Pediatric Cardiomyopathy: Importance of Genetic and Metabolic Evaluation

Kindel, Steven J.; Miller, Erin; Gupta, Rahul; Cripe, Linda H.; Hinton, Robert B.; Spicer, Robert L.; Towbin, Jeffrey A.; Ware, Stephanie M.

doi:10.1016/j.cardfail.2012.01.017

Cited by 116 publications

(87 citation statements)

References 31 publications

(51 reference statements)

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“…22,23 This patient also harbors a heterozygous missense mutation, c.1979G>A (p.R660H), which was found to be in trans with the exon 18 deletion by parental testing. 24,25 Because this patient is a compound heterozygote with a missense mutation and an exonic deletion, this result confirms the diagnosis of Pompe disease.…”

Section: Comprehensive Analysis Of Exonic Deletions Is Feasible Basedsupporting

confidence: 70%

Capture-based high-coverage NGS: a powerful tool to uncover a wide spectrum of mutation types

Wang

Zhang

et al. 2016

Genetics in Medicine

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Purpose: Next-generation sequencing (NGS) has been widely applied to clinical diagnosis. Target-gene capture followed by deep sequencing provides unbiased enrichment of the target sequences, which not only accurately detects single-nucleotide variations (SNVs) and small insertion/deletions (indels) but also provides the opportunity for the identification of exonic copy-number variants (CNVs) and large genomic rearrangements. Method:Capture NGS has the ability to easily detect SNVs and small indels. However, genomic changes involving exonic deletions/ duplications and chromosomal rearrangements require more careful analysis of captured NGS data. Misaligned raw sequence reads may be more than just bad data. Some mutations that are difficult to detect are filtered by the preset analytical parameters. "Loose" filtering and alignment conditions were used for thorough analysis of the misaligned NGS reads. Additionally, using an in-house algorithm, NGS coverage depth was thoroughly analyzed to detect CNVs. Results:Using real examples, this report underscores the importance of the accessibility to raw sequence data and manual review of suspicious sequence regions to avoid false-negative results in the clinical application of NGS. Assessment of the NGS raw data generated by the use of loose filtering parameters identified several sequence aberrations, including large indels and genomic rearrangements. Furthermore, NGS coverage depth analysis identified homozygous and heterozygous deletions involving single or multiple exons. Conclusion:Our results demonstrate the power of deep NGS in the simultaneous detection of point mutations and intragenic exonic deletion in one comprehensive step.

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Section: Comprehensive Analysis Of Exonic Deletions Is Feasible Basedsupporting

confidence: 70%

Capture-based high-coverage NGS: a powerful tool to uncover a wide spectrum of mutation types

Wang

Zhang

et al. 2016

Genetics in Medicine

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“…Previously, it was reported that approximately 5% of pediatric cardiomyopathies are due to an inborn error of metabolism [2] , however a more recent study found a substantially higher percentage, with 26% of hypertrophic and 16% of dilated cardiomyopathies having a metabolic etiology [3] . A separate study found five out of 35 infants (13.5%) diagnosed in the first year of life had a metabolic etiology to their cardiomyopathy [4] .…”

Section: Introductionmentioning

confidence: 99%

Infant with cardiomyopathy: When to suspect inborn errors of metabolism?

Byers

Fıçıcıoğlu

2014

WJC

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Inborn errors of metabolism are identified in 5%-26% of infants and children with cardiomyopathy. Although fatty acid oxidation disorders, lysosomal and glycogen storage disorders and organic acidurias are well-known to be associated with cardiomyopathies, emerging reports suggest that mitochondrial dysfunction and congenital disorders of glycosylation may also account for a proportion of cardiomyopathies. This review article clarifies when primary care physicians and cardiologists should suspect inborn errors of metabolism in a patient with cardiomyopathy, and refer the patient to a metabolic specialist for a further metabolic work up, with specific discussions of "red flags" which should prompt additional evaluation.

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“…Вместе с тем у детей гораздо чаще по сравнению со взрослыми причиной кардиомиопатий являются генетически детерминированные метаболические де-фекты. Так, если в более ранних исследованиях было показано, что врожденные нарушения обмена веществ служат причиной кардиомиопатий в 5% случаев [3], то в настоящее время установлено, что нарушения ме-таболизма значительно чаще вызывают развитие это-го заболевания -в 26 и 16% случаев соответственно гипертрофическая и дилатационная кардиомиопатии имеют метаболическую природу [10].…”

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“…Первый принцип базируется на характеристике нарушений обмена веществ: нарушения метаболизма аминокислот, ор-ганических кислот, жирных кислот, дефекты транс-порта карнитина, обмена гликопротеинов, глико-гена, дефекты гликозилирования. Второй принцип классификации основан на изменении органелл клетки: выделяют лизосомальные болезни накопле-ния, митохондриальные и пероксисомные заболева-ния [8][9][10][11]. Наиболее часто встречаются нарушения окисления жирных кислот, органические ацидурии, болезни накопления, в то время как врожденные де-фекты гликозилирования и митохондриальные бо-лезни реже диагностируются у детей первых лет жиз-ни с кардиомиопатиями [8,10,12,13].…”

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“…Ранняя диагностика и назначе-ние специфического лечения позволяют корригиро-вать метаболические расстройства, улучшить прогноз течения заболевания и профилактировать развитие ряда серьезных осложнений [3,8,10]. Следует под-черкнуть, что в случае поздней диагностики кардио-миопатий, имеющих метаболическую этиологию, прогноз резко ухудшается.…”

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