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Assessment of functional effects of unclassified genetic variants.

ABSTRACT: Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been extensively characterized at the functional level, few assays based on functional properties of the encoded proteins have been established for the purpose of predicting the contribution of rare inherited variants to disease. Much of the difficulty in establishing predictive functional assays stems from the technical complexity of the assays. However, perhaps the most challenging aspect of functional assay development for clinical testing purposes is the absolute requirement for validation of the sensitivity and specificity of the assays and the determination of positive predictive values (PPVs) and negative predictive values (NPVs) of the assays relative to a "gold standard" measure of disease predisposition. In this commentary, we provide examples of some of the functional assays under development for several cancer predisposition genes (BRCA1, BRCA2, CDKN2A, and mismatch repair [MMR] genes MLH1, MSH2, MSH6, and PMS2) and present a detailed review of the issues associated with functional assay development. We conclude that validation is paramount for all assays that will be used for clinical interpretation of inherited variants of any gene, but note that in certain circumstances information derived from incompletely validated assays may be valuable for classification of variants for clinical purposes when used to supplement data derived from other sources.

SUBMITTER: Couch FJ

PROVIDER: S-EPMC2771414 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Assessment of functional effects of unclassified genetic variants.

Couch Fergus J FJ Rasmussen Lene Juel LJ Hofstra Robert R Monteiro Alvaro N A AN Greenblatt Marc S MS de Wind Niels N

Human mutation 20081101 11

Inherited predisposition to disease is often linked to reduced activity of a disease associated gene product. Thus, quantitation of the influence of inherited variants on gene function can potentially be used to predict the disease relevance of these variants. While many disease genes have been extensively characterized at the functional level, few assays based on functional properties of the encoded proteins have been established for the purpose of predicting the contribution of rare inherited ...[more]

PMID: 18951449

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Project description:Primary progressive aphasia, a neurodegenerative syndrome, presents mainly with language impairment. Both semantic and logopenic variants are fluent variants of primary progressive aphasia. Before the research criteria of primary progressive aphasia were proposed, progressive fluent aphasias, such as progressive anomic aphasia, transcortical sensory aphasia and Wernicke's aphasia, were reported as classical progressive fluent aphasias seen in Alzheimer's disease. However, since the research criteria of primary progressive aphasia were established, classical fluent variants (other than semantic and logopenic variants) have been neglected and have not been included in the current classification of primary progressive aphasia. This study aimed to determine whether unclassified fluent variants (other than semantic and logopenic variants) can be manifestations of primary progressive aphasia. This study also reconfirmed the characteristics of classical progressive fluent aphasia, such as progressive anomic aphasia, progressive transcortical sensory aphasia and progressive Wernicke's aphasia as unclassified fluent variants of primary progressive aphasia, using comparison with the current model of primary progressive aphasia. Twelve consecutive patients with an unclassified fluent variant other than semantic or logopenic variant underwent language, neurological, neuropsychological and neuroimaging (MRI and single-photon emission computed tomography) testing. Based on comprehensive language tests, we redefined the diagnoses as primary progressive anomic aphasia (n = 8), primary progressive transcortical sensory aphasia (n = 3) and primary progressive Wernicke's aphasia (n = 1). Anomic aphasia was characterized by anomia but preserved repetition and comprehension; transcortical sensory aphasia by relatively preserved repetition but poor word comprehension; and Wernicke's aphasia by poor repetition and word comprehension. In patients with anomic aphasia, voxel-based morphometry of MRI data revealed cortical atrophy, which was most prominent in the temporoparietal lobes, with no obvious lateralization; in two-thirds of patients with transcortical sensory aphasia and in one patient with Wernicke's aphasia, it revealed atrophy, predominantly in the left temporoparietal lobe. Statistical analysis of single-photon emission computed tomography using three-dimensional stereotactic surface projections revealed patterns of left-sided hypoperfusion in the majority of patients. The temporal and parietal lobes were involved in all cases; the degree of hypoperfusion was higher in patients with transcortical sensory aphasia or Wernicke's aphasia than in patients with anomic aphasia. The present study demonstrated the clinical and imaging features of 12 patients with an unclassified fluent variant of primary progressive aphasia, which we redefined as primary progressive anomic aphasia, primary progressive transcortical sensory aphasia and primary progressive Wernicke's aphasia. Classical fluent variants other than semantic and logopenic variants can be found in primary progressive aphasia.

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Assessment of functional effects of unclassified genetic variants.

Publications

Assessment of functional effects of unclassified genetic variants.

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