During the previous two decades it has become apparent that genomic rearrangements are often the type of mutation that underlies neurological disease. This is so not only for neurodevelopmental disorders such as intellectual disability (ID) and different recognizable patterns of human malformation (e.g., Potocki-Lupski syndrome), but also for late-onset adult neurological disorders such as Charcot-Marie-Tooth disease. Moreover, genomic rearrangement can often underlie complex traits and sporadic diseases such as Parkinson?s, Alzheimer?s disease and other neurodegenerative processes. Contrary to prior interpretations, experimental evaluation of disease associated genomic rearrangements has often documented that they can be much more complex than anticipated. Complexities can occur at individual loci and give specific patterns for complex genomic rearrangements (CGR) as observed on genome-wide array CGH; such as duplication-normal-duplication (DUP-NML-DUP), or a triplication embedded within duplications (DUP-TRP-DUP). Furthermore, complexities can occur on a genomic level leading to complex chromosomal rearrangements (CCR) and the phenomena of chromothripsis observed both in cancer and neurodevelopmental disorders, as well as an unusual experimentally observed pattern of multiple de novo copy number variants (CNVs) spread apparently randomly throughout the genome. The elucidation of mechanisms that can generate such complexities is an emerging field. We propose to further characterize CGR that have been found in association with neurological disease. Specifically, we will investigate: 1) CGRs that consists of: i) a DUP-NML-DUP pattern and ii) a pattern of a triplicated segment in inverse orientation embedded within a duplicated segment of the genome (DUP-TRP/INV-DUP); these are newly observed types of CGR with one proposed mechanism elucidated in our previous application; 2) The mechanism for recurrent triplications; 3) Elucidate the underlying molecular characteristics and breakpoint junctions of CGR that are accompanied by long genomic stretches of absence of heterozygosity (AOH), and resulting in both genomic (CGR) and genetic (AOH) alterations; 4) Alu-Alu rearrangements and their role in genomic instability and disease and 5) We will attempt to isolate a gene important to the phenomena of multiple de novo CNV seemingly randomly distributed throughout the genome. The experimental approaches to be utilized to accomplish each one of these specific aims are now within our reach. These studies predominately require genomic approaches that enable genomewide assays of variation such as array comparative genomic hybridization, genomewide SNP chips, whole exome sequencing (WES), whole genome sequencing (WGS), and other mapping and molecular approaches for the delineation of specific breakpoint junctions. It is anticipated these studies will characterize these novel types of rearrangements and lend further insight into basic molecular mutational mechanisms driving gene and genome evolution and that can cause the myriad of neurological diseases.
The project will provide new insights into mechanisms underlying complex genomic changes resulting from DNA rearrangements - a common cause of neurological disease. This will enable better diagnostics and potential new avenues for therapy by the correction of gene dosage further supporting the Precision Medicine Initiative. Such genomic rearrangements cause gene copy number variations resulting in neurodevelopmental disorders including intellectual disability, behavioral disorders such as autism, psychiatric conditions such as schizophrenia, and neurodegenerative diseases such as Alzheimer?s, Parkinson?s and Charcot-Marie-Tooth disorders.
|Punetha, Jaya; Mackay-Loder, Loren; Harel, Tamar et al. (2018) Identification of a pathogenic PMP2 variant in a multi-generational family with CMT type 1: Clinical gene panels versus genome-wide approaches to molecular diagnosis. Mol Genet Metab 125:302-304|
|Karaca, Ender; Posey, Jennifer E; Coban Akdemir, Zeynep et al. (2018) Phenotypic expansion illuminates multilocus pathogenic variation. Genet Med :|
|Poli, M Cecilia; Ebstein, Frédéric; Nicholas, Sarah K et al. (2018) Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome. Am J Hum Genet 102:1126-1142|
|Wiszniewski, Wojciech; Gawlinski, Pawel; Gambin, Tomasz et al. (2018) Comprehensive genomic analysis of patients with disorders of cerebral cortical development. Eur J Hum Genet 26:1121-1131|
|Coban-Akdemir, Zeynep; White, Janson J; Song, Xiaofei et al. (2018) Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles. Am J Hum Genet 103:171-187|
|Song, Xiaofei; Beck, Christine R; Du, Renqian et al. (2018) Predicting human genes susceptible to genomic instability associated with Alu/Alu-mediated rearrangements. Genome Res 28:1228-1242|
|Yuan, Bo; Neira, Juanita; Pehlivan, Davut et al. (2018) Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies. Genet Med :|
|Liu, Jiaqi; Zhou, Yangzhong; Liu, Sen et al. (2018) The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease. Hum Genet 137:553-567|
|Grochowski, Christopher M; Gu, Shen; Yuan, Bo et al. (2018) Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. Hum Mutat 39:939-946|