Chromosome 1q21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease

Christiansen, Jesse; Dyck, John D.; Elyas, Basil G.; Lilley, Margaret; Bamforth, J.; Hicks, Matt; Sprysak, Kathleen A.; Tomaszewski, Robert; Haase, Shelagh; Vicen-Wyhony, Leanne M.; Somerville, Martin J.

doi:10.1161/01.res.0000130528.72330.5c

Cited by 139 publications

(114 citation statements)

References 37 publications

(34 reference statements)

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“…Additional testing, including DNA methylation analysis for Angelman syndrome, was normal. Deletions involving 1q21.1 have been identified in several probands with congenital heart defects, 46 but may also be a normal copy number variant. 23,47 For this reason, the identification of the genomic rearrangement in this patient was not included in the overall positive yield.…”

Section: Results Of Genetic Testingmentioning

confidence: 99%

Genetic testing in autism: how much is enough?

Herman

Henninger

Ratliff-Schaub

et al. 2007

Genetics in Medicine

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Purpose: To evaluate the yield of genetic testing in children with autism spectrum disorders. Methods: We performed a retrospective chart review of 71 unrelated patients with a diagnosis of an isolated autism spectrum disorder seen in a genetics clinic over a period of 14 months. For most, referrals occurred after evaluation by a developmental pediatrician and/or psychologist to establish the diagnosis. Tiered laboratory testing for the majority of the patients followed a guideline that was developed in collaboration with clinicians at The Autism Center at Children's Hospital, Columbus, OH. Results: The patients included 57 males and 14 females; 57 met DSM-IV criteria for autism, with the rest being Asperger or pervasive developmental disorder not otherwise specified.

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Section: Results Of Genetic Testingmentioning

confidence: 99%

Genetic testing in autism: how much is enough?

Herman

Henninger

Ratliff-Schaub

et al. 2007

Genetics in Medicine

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“…First, it is well known that gap junction channels play critical roles during cardiovascular morphogenesis (10)(11)(12)(13)(14) and loss of Cx43 in the developing ventricular myocardium could conceivably influence the patterning of the underlying Purkinje fiber network, thereby providing an anatomic basis for the aberrant activation patterns. To explore this possibility, we crossed the OCKO mice with the CCS-lacZ reporter strain, in which a ␤-galactosidase transgene is specifically expressed throughout the murine specialized cardiac conduction system, including the distal Purkinje fiber network (15).…”

Section: Resultsmentioning

confidence: 99%

Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation

Morley

Danik

Bernstein

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Ventricular tachycardia is a common heart rhythm disorder and a frequent cause of sudden cardiac death. Aberrant cell-cell coupling through gap junction channels, a process termed gap junction remodeling, is observed in many of the major forms of human heart disease and is associated with increased arrhythmic risk in both humans and in animal models. Genetically engineered mice with cardiac-restricted knockout of Connexin43, the major cardiac gap junctional protein, uniformly develop sudden cardiac death, although a detailed electrophysiological understanding of their profound arrhythmic propensity is unclear. Using voltage-sensitive dyes and high resolution optical mapping techniques, we found that uncoupling of the ventricular myocardium results in ectopic sites of ventricular activation. Our data indicate that this behavior reflects alterations in source-sink relationships and paradoxical conduction across normally quiescent Purkinje-ventricular muscle junctions. The aberrant activation profiles are associated with wavefront collisions, which in the setting of slow conduction may account for the highly arrhythmogenic behavior of Connexin43-deficient hearts. Thus, the extent of gap junction remodeling in diseased myocardium is a critical determinant of cardiac excitation patterns and arrhythmia susceptibility.arrhythmia ͉ connexin43 ͉ Purkinje fiber ͉ transgenic ͉ optical mapping E lectrical uncoupling of the murine heart by cardiac-restricted inactivation of the Connexin43 (Cx43) gap junction channel gene results in slowing of ventricular conduction velocity (CV), spontaneous ventricular arrhythmias, and sudden cardiac death (1). However, the early mortality in these conditional knockout (CKO) mice complicated mechanistic studies of arrhythmia initiation and maintenance. Therefore, by selectively breeding longer-term survivors, we recently established a subline of conditional knockout mice, termed OCKO mice, in which the Cre-dependent inactivation of Cx43 in the myocardium was temporally delayed and death from ventricular arrhythmias, although still inevitable, was correspondingly delayed on average by about a month (2). ECGs in OCKO mice during the weeks preceding their demise demonstrated that all were in normal sinus rhythm (NSR), but, surprisingly, unlike control mice, they displayed a progressive reduction in the amplitude of the QRS complex, a time-and voltage-dependent signal indicative of myocardial depolarization (2). The aim of the current study was to investigate the mechanisms through which reductions in cell-cell coupling influence cardiac electrophysiological behavior and ultimately lead to the development of ventricular tachyarrhythmias. MethodsMice. Cardiac-restricted Cx43-mutant mice have been described, as have the derivative OCKO subline, obtained by selectively breeding longer-term survivors. The OCKO mice have progressive loss of Cx43 in the ventricular myocardium without compensatory changes in the abundance of either Cx45 or Cx40 (1, 2). Control mice did not carry the Cre recombinase tr...

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“…Sequencing results were aligned with the FECH and ALAS2 sequences in the National Center of Biotechnology Information (NCBI) database. One previous study (le Gac et al, 2008) identified a hemochromatosis woman who lost two HFE alleles and another study (Christiansen et al, 2004) demonstrated several congenital heart disease patients with chromosome 1q21.1 deletion via real-time PCR analysis. We next used the same method to investigate whether the observation is a result of FECH loci deletion.…”

Section: Methodsmentioning

confidence: 99%

Identification of FECH gene multiple variations in two Chinese patients with erythropoietic protoporphyria and a review

Long

Wang

Chen

et al. 2016

J. Zhejiang Univ. Sci. B

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Erythropoietic protoporphyria (EPP), an autosomal dominant disease, is caused by partial deficiency of ferrochelatase (FECH), which catalyzes the terminal step of heme biosynthesis because of loss-of-function mutations in the FECH gene. To date, only a few cases have been described in Asia. In this study, we describe the clinical features of two Chinese patients with EPP, with diagnosis confirmed by the increase of free protoporphyrin in erythrocytes, detection of plasma fluorescence peak at 630-634 nm, and analysis of FECH gene mutations. Using gene scanning, we identified a small deletion in the FECH gene (c.973 delA) in one proband (patient A) and a pathogenic FECH mutation (c.1232 G>T) in the other (patient B) and also observed some nucleotide variations (c.798 C>G, c.921 A>G, IVS1−23 C>T, IVS3+23 A>G, IVS9+35 C>T, and IVS3−48 T>C) in these patients. The family pedigree of patient A was then established by characterization of the genotype of the patient's relatives. We also analyzed the potential perniciousness of the missense mutation with bioinformatic software, Polyphen and Sift. In summary, Chinese EPP patients have similar manifestations to those of Caucasians, and identification of the Chinese FECH gene mutations expands the FECH genotypic spectrum and may contribute to genetic counseling.

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Chromosome 1q21.1 Contiguous Gene Deletion Is Associated With Congenital Heart Disease

Cited by 139 publications

References 37 publications

Genetic testing in autism: how much is enough?

Genetic testing in autism: how much is enough?

Reduced intercellular coupling leads to paradoxical propagation across the Purkinje-ventricular junction and aberrant myocardial activation

Identification of FECH gene multiple variations in two Chinese patients with erythropoietic protoporphyria and a review

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