Dataset Information

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database.

ABSTRACT: The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n=18) or to cause erroneous splicing (n=7), with the exception of a pathogenic de novo 24?bp intronic deletion. Second, 41 unclassified variants, including 28 novel, were subjected to analysis by these tools. At least four splice-site analysis tools predicted that three of the variants would affect splicing as the mutations disrupted the canonical splice site. Urinary creatine/creatinine and brain MRS confirmed creatine transporter deficiency in five patients (four families), including one female. Another variant was predicted to moderately affect splicing by all five tools. However, transient transfection of a minigene containing the variant in a partial SLC6A8 segment showed no splicing errors, and thus was finally classified as non-disease causing. This study shows that splice tools are useful for the characterization of the majority of variants, but also illustrates that the actual effect can be misclassified in rare occasions. Therefore, further laboratory studies should be considered before final conclusions on the disease-causing nature are drawn. To provide an accessible database, the 109 currently known SLC6A8 variants, including 35 novel ones, are included in a newly developed LOVD DNA variation database.

SUBMITTER: Betsalel OT

PROVIDER: S-EPMC3039501 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database.

Betsalel Ofir T OT Rosenberg Efraim H EH Almeida Ligia S LS Kleefstra Tjitske T Schwartz Charles E CE Valayannopoulos Vassili V Abdul-Rahman Omar O Poplawski Nicola N Vilarinho Laura L Wolf Philipp P den Dunnen Johan T JT Jakobs Cornelis C Salomons Gajja S GS

European journal of human genetics : EJHG 20100818 1

The X-linked creatine transporter defect is caused by mutations in the SLC6A8 gene. Until now, 66 synonymous and intronic variants in SLC6A8 were detected in our laboratory. To gain more insight in the effect of the detected variants, we applied five free web-based splice-site analysis tools to 25 published variants that were stratified as (non-)disease causing. All were correctly predicted to have no effect (n=18) or to cause erroneous splicing (n=7), with the exception of a pathogenic de novo ...[more]

PMID: 20717164

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Project description:Implementation outcome measures are essential for monitoring and evaluating the success of implementation efforts. Yet, currently available measures lack conceptual clarity and have largely unknown reliability and validity. This study developed and psychometrically assessed three new measures: the Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM), and Feasibility of Intervention Measure (FIM).Thirty-six implementation scientists and 27 mental health professionals assigned 31 items to the constructs and rated their confidence in their assignments. The Wilcoxon one-sample signed rank test was used to assess substantive and discriminant content validity. Exploratory and confirmatory factor analysis (EFA and CFA) and Cronbach alphas were used to assess the validity of the conceptual model. Three hundred twenty-six mental health counselors read one of six randomly assigned vignettes depicting a therapist contemplating adopting an evidence-based practice (EBP). Participants used 15 items to rate the therapist's perceptions of the acceptability, appropriateness, and feasibility of adopting the EBP. CFA and Cronbach alphas were used to refine the scales, assess structural validity, and assess reliability. Analysis of variance (ANOVA) was used to assess known-groups validity. Finally, half of the counselors were randomly assigned to receive the same vignette and the other half the opposite vignette; and all were asked to re-rate acceptability, appropriateness, and feasibility. Pearson correlation coefficients were used to assess test-retest reliability and linear regression to assess sensitivity to change.All but five items exhibited substantive and discriminant content validity. A trimmed CFA with five items per construct exhibited acceptable model fit (CFI = 0.98, RMSEA = 0.08) and high factor loadings (0.79 to 0.94). The alphas for 5-item scales were between 0.87 and 0.89. Scale refinement based on measure-specific CFAs and Cronbach alphas using vignette data produced 4-item scales (?'s from 0.85 to 0.91). A three-factor CFA exhibited acceptable fit (CFI = 0.96, RMSEA = 0.08) and high factor loadings (0.75 to 0.89), indicating structural validity. ANOVA showed significant main effects, indicating known-groups validity. Test-retest reliability coefficients ranged from 0.73 to 0.88. Regression analysis indicated each measure was sensitive to change in both directions.The AIM, IAM, and FIM demonstrate promising psychometric properties. Predictive validity assessment is planned.

Dataset Information

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database.

Publications

Characterization of novel SLC6A8 variants with the use of splice-site analysis tools and implementation of a newly developed LOVD database.

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