A Multidimensional Investigation of 3q29 Deletion Syndrome Open Access
Pollak, Rebecca (Fall 2020)
Published
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
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