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Diagnosis andtreatment ofdementia: 3. Mildcognitive impairmentand cognitiveimpairment withoutdementia Howard ChertkowFadi MassoudZiad Nasreddine2008 год

Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia
review

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Аннотация:

Background

Clinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants.

Methods and results

223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%).

Conclusions

This study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.
Год издания: 2008
Авторы: Howard Chertkow, Fadi Massoud, Ziad Nasreddine, Sylvie Belleville, Yves Joanette, Christian Bocti, Valérie Drolet, John Kirk, Morris Freedman, Howard Bergman
Издательство: Canadian Medical Association
Источник: Canadian Medical Association Journal
Ключевые слова: Dementia and Cognitive Impairment Research, Diet and metabolism studies, Neurological Disease Mechanisms and Treatments
Другие ссылки: Canadian Medical Association Journal (PDF)
Canadian Medical Association Journal (HTML)
Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)