Dysmorphology, Abnormal Growth and Copy Number Variants in Autism Spectrum Disorder

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dc.contributor.advisorMaher, Brion
dc.contributor.committeeMemberFallin, Margaret Daniele
dc.contributor.committeeMemberHoover Fong, Julie E.
dc.contributor.committeeMemberBeaty, Terri L.
dc.creatorKamal Nor, Norazlin
dc.creator.orcid0000-0001-9959-8089
dc.date.accessioned2018-10-03T02:03:09Z
dc.date.available2018-10-03T02:03:09Z
dc.date.created2018-05
dc.date.issued2018-01-11
dc.date.submittedMay 2018
dc.date.updated2018-10-03T02:03:10Z
dc.description.abstractBackground and Purpose: Autism Spectrum Disorders (ASD) is a complex persistent neurodevelopmental disorder characterized by impairment in social interaction, communication difficulties and repetitive or stereotypic behaviors. In the past four decades, the prevalence of ASD has increased dramatically. The risk factors associated with ASD include genetic, environmental and possibly gene-environment interactions. Although the core features of ASD are well characterized, ASD presents heterogeneously with a wide spectrum of manifestations. These overlapping features or phenotypes are co-morbidities that occur in ASD and span developmental, medical, behavioral and psychiatric conditions. These co-morbid features can include dysmorphology and growth abnormalities. It is postulated that children with significant dysmorphology are more likely to have an underlying genetic etiology and may have a higher load of genes controlling risk to ASD, including a higher copy number variant (CNV) burden and more single location variants. CNVs are alterations of the DNA resulting in structural variants, including deletion and duplication of genome sequence. ASD sub-phenotypes (such as dysmorphology) offer the potential of determining distinct genetic etiologies and enhancing genotype-phenotype correlations in ASD. In this study, we first characterized growth abnormalities in children with ASD in the Study to Explore Early Development (SEED) study. To investigate genotype-phenotype associations in ASD, we determined the association between genome-wide CNV burden with dysmorphology and abnormal growth in SEED children and tested for association between ASD-associated CNVs with dysmorphology and growth abnormalities in children in the SEED study. Methods: The study population was drawn from the SEED Study, which was developed to identify risk factors for ASD in the prenatal and early post-natal period. To characterize abnormal growth patterns associated with ASD, we assessed growth abnormalities for all available anthropometric measures of growth (height, weight and head circumference), the bi-dimensional measure of body mass index (BMI), and a tri-dimensional growth measure of growth phenotype assessing the symmetry of growth involving all three modalities in a single individual. We examined genotype-phenotype associations between genome-wide estimated CNV burden with dysmorphology and abnormal growth. Finally, we investigated the association of specific CNVs reportedly associated with ASD for possible association with dysmorphology and abnormal growth in children in the SEED study. Results: Assessment of growth abnormalities in SEED 1 study showed females with ASD had short stature and a combination of short stature, microcephaly and normal weight compared to typically developing or control females. We found genome-wide CNV burden was negatively associated with dysmorphology, and CNV burden in recognized ASD genes was negatively associated with tall stature and macrocephaly; these associations varied by sex. Investigation of association between CNVs associated with ASD and abnormal growth revealed a potential shared genetic risk for ASD and short stature at CNV region 15p11.2, which was significantly associated only in females. Conclusions: These findings demonstrate the importance of taking into consideration the influence of sex in characterizing any association between growth abnormalities and/or dysmorphology and risk of ASD, as well as variability of reported genetic risk factors in ASD. There is potential shared genetic risk for ASD and growth abnormality that differs by sex, and this may lead to potential future clinical application in diagnosing of ASD that could be tailored to the child’s needs. Future directions: These results should be replicated in a different population, while expanding measurments of growth assessment to incorporate longitudinal change to better characterize growth abnormalities in ASD. Using a larger sample size and with parental genotyping information would enable CNV burden for de novo and rare CNVs to be considered. Whole exome sequencing would be a useful in excluding chromosomal abnormalities and non-chromosomal genetic syndromes when considering CNV burden associations. 
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/59149
dc.language.isoen_US
dc.publisherJohns Hopkins University
dc.publisher.countryUSA
dc.subjectautism spectrum disorder
dc.subjectdysmorphology
dc.subjectabnormal growth
dc.subjectcopy number variants
dc.subjectmacrocephaly
dc.subjectmicrocephaly
dc.subjecttall stature
dc.subjectshort stature
dc.subjectoverweight
dc.subjectunderweight
dc.subjecthigh BMI
dc.subjectlow BMI
dc.titleDysmorphology, Abnormal Growth and Copy Number Variants in Autism Spectrum Disorder
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentEpidemiology
thesis.degree.disciplineEpidemiology
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorBloomberg School of Public Health
thesis.degree.levelDoctoral
thesis.degree.namePh.D.
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