KBTBD13 is a novel cardiomyopathy gene.

KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions.

BACKGROUND: Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure. METHODS: Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible. RESULTS: Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0-187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives <40 years. CONCLUSIONS: During median follow-up of 16 years, 60.0% of relatives attended genetic counseling, with 41.0% in the first year. Our results may suggest that some relatives are not or inadequately informed or that barriers against genetic counseling are present. Further research is needed into interventions facilitating family communication, increasing awareness among families and healthcare professionals, and lowering thresholds for genetic counseling.

Family letters are an effective way to inform relatives about inherited cardiac disease.

Increasing numbers of individuals are being referred to cardiogenetics outpatient clinics with potentially inherited arrhythmia (ARR) or cardiomyopathy (CM). To inform relatives at-risk, we ask index patients to distribute "family letters" containing information on the risks, possible genetic and other screenings, and preventive options. We assessed the responses to these letters in terms of referrals to a cardiologist and/or clinical geneticist. Fifty-six index patients were asked to distribute 249 family letters: 85 in the ARR group and 164 in the CM group. Within a mean follow-up period of 2 years (range 1-5 years) the number of relatives actually referred to the clinical geneticist and/or cardiologist was 57% (142 of 249). There was a significant difference (P < 0.01) between the ARR (80%) and CM groups (45.1%). To verify the results obtained from our files at the cardiogenetics department we sent a questionnaire to 52 index patients (response 50%). This showed that 23/26 (88%) index patients had distributed the letters to their relatives and that for 19/23 index patients one or more relatives had been screened. This is comparable with our files, which showed that 57% of relatives of index patients with a potentially inherited cardiac disease underwent screening, particularly in the ARR group. The actual response was underestimated because some relatives were investigated elsewhere or may still decide to be screened in the future. We conclude that distributing family letters is an effective way to inform and encourage relatives to undergo screening for high-risk inherited cardiac disease.