A Multidimensional Investigation of 3q29 Deletion Syndrome 公开

Abstract

The reciprocal 3q29 deletion and duplication syndromes (3q29del and 3q29dup) are rare genomic disorders characterized by a 1.6 Mb recurrent copy number variant. 3q29del is associated with a range of phenotypes including reduced birthweight, failure to thrive, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SZ). The phenotypic spectrum of 3q29dup is not well-described, but case reports have identified phenotypes including obesity, seizures, DD, and ID. Developing a clearer understanding of the phenotypes associated with 3q29del and 3q29dup, and the biological mechanisms underlying those phenotypes, is critical for the development of effective therapeutic strategies. With data from the online 3q29 registry (https://3q29deletion.org) and the B6.Del16^+/Bdh1-Tfrc mouse model of the 3q29 deletion, we sought to develop an improved phenotypic description of 3q29del and 3q29dup, and to interrogate the role of metabolic function in the development of 3q29 deletion-associated phenotypes. Self-report data from the 3q29 registry revealed a significantly increased rate of ASD diagnosis in our 3q29del study population, and a high rate of social disability irrespective of reported ASD diagnostic status. We also defined a spectrum of ASD-associated phenotypes that is distinct from the profile observed in idiopathic ASD, with 3q29del individuals showing relatively well-preserved social motivation. We next evaluated the phenotypic spectrum of 3q29dup, and found that feeding problems, learning problems, and seizures are all prevalent among 3q29dup study subjects. Additionally, we found a high rate of reported ASD diagnosis, demonstrating that the 3q29 duplication may confer a previously unrecognized ASD liability. Finally, we used the B6.Del16^+/Bdh1-Tfrc mouse model to interrogate metabolic dysregulation caused by the 3q29 deletion. We found that the 3q29 deletion has a substantial and sex-specific impact on fat metabolism.  Taken together, these data highlight the broad phenotypic spectrum of 3q29del and 3q29dup and provide inroads toward mechanistic understanding of these complex disorders.

Table of Contents

Chapter 1        Understanding the phenotypic spectrum of copy number variant disorders and their

                          underlying biological mechanisms................................................................ 1

        1.1             Copy number variants are a class of human genetic mutations........................... 2

        1.2             CNV disorders contribute to human morbidity.................................................. 2

        1.3             CNVs can be leveraged to gain insight into human phenotypes.......................... 2

        1.4             Methods to study CNVs.................................................................................. 3

        1.4.1          The study of CNVs in human populations......................................................... 4

        1.4.2          Rodent models can be used to study CNVs........................................................ 5

        1.5             The 3q29 CNV locus is poorly understood....................................................... 6

        1.6             Research aims................................................................................................ 7

        1.7             Figures........................................................................................................ 10

        1.8             References................................................................................................... 11

Chapter 2        Neuropsychiatric phenotypes as a distinct constellation of ASD features in 3q29

                          deletion syndrome: Results from the 3q29 registry..................................... 28

        2.1             Background.................................................................................................. 29

        2.2             Materials and methods.................................................................................. 30

        2.3             Results......................................................................................................... 32

        2.4             Discussion................................................................................................... 37

        2.5             Conclusions................................................................................................. 44

        2.6             Tables.......................................................................................................... 46

        2.7             Figures........................................................................................................ 50

        2.8             References................................................................................................... 54

        2.9             Supplemental information............................................................................. 67

Chapter 3        New phenotypes associated with 3q29 duplication syndrome: Results from the 3q29

                          Registry...................................................................................................... 85

        3.1             Introduction................................................................................................. 86

        3.2             Methods....................................................................................................... 88

        3.3             Results......................................................................................................... 90

        3.4             Discussion................................................................................................... 97

        3.5             Tables........................................................................................................ 103

        3.6             Figures....................................................................................................... 107

        3.7             References.................................................................................................. 117

        3.8             Supplemental information........................................................................... 124

Chapter 4        Metabolic effects of the schizophrenia-associated 3q29 deletion are highly sex

                          specific and uncoupled from behavioral phenotypes................................. 139

        4.1             Introduction................................................................................................ 140

        4.2             Results....................................................................................................... 141

        4.3             Discussion.................................................................................................. 148

        4.4             STAR methods........................................................................................... 153

        4.5             Key resources table..................................................................................... 164

        4.6             Figures....................................................................................................... 165

        4.7             References.................................................................................................. 173

        4.8             Supplemental information........................................................................... 195

Chapter 5         Discussion and future directions............................................................... 211

        5.1             Summary.................................................................................................... 212

        5.2             Limitations................................................................................................. 215

        5.3             Future directions......................................................................................... 216

        5.4             References.................................................................................................. 218

Table of Tables

Table 2-1          Characteristics of study participants with 3q29Del and controls....................... 46

Table 2-2          Self-reported neuropsychiatric diagnoses........................................................ 47

Table 2-3          SRS sub-scale score comparison stratified by genotype, ASD status, and sex.... 49

Table 3-1          Characteristics of study participants with 3q29dup, 3q29del, and controls....... 103

Table 3-2          SRS sub-score comparison stratified by genotype, sex, and ASD status........... 104

Table 3-3          CBCL/ABCL Withdrawn sub-score comparison stratified by genotype, sex, and ASD

                          Status......................................................................................................... 105

Table 3-4          Comparison of reported medical and neuropsychiatric phenotypes between 3q29dup

                          (n=31) and 3q29del (n=117) participants...................................................... 106

Table of Figures

Figure 1-1         Structure of the 3q29 reciprocal CNV locus.................................................... 10

Figure 2-1         Score distribution for 3q29Del and controls on the SRS, SCQ, ASSQ, and

                          CBCL/ABCL............................................................................................... 50

Figure 2-2         Comparison of ASD prevalence and SRS scores between 3q29Del and

                          controls........................................................................................................ 51

Figure 2-3         Comparison of SRS sub-scales and CBCL/ABCL DSM-oriented sub-scales between

                          3q29Del and controls.................................................................................... 52

Figure 3-1         Gestational age and birthweight distributions for 3q29dup and controls.......... 107

Figure 3-2         Reported problems in the first year of life by participants with 3q29dup and

                          controls...................................................................................................... 108

Figure 3-3         Comparison of developmental milestone achievement between participants with 3q29dup

                          and controls................................................................................................ 109

Figure 3-4         Reported learning problems by participants with 3q29dup and controls.......... 110

Figure 3-5         Overlap between reported global developmental delay, seizures, anxiety, and ASD

                          among participants with 3q29dup................................................................. 111

Figure 3-6         Comparison of SRS total scores and sub-scores between 3q29dup and

                          controls...................................................................................................... 112

Figure 3-7         Comparison of CBCL/ABCL Withdrawn and DSM-oriented sub-scales between 3q29dup

                          and controls................................................................................................ 114

Figure 3-8         Comparison of SRS and CBCL/ABCL scores between 3q29dup and 3q29del. 116

Figure 4-1         Experimental approach to interrogating the effect of the B6.Del16^+/Bdh1-Tfrc genotype on

                          metabolism and the effect of sex on 3q29 deletion-associated metabolic

                          phenotypes................................................................................................. 165

Figure 4-2         Reduced energy expenditure and respiratory exchange ratio in B6.Del16^+/Bdh1-Tfrc

                          mice........................................................................................................... 166

Figure 4-3         Untargeted metabolomics reveals small molecule alterations in B6.Del16^+/Bdh1-Tfrc mice

                          that are highly sex-dependent....................................................................... 167

Figure 4-4         A high-fat diet reduces the B6.Del16^+/Bdh1-Tfrc weight deficit and affects RER in a sex

                          specific manner.......................................................................................... 169

Figure 4-5         Widespread changes in the global metabolic environment of B6.Del16^+/Bdh1-Tfrc mice after

                          HFD treatment............................................................................................ 170

Figure 4-6         HFD treatment does not affect B6.Del16^+/Bdh1-Tfrc brain size............................ 172

Table of Supplemental Tables

Table S2-1        Questionnaire demographics.......................................................................... 68

Table S2-2        Sensitivity analysis for self-reported neuropsychiatric diagnoses...................... 70

Table S2-3        Sensitivity analysis for symptomology questionnaire scores............................ 71

Table S2-4        Symptomology questionnaire score comparison.............................................. 72

Table S2-5        SRS score comparison stratified by ASD status and sex.................................. 73

Table S2-6        SCQ score comparison stratified by ASD status and sex.................................. 74

Table S2-7        CBCL/ABCL DSM-oriented sub-scale comparison......................................... 75

Table S2-8        Contribution of congenital heart defects to phenotypes of interest.................... 76

Table S2-9        Test for confounding factors contributing to symptomology questionnaire

                          scores.......................................................................................................... 77

Table S2-10      CBCL/ABCL Withdrawn sub-scale score comparison..................................... 78

Table S2-11      Heart defects present in study sample............................................................. 79

Table S2-12      Comparison of 3q29 registry-leveraged and gold-standard phenotyping

                          measures...................................................................................................... 80

Table S2-13      Comparison of CBCL/ABCL sub-scale scores between 3q29Del and 22q11.2

                          deletion........................................................................................................ 81

Table S3-1        Questionnaire demographics........................................................................ 125

Table S3-2        Goodness-of-fit analysis.............................................................................. 126

Table S3-3        Problems in the first year of life................................................................... 127

Table S3-4        Kaplan-Meier time-to-event analysis for developmental milestones................ 128

Table S3-5A     Early learning problems............................................................................... 131

Table S3-5B     School-age learning problems...................................................................... 131

Table S3-6        Gastrointestinal problems............................................................................ 132

Table S3-7        Psychiatric diagnoses.................................................................................. 133

Table S3-8        SRS score comparison stratified by ASD status and sex................................. 134

Table S3-9        Ear problems.............................................................................................. 135

Table S3-10      Dental problems.......................................................................................... 136

Table of Supplemental Figures

Figure S2-1       Comparison of SCQ scores between 3q29Del and controls, stratified by ASD status and

                          Sex.............................................................................................................. 82

Figure S2-2       Comparison of CBCL/ABCL Withdrawn sub-scale scores between 3q29Del and controls,

                          stratified by ASD status and sex.................................................................... 83

Figure S2-3       Geographic distribution of participants with 3q29Del...................................... 84

Figure S3-1       Comparison of SRS scores between participants with 3q29dup and controls, stratified by

                          sex............................................................................................................. 138

Figure S4-1       Indirect calorimetry of WT and B6.Del16^+/Bdh1-Tfrc mice on the STD and

                          HFD.......................................................................................................... 197

Figure S4-2       Correlation between replicate samples from untargeted metabolomics............ 201

Figure S4-3       Learning phenotypes in STD- and HFD-treated B6.Del16^+/Bdh1-Tfrc mice.......... 207

Figure S4-4       Acoustic startle, prepulse inhibition, and amphetamine-induced locomotion phenotypes in

                          STD- and HFD-treated B6.Del16^+/Bdh1-Tfrc mice    209

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Genetics and Molecular Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Genetics
关键词	3q29 deletion genetics 3q29 duplication
Committee Chair / Thesis Advisor	Michael Zwick, Emory University Jennifer Mulle, Emory University
Committee Members	Andrew Neish, Emory University Tamara Caspary, Emory University Michael Epstein, Emory University Dean Jones, Emory University

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