Clinical Neurological Sciences Articles Copyright (c) 2013 Royal College of Surgeons in Ireland All rights reserved. http://epubs.rcsi.ie/clinneursciart Recent documents in Clinical Neurological Sciences Articles en-us Sat, 26 Jan 2013 22:21:24 PST 3600 Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD. http://epubs.rcsi.ie/clinneursciart/2 http://epubs.rcsi.ie/clinneursciart/2 Mon, 12 Dec 2011 05:08:23 PST BACKGROUND: A new locus for amyotrophic lateral sclerosis--frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p.

METHODS: We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus.

RESULTS: Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples.

CONCLUSION: Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.

]]> Parastoo Momeni et al. Amyotrophic Lateral Sclerosis Base Sequence Chromosome Aberrations Chromosome Mapping Chromosomes, Human, Pair 9 Dementia Genetic Predisposition to Disease Heterozygote Humans Male Middle Aged Molecular Sequence Data Mutation North America Polymorphism, Single Nucleotide Prevalence Risk Assessment Risk Factors Sequencing and analysis of an Irish human genome http://epubs.rcsi.ie/clinneursciart/1 http://epubs.rcsi.ie/clinneursciart/1 Tue, 22 Feb 2011 07:33:57 PST BACKGROUND: Recent studies generating complete human sequences from Asian, African and European subgroups have revealed population-specific variation and disease susceptibility loci. Here, choosing a DNA sample from a population of interest due to its relative geographical isolation and genetic impact on further populations, we extend the above studies through the generation of 11-fold coverage of the first Irish human genome sequence. RESULTS: Using sequence data from a branch of the European ancestral tree as yet unsequenced, we identify variants that may be specific to this population. Through comparisons with HapMap and previous genetic association studies, we identified novel disease-associated variants, including a novel nonsense variant putatively associated with inflammatory bowel disease. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. This analysis has implications for future re-sequencing studies and validates the imputation of Irish haplotypes using data from the current Human Genome Diversity Cell Line Panel (HGDP-CEPH). Finally, we identify gene duplication events as constituting significant targets of recent positive selection in the human lineage. CONCLUSIONS: Our findings show that there remains utility in generating whole genome sequences to illustrate both general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that even armed with the resources of a small research group a number of similar initiatives geared towards answering specific biological questions will emerge.

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