Elizabeth Leslie and Danielle Rudd present in Seminar this Thursday (11th August)
Background for Elizabeths talk
“Pursuit of etiologic variants for cleft lip and palate following a successful genome wide association study”
Nonsyndromic cleft lip and/or cleft palate (NSCL/P) is a common birth defect with complex etiology reflecting the action of multiple genetic and/or environmental factors. The search for genetic contributors to NSCL/P has been intensive using a variety of approaches including candidate gene, genome wide linkage, and genome wide association. Four genome wide association studies have been published in recent years, identifying several novel associations and confirming previous associations from candidate gene studies. The challenge following genome wide association studies is identifying the disease-causing etiologic variants at each associated locus tagged by presumably non-causal markers. We hypothesize that etiologic variants contributing to NSCL/P will be a combination of common and rare variants, possibly located in noncoding regulatory regions of the genome. I am using two approaches to identify these variants. The first approach could be considered “sequence first” and will leverage next generation sequencing technologies by capturing large intervals surrounding thirteen genes and loci associated with NSCL/P and deep sequencing them in a large set of case-parent triads with NSCL/P. The second approach uses craniofacial enhancers identified by collaborators to prioritize regions of the genome for sequencing. At seminar I will discuss these approaches and present new results identifying potential etiologic variants at a GWAS locus near the transcription factor, VAX1.
Background for Danielle’s talk
Schizophrenia is characterized by positive and negative symptoms that include hallucinations, delusions and disorganized thought as well as flat affect and decreased speech. Genomic copy number variation (CNV) has been found to underlie and increase risk for a large number of neuropsychiatric disorders including schizophrenia. This project focuses on identification and characterization of pathogenic CNVs in a sample set of 457 schizophrenia patients and 290 psychiatrically healthy controls. To date, 181 probands and 141 controls have been genotyped using the Affymetrix Genome-Wide Human SNP 6.0 Arrays and analyzed for CNVs with Genotyping Console and CNAG. CNVs were compared between cases and controls and cross-referenced with the Database of Genomic Variants. The proximal arm of chromosome 15 contains canonical segmental duplications that predispose the region to CNV formation, but only recently have disease-associated CNVs been reported between the two most proximal breakpoints (BPs), BP1 and BP2. Here we report three case subjects that have a ~1Mb deletion of the BP1-BP2 region at chromosome 15q11.2. The BP1-BP2 deletion encompasses the four genes CYFIP1, NIPA1, NIPA2 and GCP5. The deletion is present in three probands, two were maternally inherited and none were found in controls. All CNVs of interest were validated by qPCR or NimbleGen 385K whole-genome array CGH. The four genes within the deletion have previous association with Prader Willi syndrome, Angleman syndrome, autism and schizophrenia and are often inherited from a mildly or unaffected parent. CYFIP1 is of primary interest due to its direct interaction with the Fragile X Mental Retardation Protein (FMRP) and its reported role in regulation of neuronal translation during brain development. NIPA1, NIPA2 and GCP5 are also expressed in the brain. It is a distinct possibility that in addition to the 15q11.2 deletion in probands, a “second CNV hit” contributes to disease pathology. Thus, the two probands with maternal inheritance of the deletion were further analyzed for sporadic secondary CNVs. For example, a de novo duplication of four exons of ATXN2 as well as a de novo deletion of the promoter and the first three exons in SYN3, a gene with previous association with schizophrenia, was called in one proband. In the second family the proband had an additional de novo duplication of two exons in two synapse-associated genes CACNA1B and DLGAP2 as well as a de novo intronic duplication of SYN3.