Impact of Copy Number Variation of the 7q11.23 Williams Syndrome Critical Region on Brain Structure

880 

Abstract Submission 

Madeline Garvey¹, Tiffany Nash², Shane Kippenhan³, Philip Kohn², Carolyn Mervis⁴, Daniel Eisenberg², Anne Ilsley⁵, Anna Kelemen⁵, Megan Spurney⁶, Ariana Chavannes⁵, Michael Gregory⁷, Karen Berman²

¹NIMH/University of Cambridge, Washington, DC, ²NIMH, National Institutes of Health, Bethesda, MD, ³NIH, Bethesda, MD, ⁴University of Louisville, Louisville, KY, ⁵National Institute of Mental Health, Bethesda, MD, ⁶Section on Functional Imaging Methods, NIMH, Bethesda, MD, ⁷NIMH, Bethesda, MD

Madeline Garvey  
NIMH/University of Cambridge
Washington, DC

Tiffany Nash  
NIMH, National Institutes of Health
Bethesda, MD

Shane Kippenhan  
NIH
Bethesda, MD

Philip Kohn  
NIMH, National Institutes of Health
Bethesda, MD

Carolyn Mervis  
University of Louisville
Louisville, KY

Daniel Eisenberg  
NIMH, National Institutes of Health
Bethesda, MD

Anne Ilsley  
National Institute of Mental Health
Bethesda, MD

Anna Kelemen  
National Institute of Mental Health
Bethesda, MD

Megan Spurney  
Section on Functional Imaging Methods, NIMH
Bethesda, MD

Ariana Chavannes  
National Institute of Mental Health
Bethesda, MD

Michael Gregory, M.D.  
NIMH
Bethesda, MD

Karen Berman  
NIMH, National Institutes of Health
Bethesda, MD

Copy number variations (CNVs), where the number of copies of one or more genes varies from the expected two copies, can result from deletions or duplications of segments of DNA.(7) One particularly interesting example of such a CNV occurs at chromosomal locus 7q11.23, where hemideletion of ~26 genes results in Williams syndrome (WS) and duplication of these same genes results in 7q11.23 duplication syndrome (Dup7). Because the affected 7q11.23 DNA segment is flanked by low copy DNA repeats, >90% of these deletions or duplications span the same ~1.5 megabase region.(1) Cognitively, people with WS often have mild to moderate intellectual disability, pronounced deficits in visuospatial abilities, and relative strength in overall language skills;(2) whereas people with Dup7 typically have low-average intellectual ability, relatively preserved visuospatial abilities, and language delays.(3,6) Additionally, while individuals with WS are often described as "hypersocial," people with Dup7 have significant social anxiety and shyness.(6) Because both the genetics and neurobehavioral phenotypes of these two conditions are well-circumscribed and well-defined, they offer a privileged setting to explore how genetic changes affect brain development and translate into complex behaviors. Previous neuroimaging literature has consistently shown that individuals with WS have smaller brains with regionally decreased volume of parieto-occipital areas and relatively increased cerebellar volume,(5) but neuroimaging studies of individuals with Dup7 have been relatively sparse, with data primarily from case series. Some of these case series have shown increased ventricle size, increased total brain volume, and decreased corpus callosal volume,(4) but quantitative, group-level studies directly comparing people with WS and Dup7 are lacking. Here, we investigated the effect of 7q11.23 CNVs on macrostructural brain volume measures to better define the brain phenotypes of these disorders and to test for gene-dosage effects.

Children and adolescents with WS and Dup7, along with age- and sex-matched typically developing individuals (TDs), participated in the NIMH Intramural Research Program Study of Brain Development in 7q11.23 CNVs. Three T1-weighted Multi Echo MPRAGE scans were collected for each participant. Scans were averaged together and processed with Freesurfer version 7.1.1 to determine volumetric measures in each person's native brain space. Linear regressions in SPSS tested for relations between 7q11.23 copy number (WS=1 copy, TD=2 copies, Dup7=3 copies), and total brain volume (TBV), relative gray matter, cortical gray, subcortical gray, white matter, ventricular, and cerebellar volumes, with each analysis controlling for age and sex. Participants included 30 individuals with WS (age=12.5±3.9, 9 males), 92 TD individuals (age=13.1±3.2, 34 males), and 16 individuals with Dup7 (age=14.5±2.3, 8 males).

Gene dosage was related to TBV in a step-wise manner, with children with Dup7 having the largest brains and those with WS having the smallest (p<0.001). Given that TBV differed as a function of 7q11.23 copy number, subsequent analyses controlled for TBV to test for relative volume differences. Relative ventricular volume, relative total white matter volume, and relative subcortical gray matter volume all varied by copy number in a step-wise, increasing manner (Dup7>TD>WS, p<0.001). Conversely, relative total gray matter volume, relative cortical gray volume, and relative cerebellar volume all significantly varied by copy number in a step-wise, decreasing manner (WS>TD>Dup7, p<0.001).

These results document the effects of 7q11.23 copy number variation on macrostructural brain measures. The step-wise nature of these findings with copy number offer insights into genetic mechanisms driving neural development. Future work will attempt to uncover the contributions of specific genes to these phenotypes and will explore associations with regional brain measures.

Neurodevelopmental/ Early Life (eg. ADHD, autism)

Neurogenetic Syndromes ¹

Segmentation and Parcellation

Cortical Anatomy and Brain Mapping ²

Congenital

Development

DISORDERS

MRI

Pediatric Disorders

STRUCTURAL MRI