Abstract
NKX2-5 is a homeodomain-containing transcription factor implied in both heart and thyroid development. Numerous mutations in NKX2-5 have been reported in individuals with congenital heart disease (CHD), but recently a select few have been associated with thyroid dysgenesis, among which the p.A119S variation. We sequenced NKX2-5 in 303 sporadic CHD patients and 38 families with at least two individuals with CHD. The p.A119S variation was identified in two unrelated patients: one was found in the proband of a family with four affected individuals with CHD and the other in a sporadic CHD patient. Clinical evaluation of heart and thyroid showed that the mutation did not segregate with CHD in the familial case, nor did any of the seven mutation carriers have thyroid abnormalities. We tested the functional consequences of the p.A119S variation in a cellular context by performing transactivation assays with promoters relevant for both heart and thyroid development in rat heart derived H10 cells and HELA cells. There was no difference between wildtype NKX2-5 and p.A119S NKX2-5 in activation of the investigated promoters in both cell lines. Additionally, we reviewed the current literature on the topic, showing that there is no clear evidence for a major pathogenic role of NKX2-5 mutations in thyroid dysgenesis. In conclusion, our study demonstrates that p.A119S does not cause CHD or TD and that it is a rare variation that behaves equal to wildtype NKX2-5. Furthermore, given the wealth of published evidence, we suggest that NKX2-5 mutations do not play a major pathogenic role in thyroid dysgenesis, and that genetic testing of NKX2-5 in TD is not warranted.
Highlights
Persistent congenital hypothyroidism of thyroidal origin is a relatively common disorder, occurring in about 1/2500 live births [1]
Mutational Analysis We identified a total of three missense NKX2-5 variations in our cohort of 341 congenital heart disease (CHD) patients: a p.C270Y variant in a patient with ASDI and cleft mitral valve, and twice the p.A119S variant in separate probands
Our results strongly suggest that the p.A119S variation behaves similar to wild type NKX2-5 and that it has no discernible pathogenic role in either CHD or thyroid dysgenesis (TD)
Summary
Persistent congenital hypothyroidism of thyroidal origin is a relatively common disorder, occurring in about 1/2500 live births [1]. TD is a heterogeneous disorder that occurs mostly sporadically, though 2% of cases are reported as familial [3]. In a recent study mutations in NKX2-5 were reported in a small proportion of patients with persistent congenital hypothyroidism [8]. NKX2-5 encodes a homeodomain-containing transcription factor that is expressed during thyroid development (for review see [9]), but it is mainly known to play a crucial role in heart development [10]. NKX2-5 mutations have been found in a subset of patients with congenital heart disease (CHD), mostly septal defects [11,12]. As CHD is overrepresented among children with TD and vice versa, a developmental association between the cardiac and thyroid systems has been suggested [13,14,15]
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