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In their interesting manuscript, Tomita-Mitchell and colleagues present four novel GATA4 sequence variations as pathogenic substrates for congenital heart disease (CHD) in humans. CHD are the most common birth defect and affect almost 1% of all newborns. Since surgical approaches have substantially improved over the last decades, the number of grown ups with CHD (GUCH) is growing continuously. This fact dema...
In their interesting manuscript, Tomita-Mitchell and colleagues present four novel GATA4 sequence variations as pathogenic substrates for congenital heart disease (CHD) in humans. CHD are the most common birth defect and affect almost 1% of all newborns. Since surgical approaches have substantially improved over the last decades, the number of grown ups with CHD (GUCH) is growing continuously. This fact demands better insights into genetics and heredity of CHD.
The authors identified a variety of synonymous variants with a potential impact on translational kinetics of GATA4. Interestingly, all eighteen CHD associated synonymous sequence variants were exclusively found in patients with septal or conotruncal defects (excluding D-TGA), which led to the conclusion that the genetic aetiology of D-TGA may be different from other conotruncal defects. We agree that there is growing evidence about functional consequences of “silent” sequence variations in cardiac diseases. Recently, mRNA analysis of plakophilin-2 in a patient with a congenital arrhythmogenic cardiac disease revealed a cryptic splice site induced by a variant, which was predicted to be translationally silent . We also report the GATA4 C274C variant in two patients with isolated secundum ASDII  supporting the authors’ conclusion of an association of
prevalent synonymous variants with congenital septal defects. Yet, functional studies are needed to further investigate this important issue.
As mentioned above Tomita-Mitchell et al. present four CHD associated GATA4 mutations . The large screening population allows the authors to draw conclusion about an overall prevalence of GATA4 mutations among patients with sporadic CHD. When combining results from previous sequencing approaches the prevalence of GATA4 mutations ranges among 0.4% (2 out of 482) in patients with sporadic CHD [3,4,5]. Thus, the overall rarity of CHD associated GATA4 mutations is reinforced by Tomita-Mitchell et al. who report four mutations among 628 subjects with sporadic CHD
(0.6%). Yet, the A411V variant appears to our knowledge to be the first GATA4 mutation in a patient with isolated ventricular septal defect. We have also identified the A411V mutation in a female patient with cribriform ASDII and partial anomalous pulmonary venous return (PAPVR). A secundum ASD of cribriform type was previously described as a remarkable phenotype in a patient with a secundum ASD due to a mutation in NKX2.5 . Therefore, one may assume that cribriform atrial septal defects are more excessively associated with transcription factor mutations than other
forms of ASDII and patients with this specific phenotype may constitute interesting screening candidates. Thorough assessment of minor and more subtle clinical features may thus help to find common phenotypes in patients with a genetic CHD. That is why we do regret the lack of any medical features of the index patients and affected relatives in the paper of Tomita-Mitchell et al . Information about specific phenotypes of mutation carriers is indispensable for dealing with the future challenges
of GUCH patients. We believe that the vast heterogeneity of genetics and CHD demands systematic and detailed phenomic approaches, which may allow an identification of common clinical features among patients with genetic CHD. This may alleviate the identification and genetic counselling of
patients with hereditary CHD.
1 Tomita-Mitchell A, Maslen CL, Morris CD, Garg V, Goldmuntz E. GATA4 sequence variants in patients with congenital heart disease.J Med Genet. 2007 Dec;44(12):779-783
2 Awad MM, Dalal D, Tichnell C, James C, Tucker A, Abraham T, Spevak PJ, Calkins H, Judge DP. 2006. Recessive arrhythmogenic right ventricular dysplasia due to novel cryptic splice mutation in PKP2. Hum Mutat 27:1157.
3 Posch MG, Perrot A, Schmitt K, Mittelhaus S, Esenwein EM, Stiller B, Geier C, Dietz R, Gessner R, Ozcelik C, Berger F Mutations in GATA4, NKX2.5, CRELD1 and BMP4 are infrequently found in patients with congenital
cardiac septal defects Am J Med Genet Part A in press
4 Nemer G, Fadlalah F, Usta J, Nemer M, Dbaibo G, Obeid M, Bitar F. 2006. A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot. Hum Mutat 27:293-294.
5 Schluterman MK, Krysiak AE, Kathiriya IS, Abate N, Chandalia M, Srivastava D, Garg V. 2007. Screening and biochemical analysis of GATA4 sequence variations identified in patients with congenital heart disease. Am J Med Genet A 143:817-823.
6 Hirayama-Yamada K, Kamisago M, Akimoto K, Aotsuka H, Nakamura Y, Tomita H, Furutani M, Imamura S, Takao A, Nakazawa M, Matsuoka R. 2005. Phenotypes with GATA4 or NKX2.5 mutations in familial atrial septal defect. Am J Med Genet A 135:47-52.