Interrupted aortic arch vsd genetic9/9/2023 Conditional inactivation of Nkx2-5 at later stages of heart development revealed that it controls cardiac trabeculation through another cardiac growth factor,īMP10 ( Pashmforoush et al. Nkx2-5 also regulates cardiac progenitor expansion and differentiation and cardiac outflow tract morphology by controlling expression 1999), a gene essential for left ventricular development ( Srivastava et al. Subsequently, studies revealed that Nkx2-5 regulates expression of a number of other cardiac genes and transcription factors, including Hand1 ( Tanaka et al. Hearts formed, but development arrested at the looping heart tube stage, yielding unlooped hearts with one atrial and one Embryos engineered to lack expression of Nkx2-5 died at midgestation with severe heart defects ( Lyons et al. Nkx2-5 regulation of heart development has been studied extensively in mouse models. Some ostensibly sporadic CHD-associated NKX2-5 mutations arose de novo, whereas others were inherited from a parent without clinically detectable disease, indicative of Review of NKX2-5 variants and associated CHD shows a lack of a discernable relationship between mutation location and phenotype. Subsequently, targeted sequencing of NKX2-5 in cohorts of patients with different forms of nonfamilial CHD revealed that NKX2-5 mutations contribute to nonsyndromic, ostensibly sporadic CHD that affects diverse chambers and structures, with or withoutĬonduction system disease ( Fig. (VSDs), and left ventricular hypertrophy with or without ASD or AVB. Most affected family members had secundum atrial septalĭefects (ASDs) and progressive atrioventricular block (AVB), but others had tetralogy of Fallot, ventricular septal defects Terminated translation just carboxy terminal to the DNA-binding domain. Two of the families shared an NKX2-5 missense mutation in the region encoding the DNA-binding domain, whereas the remaining two harbored mutations that prematurely In four families with familial, autosomal-dominant CHD, genome-wide linkage studies showed that mutations in NKX2-5 segregated with CHD ( Schott et al. Through embryonic, fetal, and adult life ( Lints et al. NKX2-5 transcripts are detected in murine cardiomyocytes at the onset of cardiomyocyte differentiation, with continued expression The NKX2-5 gene in humans encodes a cardiac-specific homeobox transcription factor. We also touch on monogenic mutation of T-box genes insofar as they reinforce or add to our understanding of In this work, we will review, in depth, the literature on monogenic mutation of two cardiac transcription factors, NKX2-5 and GATA4, and reflect on how the interplay of human genetics and murine modeling has informed our understanding of CHD pathogenesisĪnd genetics. Gene mutations provide an alternative mechanism that accounts for epidemiological CHD recurrence risk ( Bruneau et al. These studies indicate that variable expression and incomplete penetrance of many rare single Understanding of how the complex interaction of stochastic factors, the environment, and modifier genes influence phenotypicĮxpression of CHD gene mutations. However, detailed studies of several monogenic CHD disease genes in mice and humans over the past decade have broadened our The variable penetrance and phenotype intuitively suggest a multifactorial mode of inheritance for CHD, first proposed Among affected relatives, CHD may vary significantly in specific type and severity ( Whittemore et al. The overall recurrence risk of nonsyndromic CHD is between 2% and 10%, depending on the defect and sex of the parent concerned The complex mechanisms underpinning congenital cardiac malformations. With burgeoning survival and rapid advances in genetic technologies, there has never been a more compelling time to unravel To reach reproductive age ( Friedberg et al. More than half of all survivors of severe CHD are now adults, and most individuals with even complex CHD are now expected The severe CHD prognosis, so that the large majority of patients survive into adulthood ( Khairy et al. In the past four decades, extraordinary advances in management have transformed Twenty-four percent of infants who die of a birth defect have a heart defect, making it the most common congenital defectĬontributing to death in that first year. Require invasive treatment in the first year of life ( Roger et al. An estimated 32,000 infants with congenital heart disease (CHD) are born each year in the United States, and ∼25% of them births, congenital heart defects are the most common major malformations seenĪt birth, accounting for nearly one-third of all major congenital anomalies ( Reller et al. Previous Section Next Section THE IMPACT OF CONGENITAL HEART DISEASE
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