Uncovering the contribution of rare genetic variants in orofacial clefts Pubblico
Diaz Perez, Kimberly (Spring 2023)
Abstract
Orofacial clefts (OFCs) are common craniofacial congenital anomalies that occur when the palate and/or the lip fail to form properly during development. Approximately 70% of OFCs are considered non-syndromic, occurring as isolated events without additional structural or cognitive anomalies. They are heterogeneous etiologies involving environmental and genetic risk factors that include Mendelian and non-Mendelian causes. However, much of the focus has been on common variants and genome-wide association studies, which only account for ~25% of the heritable risk for OFCs. The unaccounted heritability may be attributed to other sources of variation, including rare variants that are examined using sequencing approaches (e.g., whole-exome sequencing (WES) and whole-genome sequencing (WGS)). We hypothesize that rare variants contribute to the OFC risk through different genetic mechanisms. We first investigated rare variants using WES in 31 multiplex families, each with multiple affected individuals that were consistent with Mendelian inheritance. Nineteen of these families were deeply phenotyped to assess subclinical phenotypes, which are subtle phenotypes hypothesized to exist within the same etiological spectrum as OFCs. We identified likely causal variants in 25% of multiplex families. Several variants were in genes that are mutated in Mendelian syndromes that include OFCs as a feature. Although some variants were found in individuals with subclinical phenotypes, we cumulatively failed to find clear evidence supporting the subclinical phenotype hypothesis. To explore all possible types of inheritance, we next analyzed 50 consanguineous families from Colombia and Turkey. The identified variants of interest included dominant-acting heterozygous variants as well as recessive homozygous variants. Finally, we estimated the diagnostic yield of 841 cases and 294 controls with WGS using 418 genes previously implicated in OFCs. We found 9.04% of cases had a pathogenic variant and nine genes alone accounted for 4.64% of the yield. Taken together, these findings provide evidence of the role of rare variants in OFCs and underscore the etiologic heterogeneity of OFCs. Further elucidation of the genetic architectures of all OFC types will aid in improving recurrence risk estimations and developing tailored management plans for individuals with OFCs.
Table of Contents
CHAPTER I. INTRODUCTION 1
What are OFCs? 1
Overview of Craniofacial Development 2
Broadening the Phenotypic Spectrum of OFCs 3
Syndromic and Non-Syndromic Forms of OFCs 6
What causes OFCs? 7
Environment in OFCs 7
Genetics and Environment Contributions in OFCs 9
Epigenetics Contributions in OFCs 9
Genetic Contributions in OFCs 10
Syndromic Gene Mapping 12
Genetics in Non-Syndromic OFCs 12
Overlap in Genetics Between Syndromic and Non-Syndromic OFCs 17
A Phenotypic Spectrum from Syndromic to Non-Syndromic OFCs 19
Conclusion 21
Tables 23
Figures 25
References 27
CHAPTER II. RARE VARIANTS FOUND IN MULTIPLEX FAMILIES WITH OROFACIAL CLEFTS: DOES EXPANDING THE PHENOTYPE MAKE A DIFFERENCE? 45
Introduction 46
Methods 48
Results 52
Discussion 57
Figures 60
Supplementary Tables 62
References 67
CHAPTER III. IDENTIFYING RARE RECESSIVE MUTATIONS IN CONSANGUINEOUS FAMILIES WITH OROFACIAL CLEFTS 72
Introduction 73
Methods 74
Results 76
Discussion 80
Tables 84
Figures 85
References 86
CHAPTER IV. RARE VARIANTS FOUND IN CLINICAL GENE PANELS ILLUMINATE THE GENETIC AND ALLELIC ARCHITECTURE OF OROFACIAL CLEFTING 90
Introduction 91
Methods 92
Results 99
Discussion 104
Figures 108
Supplementary Tables 111
Supplementary Figures 133
References 141
CHAPTER V. DISCUSSION 145
Summary 145
Diagnostic Yield Comparisons Across Studies 146
Genetic Heterogeneity of OFCs 148
Genetic Architecture of Cleft Subtypes and Subclinical Phenotypes 149
Future Directions 151
Conclusion 152
References 154
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