A young boy with ventricular arrhythmias and thyroid dysgenesis: two genes are not enough?

Abstract

Congenital hypothyroidism (CH) may be caused by biallelic variants in the TSHR gene. CH due to thyroid dysgenesis has also been linked to pathogenic variants of the nucleotide kinase 2, homeobox 5 (NKX2-5) gene, which can also cause sudden cardiac death from ventricular arrhythmia. In particular, the NKX2-5 p.Arg25Cys missense variant has been repeatedly reported in patients with congenital heart defects and, more rarely, with hypogonadism. We report the case of a 7 year old boy with ventricular arrhythmias, thyroid dysgenesis and intellectual disability, born from consanguineous Tunisian parents. Exome sequencing and segregation analysis revealed two potentially relevant variants: the NKX2-5 p.Arg25Cys variant (maternally inherited), as well as a single heterozygous TSHR p.Gln90Pro variant (paternally inherited). Of note, a male sibling of the proband, presenting with intellectual disability only, carried the same two variants. No other TSHR variants, or other potentially relevant variants were identified. In this proband, despite the identification of variants in two genes potentially correlated to the phenotype, a definite genetic diagnosis could not be reached. This case report highlights the complexity of exome data interpretation, especially when dealing with families presenting complex phenotypes and variable expression of clinical traits.

Figure 1. On the ECG at 7 years and 3 month of age (Figure 1A), there was a large QRS tachycardia, right bundle branch block and left anterior hemiblock. One month later (Figure 1B), he presented again ventricular fascicular tachycardia.

Figure 2. Pedigree of the family harboring the c.73C>T mut. in NKX2.5 gene. The index patient is indicated by an arrow. Squares: male; circles: female; the transmission of the NKX2.5 variant is shown by a filled black area within each symbol, whereas the segregation of TSHR variant by a corresponding grey area. Results of thyroid and heart investigations are aligned with each symbol.