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.

Project description:The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.

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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