The effect of p.Arg25Cys alteration in NKX2-5 on conotruncal heart anomalies: mutation or polymorphism?

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Mutations in the NKX2-5 gene are associated with congenital heart defects, particularly conotruncal anomalies like tetralogy of Fallot.
• Previous research suggested potential structural or functional impacts of certain NKX2-5 alterations.

Purpose of the Study:

• To investigate the presence and pathogenicity of NKX2-5 alterations in Turkish children with conotruncal heart anomalies.
• To evaluate the significance of the previously documented c.73C>T (p.Arg25Cys) missense alteration.

Main Methods:

• Genetic screening of 72 Turkish children diagnosed with conotruncal heart anomalies.
• Screening of 185 healthy Turkish individuals as a control group.
• Analysis of NKX2-5 gene alterations, specifically the c.73C>T (p.Arg25Cys) variant.

Main Results:

• One previously documented heterozygous NKX2-5 missense alteration, c.73C>T (p.Arg25Cys), was identified in a 10-year-old boy with tetralogy of Fallot.
• The same heterozygous alteration was also found in the patient's healthy father and in two unrelated individuals within the healthy control group.
• This study marks the first observation of the p.Arg25Cys alteration in healthy non-African American individuals.

Conclusions:

• The presence of the p.Arg25Cys alteration in healthy individuals suggests it lacks strong genetic support for pathogenicity in congenital heart defects.
• Further investigation is needed to reconcile these findings with previous in vitro studies and theoretical predictions regarding the protein's structure and function.
• The clinical significance of the NKX2-5 p.Arg25Cys variant requires careful evaluation in diverse populations.