Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs

Al-Shafai, Kholoud; Alhashemi, Mohammed; Chidambaram, Manickam; Musa, Rania; Selvaraj, Senthil; Syed, Najeeb; Vempalli, Fazulur Rehaman; Ali, Muneera; Yacoub, Magdi H.; Estivill, Xavier

doi:10.1002/mgg3.1709

Cited by 4 publications

(2 citation statements)

References 38 publications

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“…Cardiac symptoms have been more often reported during the second decade of life, especially in patients with subtypes caused by p.Q358P and p.R179T mutations, who experience DCM with minimal muscle weakness [14]. Our systematic search results in 77 patients with FKTN deficiency and cardiac manifestations, encompassing DCM, VD, DI, SI, AF, PFO, double subaortic ventricular defect, HoLV, PPS, MF and infundibular TGA (with no innominate vein) [14,185,[330][331][332][333][334][335][336][337][338][339][340][341][342][343] (Table 5, Supplementary Tables S2 and S3).…”

Section: Fktn-cdgmentioning

confidence: 99%

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Conte,

Sam,

Lefeber

et al. 2023

IJMS

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Heart failure (HF) is a progressive chronic disease that remains a primary cause of death worldwide, affecting over 64 million patients. HF can be caused by cardiomyopathies and congenital cardiac defects with monogenic etiology. The number of genes and monogenic disorders linked to development of cardiac defects is constantly growing and includes inherited metabolic disorders (IMDs). Several IMDs affecting various metabolic pathways have been reported presenting cardiomyopathies and cardiac defects. Considering the pivotal role of sugar metabolism in cardiac tissue, including energy production, nucleic acid synthesis and glycosylation, it is not surprising that an increasing number of IMDs linked to carbohydrate metabolism are described with cardiac manifestations. In this systematic review, we offer a comprehensive overview of IMDs linked to carbohydrate metabolism presenting that present with cardiomyopathies, arrhythmogenic disorders and/or structural cardiac defects. We identified 58 IMDs presenting with cardiac complications: 3 defects of sugar/sugar-linked transporters (GLUT3, GLUT10, THTR1); 2 disorders of the pentose phosphate pathway (G6PDH, TALDO); 9 diseases of glycogen metabolism (GAA, GBE1, GDE, GYG1, GYS1, LAMP2, RBCK1, PRKAG2, G6PT1); 29 congenital disorders of glycosylation (ALG3, ALG6, ALG9, ALG12, ATP6V1A, ATP6V1E1, B3GALTL, B3GAT3, COG1, COG7, DOLK, DPM3, FKRP, FKTN, GMPPB, MPDU1, NPL, PGM1, PIGA, PIGL, PIGN, PIGO, PIGT, PIGV, PMM2, POMT1, POMT2, SRD5A3, XYLT2); 15 carbohydrate-linked lysosomal storage diseases (CTSA, GBA1, GLA, GLB1, HEXB, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, ARSB, GUSB, ARSK). With this systematic review we aim to raise awareness about the cardiac presentations in carbohydrate-linked IMDs and draw attention to carbohydrate-linked pathogenic mechanisms that may underlie cardiac complications.

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Section: Fktn-cdgmentioning

confidence: 99%

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Conte,

Sam,

Lefeber

et al. 2023

IJMS

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“…Unfortunately, the genetic architecture of CMPs is under-investigated in the Middle East, increasing the likelihood of inconclusive findings in patients with CMPs from this region 12 – 14 . To our knowledge, the genetic basis of pediatric CMPs has never been previously studied in Jordan.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the genetic tapestry of pediatric sarcomeric cardiomyopathies and masquerading phenocopies in Jordan

Azab,

Aburizeg,

Shaaban

et al. 2024

Sci Rep

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Pediatric cardiomyopathies are mostly attributed to variants in sarcomere-related genes. Unfortunately, the genetic architecture of pediatric cardiomyopathies has never been previously studied in Jordan. We sought to uncover the genetic landscape of 14 patients from nine families with several subtypes of pediatric cardiomyopathies in Jordan using Exome sequencing (ES). Our investigation identified pathogenic and likely pathogenic variants in seven out of nine families (77.8%), clustering in sarcomere-related genes. Surprisingly, phenocopies of sarcomere-related hypertrophic cardiomyopathies were evident in probands with glycogen storage disorder and mitochondrial-related disease. Our study underscored the significance of streamlining ES or expanding cardiomyopathy-related gene panels to identify plausible phenocopies of sarcomere-related cardiomyopathies. Our findings also pointed out the need for genetic testing in patients with cardiomyopathy and their at-risk family members. This can potentially lead to better management strategies, enabling early interventions, and ultimately enhancing their prognosis. Finally, our findings provide an initial contribution to the currently absent knowledge about the molecular underpinnings of cardiomyopathies in Jordan.

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Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs

Al-Shafai

Alhashemi

Chidambaram³

et al. 2021

Molec Gen & Gen Med

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Background Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are serious inherited heart diseases with various causative mutations identified. The full spectrum of causative mutations remains to be discovered, especially in understudied populations. Methods Here, we established the DOHA Registry and Biobank for cardiomyopathies in Qatar, followed by sequencing of 174 genes on 51 HCM and 53 DCM patients, and 31 relatives. Results In HCM, the analysis of 25 HCM‐associated genes showed that 20% of HCM cases had putative pathogenic variants for cardiomyopathy, mainly in sarcomere genes. Additional 49% of HCM cases had variants of uncertain significance, while 31% of HCM cases had likely benign variant(s) or had no variants identified within the analyzed HCM genes. In DCM, 56 putative DCM genes were analyzed. Eight percent of DCM cases had putative pathogenic variants for DCM, in the TTN gene while 70% of cases had variants of uncertain significance, in the analyzed DCM genes, that will need further pathogenicity assessment. Moreover, 22% of DCM cases remain unexplained, by having likely benign variant(s) or having no variants detected in any of the analyzed DCM genes. Conclusion We identified or replicated at least four recurrent variants among cardiomyopathy patients, which could be founder disease mutations in the Arabic population, including a frameshift variant (c.1371_1381dupTATCCAGTTAT) of unknown significance in the FKTN gene which seems to cause DCM in homozygosity, and HCM in heterozygosity. In vivo and/or in vitro functional validation need to be pursued in order to assess the pathogenicity of the identified variants.

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Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs

Cited by 4 publications

References 38 publications

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review

Unraveling the genetic tapestry of pediatric sarcomeric cardiomyopathies and masquerading phenocopies in Jordan

Genetic evaluation of cardiomyopathies in Qatar identifies enrichment of pathogenic sarcomere gene variants and possible founder disease mutations in the Arabs

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