms that underlie both rare and common diseases and have led to the development and improvement of interventions for them. The advent of next-generation sequencing (NGS) technologies has increased our ability to detect and interpret the genetic variation that underlies rare genetic diseases and has accelerated essential discoveries. Thus, our continued study of RGDs will only increase our understanding of RGDs and human biology. Through my dissertation work, I sought to improve our understanding of human biology by investigating two classes of rare genetic diseases and their underlying variation: a rare monogenic disorder caused by a single nucleotide variant (SNV) and rare, genomic disorders caused by repeat-mediated copy-number variants (CNVs). First, we ascertained two siblings of Middle Eastern descent presenting with a rare syndrome consisting of short stature and insulin resistance. Then, using whole-genome sequencing (WGS), genetic analysis, and functional testing, I identified the underlying genetic cause as an intronic splicing variant in POC1A, thereby giving insights into the allelic spectrum of POC1A-related primordial dwarfism disorders and insulin resistance. For my genomic disorders project, I used a systematic and comprehensive literature search, single nucleotide polymorphism (SNP) genotyping, and WGS, to determine the parent of origin data for multiple pathogenic CNV loci. I demonstrated a significant association between sex-specific patterns in meiotic recombination and parental origin at these loci, which has implications for assessing risks for forming pathogenic CNVs. Taken together, my dissertation work advances our knowledge of the genetic causes underlying rare genetic diseases, has future implications for prospective interventions and counseling for individuals with rare genetic disorders, and gives insight into essential biological processes in human beings.

Table of Contents

Chapter I. Introduction 1

History of Genetic Diseases and Variation 2

Common Genetic Diseases and the Utility of Genome-wide Association Studies 3

Investigating Rare Genetic Diseases 4

Contributions of Variation to Rare Genetic Diseases 8

Utility of Next-Generation Sequencing in Rare Genetic Diseases 12

References 15

Chapter II. A novel intronic mutation causes aberrant splicing in variant POC1A-related syndrome 24

Introduction 25

Materials and Methods 26

Results 38

Discussion 41

Conclusions 46

Tables 47

Figures 48

Supplemental Tables 53

Supplemental Figures 56

References 58

Chapter III. Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders 67

Introduction 68

Methods 69

Results 73

Discussion 75

Conclusions 79

Tables 81

Figures 85

Supplemental Methods 86

Supplemental Tables 98

Supplemental Figures 108

References 123

Chapter IV. Discussion 142

Summary 143

Future Directions 145

Conclusions 149

References 150


About this Dissertation

Rights statement
  • Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.
Subfield / Discipline
  • English
Research Field
Committee Chair / Thesis Advisor
Committee Members
Last modified

Primary PDF

Supplemental Files