Recurrent and Founder Mutations in the Netherlands: the Long-QT Syndrome*

Hofman, Nynke; Jongbloed, Roselie; Postema, Pieter G.; Nannenberg, Eline A.; Alders, Mariëlle; Wilde, Arthur A.M.

doi:10.1007/978-90-368-0705-0_3

Cited by 1 publication

(2 citation statements)

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“…Three MYBPC3 mutations, the risk haplotype on chromosome 7 associated with idiopathic ventricular fibrillation, several recurrent mutations in LQTS, and a PLN mutation demonstrated a founder effect. [22][23][24][25][26][27][28] Thirty-three percent (747/2241) of all positively genotyped individuals carried 1 of these founder mutations. Testing for the risk haplotype on chromosome 7 had the largest impact, yielding an average of 7.9 mutation-positive subjects per family.…”

Section: Resultsmentioning

confidence: 99%

“…8,33,34 Through phenotype-directed DNA testing of patients with a (probable) inherited disease, we discovered a substantial number of recurrent or founder mutations, that is, mutations arising from a common ancestor, often many generations ago. [22][23][24][25][26]28 Phenotype-genotype studies in these large founder families have not only aided us in developing risk stratification and treatment strategies in the involved families 22 but have also allowed us to obtain novel insights into the role of the aberrant gene product and the molecular basis of SCD in general, sometimes through the construction of transgenic mouse models. 35 Large founder families are of particular interest because the relative homogeneity of the genetic substrate (identical primary mutation) is likely to increase the power of studies that aim to identify gene variants that modify the phenotype (genetic modifiers).…”

Section: Discussionmentioning

confidence: 99%

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Yield of Molecular and Clinical Testing for Arrhythmia Syndromes

et al. 2013

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Background-Sudden cardiac death is often caused by inherited arrhythmia syndromes, particularly if it occurs at a young age. In 1996, we started a cardiogenetics clinic aimed at diagnosing such syndromes and providing timely (often presymptomatic) treatment to families in which such syndromes or sudden cardiac death existed. We studied the yield of DNA testing for these syndromes using a candidate-gene approach over our 15 years of experience. Methods and Results-We analyzed the yield of DNA testing. In subanalyses, we studied differences in the yield of DNA testing over time, between probands with isolated or familial cases and between probands with or without clear disease-specific clinical characteristics. In cases of sudden unexplained death (antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiological investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (aged 41±19 years; 49% male) were analyzed. In 702 families (31%), a possible disease-causing mutation was detected. Most mutations were found in families with long-QT syndrome (47%) or hypertrophic cardiomyopathy (46%). Cascade screening revealed 1539 mutation-positive subjects. The mutation detection rate decreased over time, in part because probands with a less severe phenotype were studied, and was significantly higher in familial than in isolated cases. We counseled 372 families after sudden unexplained death; in 29% of them (n=108), an inherited arrhythmia syndrome was diagnosed. Conclusions-The proportion of disease-causing mutations found decreased over time, in part because probands with a less severe phenotype were studied. Systematic screening of families identified many (often presymptomatic) mutationpositive subjects.

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