Dataset Information

Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription.

ABSTRACT: BACKGROUND:The deletion of the distal 7q region is a rare chromosomal syndrome characterized by wide phenotypic manifestations including growth and psychomotor delay, facial dysmorphisms, and genitourinary malformations. METHODS:We describe a 6-year-old child with a 12-Mb deletion of the region 7q35q36.3. RESULTS:Among the deleted genes, two genes have cardiac implications: PRKAG2 (OMIM #602743), associated with hypertrophic cardiomyopathy, cardiac conduction disease, and sudden death, and KCNH2 (OMIM #152427), coding for a cardiac potassium channel involved in long QT syndrome, unmasked by the chlorpheniramine treatment. At same time, the SHH gene (OMIM #600725), encoding sonic hedgehog, a secreted protein that is involved in the embryonic development, is deleted. CONCLUSION:Our report underlines potential cardiac complications linked to the common pharmacological treatment in this rare multiorgan and proteiform disease.

SUBMITTER: Di Stolfo G

PROVIDER: S-EPMC6732270 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription.

Di Stolfo Giuseppe G Accadia Maria M Mastroianno Sandra S Leone Maria P MP Palumbo Orazio O Palumbo Pietro P Potenza Domenico D Maccarone Pasquale P Sacco Michele M Russo Aldo A Carella Massimo M

Molecular genetics & genomic medicine 20190725 9

<h4>Background</h4>The deletion of the distal 7q region is a rare chromosomal syndrome characterized by wide phenotypic manifestations including growth and psychomotor delay, facial dysmorphisms, and genitourinary malformations.<h4>Methods</h4>We describe a 6-year-old child with a 12-Mb deletion of the region 7q35q36.3.<h4>Results</h4>Among the deleted genes, two genes have cardiac implications: PRKAG2 (OMIM #602743), associated with hypertrophic cardiomyopathy, cardiac conduction disease, and s ...[more]

PMID: 31347270

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Project description:BackgroundThe proliferation of genetic profiling has revealed many associations between genetic variations and disease. However, large-scale phenotyping efforts in largely healthy populations, coupled with DNA sequencing, suggest variants currently annotated as pathogenic are more common in healthy populations than previously thought. In addition, novel and rare variants are frequently observed in genes associated with disease both in healthy individuals and those under suspicion of disease. This raises the question of whether these variants can be useful predictors of disease. To answer this question, we assessed the degree to which the presence of a variant in the cardiac potassium channel gene KCNH2 was diagnostically predictive for the autosomal dominant long QT syndrome.MethodsWe estimated the probability of a long QT diagnosis given the presence of each KCNH2 variant using Bayesian methods that incorporated variant features such as changes in variant function, protein structure, and in silico predictions. We call this estimate the posttest probability of disease. Our method was applied to over 4000 individuals heterozygous for 871 missense or in-frame insertion/deletion variants in KCNH2 and validated against a separate international cohort of 933 individuals heterozygous for 266 missense or in-frame insertion/deletion variants.ResultsOur method was well-calibrated for the observed fraction of heterozygotes diagnosed with long QT syndrome. Heuristically, we found that the innate diagnostic information one learns about a variant from 3-dimensional variant location, in vitro functional data, and in silico predictors is equivalent to the diagnostic information one learns about that same variant by clinically phenotyping 10 heterozygotes. Most importantly, these data can be obtained in the absence of any clinical observations.ConclusionsWe show how variant-specific features can inform a prior probability of disease for rare variants even in the absence of clinically phenotyped heterozygotes.

Dataset Information

Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription.

Publications

Long QT syndrome in chromosome 7q35q36.3 deletion involving KCNH2 gene: Warning for chlorpheniramine prescription.

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