The genetics of dementia

Over the past decade, there has been a dramatic evolution of genetic methodologies that can be used to identify genes contributing to disease. Initially, the focus was primarily on classical linkage analysis; more recently, genomewide association studies, and high-throughput whole genome and whole exome sequencing have provided efficient approaches to detect common and rare variation contributing to disease risk. Application of these methodologies to dementias has led to the nomination of dozens of causative and susceptibility genes, solidifying the recognition that genetic factors are important contributors to the disease processes. In this review, the authors focus on current knowledge of the genetics of Alzheimer's disease and frontotemporal lobar degeneration. A working understanding of the genes relevant to common dementias will become increasingly critical, as options for genetic testing and eventually gene-specific therapeutics are developed

Familial Studies in Whole Exome and Genome Sequencing

Indiana University-Purdue University Indianapolis (IUPUI)Population genetics has been revolutionized by the advent of high-throughput sequencing (HTS) methods in the 21st century. Modern day sequencers are now capable of sequencing entire exomes and genomes at unprecedented speed and accuracy. An explosion of bioinformatics software and data analysis tools now makes sequencing accessible for gene discovery in both rare Mendelian and complex disease. Family-based sequencing studies in particular have great potential for elucidating the genetic basis for many more diseases. We apply both whole exome and genome sequencing to three different cases of familial disease: intracranial aneurysm (IA), Parkinson disease (PD), and X-linked ataxia dementia (XLAD). IA and PD are both common, complex traits that inflict a devastating disease burden worldwide, mostly due to few effective therapeutic interventions. Little of the heritability of both IA and PD has been explained to date, especially as it relates to the impact of rare variation on disease. XLAD is an extremely rare neurological disease described thus far in one kindred. Although promising results have been achieved through previous genetic study designs, the causative gene has not yet been identified. For all three diseases, HTS offers an opportunity to explore the role of rare variation in disease pathogenesis. In each study, we explore the opportunities and challenges of family-based HTS for different disease models. The work presented herein contributes effective practices for study design, analysis, and interpretation in a rapidly growing field still replete with questions about how best to implement HTS in studying familial disease

Ultrasonographic assessment of costochondral cartilage for microtia reconstruction

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149363/1/lary27390_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149363/2/lary27390.pd

PRIORITIZATION OF RESULTS FROM WHOLE EXOME SEQUENCING IN FAMILIAL INTRACRANIAL ANEURYSM

poster abstractWhole exome sequencing (WES) is an innovative approach to identifying rare variants associated with disease; however, reducing the large number of variants to a useful set of candidate genes is challenging. We developed a ranking system utilizing data from a previous genome-wide linkage analysis and various bioinformatics databases to prioritize the results of WES from families having multiple members with intracranial aneurysms. WES was performed in 35 affected individuals and 10 unaffected individ-uals across 7 families. All samples were genotyped (Illumina® OmniExpress) and sequenced (Agilent© SureSelect™ 50Mb Human All Exon Kit). Linkage analysis (Illumina 6K) was previously performed using autosomal domi-nant/recessive modes of inheritance. Application of quality filters resulted in 91,659 single nucleotide variants (SNVs). Nonsynonymous SNVs within an exon having an allele frequency of <3% were retained. Further filtering was performed based on Mendelian in-heritance (autosomal dominant or recessive). A ranking system prioritized retained variants based on the inheritance pattern specific to each family, occurrence in multiple families, relation to pathways and genes of interest, degree of penetrance, presence within a linkage peak, and whether the re-sultant proteins were predicted to be deleterious. Out of a 9-point score, 292 variants in 190 genes received scores of at least 5. Of these, 14 variants in 10 genes met the majority of prioritization criteria by achieving scores of over 7. While several WES studies have been successful at identifying genes im-portant to rare diseases, few have examined how to produce a list of candi-date genes contributing to a complex disease from WES data. We show that a ranking system that combines WES with bioinformatics resources and link-age data is a powerful approach to prioritize candidate genes for a complex disease like familial intracranial aneurysms. Subsequent studies are required to validate the utility of this approach

Whole-Exome Sequencing in Familial Parkinson Disease

IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained. Genes with retained variants were prioritized if expressed in the brain and located within PD-relevant pathways. Genes in which prioritized variants were observed in at least 4 families were selected as candidate genes for replication in the replication cohort. The setting was among individuals with familial PD enrolled from academic movement disorder specialty clinics across the United States. All participants had a family history of PD. MAIN OUTCOMES AND MEASURES: Identification of genes containing rare, likely deleterious, genetic variants in individuals with familial PD using a 2-stage exome sequencing study design. RESULTS: The 93 individuals from 32 families in the discovery cohort (49.5% [46 of 93] female) had a mean (SD) age at onset of 61.8 (10.0) years. The 49 individuals with familial PD in the replication cohort (32.6% [16 of 49] female) had a mean (SD) age at onset of 50.1 (15.7) years. Discovery cohort recruitment dates were 1999 to 2009, and replication cohort recruitment dates were 2003 to 2014. Data analysis dates were 2011 to 2015. Three genes containing a total of 13 rare and potentially damaging variants were prioritized in the discovery cohort. Two of these genes (TNK2 and TNR) also had rare variants that were predicted to be damaging in the replication cohort. All 9 variants identified in the 2 replicated genes in 12 families across the discovery and replication cohorts were confirmed via Sanger sequencing. CONCLUSIONS AND RELEVANCE: TNK2 and TNR harbored rare, likely deleterious, variants in individuals having familial PD, with similar findings in an independent cohort. To our knowledge, these genes have not been previously associated with PD, although they have been linked to critical neuronal functions. Further studies are required to confirm a potential role for these genes in the pathogenesis of PD

AluY-mediated germline deletion, duplication and somatic stem cell reversion in <i>UBE2T</i> defines a new subtype of Fanconi anemia

Fanconi anemia (FA) is a rare inherited disorder clinically characterized by congenital malformations, progressive bone marrow failure and cancer susceptibility. At the cellular level, FA is associated with hypersensitivity to DNA-crosslinking genotoxins. Eight of 17 known FA genes assemble the FA E3 ligase complex, which catalyzes monoubiquitination of FANCD2 and is essential for replicative DNA crosslink repair. Here, we identify the first FA patient with biallelic germline mutations in the ubiquitin E2 conjugase UBE2T. Both mutations were aluY-mediated: a paternal deletion and maternal duplication of exons 2-6. These loss-of-function mutations in UBE2T induced a cellular phenotype similar to biallelic defects in early FA genes with the absence of FANCD2 monoubiquitination. The maternal duplication produced a mutant mRNA that could encode a functional protein but was degraded by nonsense-mediated mRNA decay. In the patient's hematopoietic stem cells, the maternal allele with the duplication of exons 2-6 spontaneously reverted to a wild-type allele by monoallelic recombination at the duplicated aluY repeat, thereby preventing bone marrow failure. Analysis of germline DNA of 814 normal individuals and 850 breast cancer patients for deletion or duplication of UBE2T exons 2-6 identified the deletion in only two controls, suggesting aluY-mediated recombinations within the UBE2T locus are rare and not associated with an increased breast cancer risk. Finally, a loss-of-function germline mutation in UBE2T was detected in a high-risk breast cancer patient with wild-type BRCA1/2. Cumulatively, we identified UBE2T as a bona fide FA gene (FANCT) that also may be a rare cancer susceptibility gene.</p

Genome Stability of Lyme Disease Spirochetes: Comparative Genomics of Borrelia burgdorferi Plasmids

Lyme disease is the most common tick-borne human illness in North America. In order to understand the molecular pathogenesis, natural diversity, population structure and epizootic spread of the North American Lyme agent, Borrelia burgdorferi sensu stricto, a much better understanding of the natural diversity of its genome will be required. Towards this end we present a comparative analysis of the nucleotide sequences of the numerous plasmids of B. burgdorferi isolates B31, N40, JD1 and 297. These strains were chosen because they include the three most commonly studied laboratory strains, and because they represent different major genetic lineages and so are informative regarding the genetic diversity and evolution of this organism. A unique feature of Borrelia genomes is that they carry a large number of linear and circular plasmids, and this work shows that strains N40, JD1, 297 and B31 carry related but non-identical sets of 16, 20, 19 and 21 plasmids, respectively, that comprise 33–40% of their genomes. We deduce that there are at least 28 plasmid compatibility types among the four strains. The B. burgdorferi ∼900 Kbp linear chromosomes are evolutionarily exceptionally stable, except for a short ≤20 Kbp plasmid-like section at the right end. A few of the plasmids, including the linear lp54 and circular cp26, are also very stable. We show here that the other plasmids, especially the linear ones, are considerably more variable. Nearly all of the linear plasmids have undergone one or more substantial inter-plasmid rearrangements since their last common ancestor. In spite of these rearrangements and differences in plasmid contents, the overall gene complement of the different isolates has remained relatively constant

Otolaryngology Curriculum During Residency Preparation Course Improves Preparedness for Internship

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168319/1/lary29443_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168319/2/lary29443.pd