Congenital Cardiac Defects
In a female patient with tetralogy of Fallot (TOF; 187500) who was negative for del(22q11), Benson et al. (1999) identified heterozygosity for a 182C-T transition in the 5-prime coding region of the NKX2-5 gene, resulting in an arg25-to-cys (R25C) substitution that changes a highly conserved amino acid from basic to neutral. The mutation was not found in 100 control chromosomes from a randomly selected population. The patient, who had undergone surgical repair of typical TOF and 2 small muscular ventricular septal defects at 1 year of age, did not have atrioventricular block or atrial septal defect.
Kasahara et al. (2000) demonstrated impaired DNA binding of the R25C variant CSX peptide to dimeric sites.
Goldmuntz et al. (2001) identified the R25C mutation in 3 unrelated probands with tetralogy of Fallot who were negative for del(22q11). None of the patients had atrioventricular conduction abnormalities. The father of 1 of the probands was also heterozygous for the R25C mutation and had a history of ventricular septal defect.
McElhinney et al. (2003) screened the NKX2-5 gene in 474 patients with congenital cardiac defects and identified heterozygosity for the R25C mutation in 1 (4%) of 23 patients with interrupted aortic arch (see 217095), 1 (4%) of 22 patients with truncus arteriosus (see 217095), and 1 (1%) of 80 patients with hypoplastic left heart syndrome (HLHS2; 614435).
In 2 (0.9%) of 230 patients with TOF, Rauch et al. (2010) identified heterozygosity for the R25C mutation.
In 1 of 9 patients with hypoplastic left heart syndrome, Stallmeyer et al. (2010) identified heterozygosity for the R25C mutation. The complete cardiac phenotype of the male infant included atresia of the aortic and mitral valves and a small VSD that required corrective surgery.
In 2 sporadic Italian patients with TOF associated with a left-sided arch, subaortic ventricular septal defect, and patent pulmonary valve, De Luca et al. (2011) identified the R25C mutation in the NKX2-5 gene. Parental DNA was unavailable for analysis; the mutation was not found in 500 population-matched controls.
Congenital Nongoitrous Hypothyroidism 5
In a 24-year-old woman with thyroid ectopy and a 15-year-old boy with athyreosis of the gland (see CHNG5, 225250), Dentice et al. (2006) identified a heterozygous 73C-T transition in the NKX2-5 gene, resulting in an R25C substitution. The mutation in each case was inherited from a parent. Neither patient had a history of cardiac disease; the boy showed bilateral cortex atrophy at birth and had attention deficit hyperactivity disorder. The mutation, which was identified in 1 of 561 control individuals, exhibited significant functional impairment, with reduction of transactivation properties and dominant-negative effect. In addition, the results indicated that although the R25C mutant normally also binds the DIO2 (601413) promoter, its activity on the DIO2, TG (188450), and TPO (606765) promoters is significantly impaired.
