Date of Award


Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

First Advisor

Murat Gunel, MD

Second Advisor

Anne Williamson, MD/PHD


Copy Number Variants (CNVs) are DNA fragment that are approximately 1 kilobase (kb) to several megabases for which copy-number differences have been revealed by comparison of two or more genomes. The Human Genome project has led to the identification of close to 1500 of these variable regions covering 12% of the human genome. Even though many of these variants are considered to be benign, some of these genomic rearrangement have been found to be disease causing, including several nervous system disorders such as Charcot-Marie-Tooth, Williams-Beuren Syndrome, and Prader-Willi syndrome. In this study we have performed copy number variant analysis on 252 patients with cortical malformations. Cortical malformations represented in our cohort included patients with cortical dysplasia (95), lissencephaly (33), heterotopia (10), pachygyria (8), and polymicrogyria (20), among other diseases. Two disease-causing copy number variants were identified, and those two diseases are the focus of this manuscript: a diffuse villous hyperplasia of the choroid plexus, and cerebellar atrophy with pachygyria. Diffuse villous hyperplasia of the choroid plexus is a rare cause of hydrocephalus not amenable to shunting alone. Tetrasomy of the short arm of Chromosome 9 was identified using high-resolution genomic array mapping, broadening the phenotype of this described entity to include diffuse villous hyperplasia of the choroid plexus. Congenital ataxia with cerebellar hypoplasia is a heterogeneous group of disorders that presents with motor disability, hypotonia, incoordination, and impaired motor development. A homozygous deletion in the VLDLR gene was identified using high density single nucleotide polymorphism (SNP) micro arrays in a Turkish family with two siblings affected with cerebellar atrophy and pachygyria. Previous identification of VLDLR mutations in a Turkish family with quadrupedal gait led to various speculations ranging from reverse evolution to cultural influences. Discovery of disease causing homozygous deletions in a new Turkish family, which maintained bipedal movement, constitutes significant evidence against these speculations.