Elucidating the Etiology of Autism Using Genomic Methods

Abstract

In 1943, Dr. Leo Kanner, at the Johns Hopkins Hospital, identified the childhood neuro-psychiatric disorder called autism. However, it was not until the 1970s that there was even one article mentioning both the words gene and autism. In 1989, a twin study provided the first evidence for a genetic element to this disorder. The 1990s brought about the initial comprehension of autism at a molecular level, in particular, through the identification of FMR1 in Fragile X Syndrome and MECP2 in Rett Syndrome. By 2003, when the human genome project was completed, the study of genetics in autism began to rapidly advance not only in the number of publications but also in the diversity of researchers involved around the world. Herein, I present my findings, at the Johns Hopkins University School of Medicine 70 years after Kanner's original discovery, on the genetics of autism etiology through a large epidemiological study and a detailed molecular genetic study of female-enriched multiplex families (FEMFs) with a particular focus on the gene delta catenin (CTNND2). In this dissertation, I show that second borns in families are more often affected then others, female affected containing families show linkage to 19p and Xq (encompassing the FMR1 gene), females cases are enriched for mutations in 18 different “candidate” autism genes, and CTNND2 is an autism gene based on genetics, gene expression, dysregulation of its function, and pathway analyses.