Identification of Cadherin 2 (
            <i>CDH2</i>
            ) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy

Mayosi, Bongani M.; Fish, Maryam; Shaboodien, Gasnat; Mastantuono, Elisa; Kraus, Sarah; Wieland, Thomas; Kotta, Maria Christina; Chin, Ashley; Laing, Nakita; Ntusi, Ntobeko; Chong, Michael; Horsfall, Christopher; Pimstone, Simon N.; Gentilini, Davide; Parati, Gianfranco; Strom, Tim M.; Meitinger, Thomas; Paré, Guillaume; Schwartz, Peter J.; Crotti, Lia

doi:10.1161/circgenetics.116.001605

Cited by 130 publications

(103 citation statements)

References 43 publications

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“…Studies in mouse embryos have noted the importance of Cdh2 in the proper development of the heart, brain, and skeletal structures . The observed abnormalities of the cardiac outflow tract were consistent with the left‐sided cardiac phenotypes noted in the patients reported here as well as a previously published inherited novel splicing variant in a patient with a congenital left‐sided cardiac lesion; additionally, two novel missense variants within EC‐I and EC‐III were identified in patients with arrhythmogenic cardiomyopathy . In zebrafish, variants in the EC‐I or EC‐IV domains of cdh2 resulted in the glo , pac , and lyr phenotypes characterized by defects in the brain, somites and cardiac/circulatory system, along with retinal and lens defects .…”

Section: Discussionsupporting

confidence: 90%

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

et al. 2019

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Peters anomaly (PA) is a congenital corneal opacity associated with corneo‐lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA. Syndromic anomalies were seen in three individuals and included left‐sided cardiac lesions, dysmorphic facial features, and decreasing height percentiles; brain magnetic resonance imaging identified agenesis of the corpus callosum and hypoplasia of the inferior cerebellar vermis. CDH2 encodes for N‐cadherin, a transmembrane protein that mediates cell‐cell adhesion in multiple tissues. Immunostaining in mouse embryonic eyes confirmed N‐cadherin is present in the lens stalk at the time of separation from the future cornea and in the developing lens and corneal endothelium at later stages, supporting a possible role in PA. Previous studies in animal models have noted the importance of Cdh2/cdh2 in the development of the eye, heart, brain, and skeletal structures, also consistent with the patient features presented here. Examination of CDH2 in additional patients with PA is indicated to confirm this association.

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Section: Discussionsupporting

confidence: 90%

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

et al. 2019

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“…The third was his establishment of “genetic studies of cardiomyopathy and familial fibrosis, which have led to the discovery of novel biological mechanisms of heart disease and fibrosis.”6…”

Section: Research and Evidencementioning

confidence: 99%

Bongani Mayosi: renowned cardiologist and visionary medical researcher

Stafford¹

2018

BMJ

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“…In most cases, ACM are inherited in an autosomal dominant pattern, whereas a few cases are inherited in an autosomal recessive mode such as Naxos disease and Carvajal syndrome . Hitherto, 15 genes have been reported to be associated with ACM: five genes encode the desmosomal junction: DSC2, DSG2, DSP, JUP and PKP2 and 10 other extra desmosomal genes: CTNNA3, DES, LMNA, PLN, TTN, TMEM43, TGFB3, RYR2, FLNC and CDH2 . Most of ACM probands have a family history and bear rare/pathogenic variants in ACM‐related genes; however, genetic basis underlines this disease is still missing in more than one‐third ACM probands …”

Section: Introductionmentioning

confidence: 99%

The homozygous variant c.245G > A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations

Rao

Guo

et al. 2019

Clinical Genetics

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Arrhythmogenic cardiomyopathy (ACM) is a familial cardiomyopathy featured by fibrofatty replacement of cardiomyocytes. Responsible genetic factors are not discernible in approximately one‐third of ACM probands. To investigate this further, we performed whole genome sequencing in 14 mutation‐negative ACM probands who underwent cardiac transplantation, and we identified one ACM proband with a rare homozygous missense variant in PNPLA2 (c.245G > A, p.G82D), a rate‐limiting enzyme that hydrolyzes triglycerides into fatty acids and diacylglycerol. Bioinformatic analysis suggested that this missense variant may lead to loss of function and therefore impair lipid catabolism. Genetic screening in this proband's family also inferred that the homozygous variant cosegregated with disease. To validate the pathogenicity of this variant and confirm its association with ACM, we established a knockin mouse model carrying the orthologous human homozygous PNPLA2 variant. Interestingly, mice with the homozygous variant presented with arrhythmias and significant cardiac dysfunction at 12 weeks, whereas heterozygous mice were not affected. Moreover, those homozygous mice suffered sudden death and/or heart failure by the age of 14 weeks. Pathological examination showed that extensive lipogenesis in cardiomyocytes and cardiac fibrosis were prominent in the myocardium. Herein, our data demonstrated that the homozygous missense variant PNPLA2 (c.245G > A, p.G82D) associated with a recessive form of ACM.

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Identification of Cadherin 2 ( CDH2 ) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract: These data implicate mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.

Cited by 130 publications

References 43 publications

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly

Bongani Mayosi: renowned cardiologist and visionary medical researcher

The homozygous variant c.245G > A/p.G82D in PNPLA2 is associated with arrhythmogenic cardiomyopathy phenotypic manifestations

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