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NKX2-6 related congenital heart disease: Biallelic homeodomain-disrupting variants and truncus arteriosus

Alyssa Ritter1,2, Petra Werner2, Brande Latney2

  • 1Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Pennsylvania, USA.

American Journal of Medical Genetics. Part A
|March 22, 2020
PubMed

Insights

Truncus arteriosus (TA), a rare congenital heart defect (CHD), can be caused by biallelic loss of function in the NKX2-6 gene. This study identifies compound heterozygous variants in NKX2-6 in siblings with TA, suggesting a new genetic etiology for CHD.

Area of Science:

  • Genetics
  • Cardiology
  • Developmental Biology

Background:

  • Congenital heart defects (CHD) are the most common birth defects, with truncus arteriosus (TA) accounting for 1% of cases.
  • Previous research linked homozygous NKX2-6 variants to TA in consanguineous families.
  • NKX2-6 is a downstream target of TBX1, crucial in 22q11.2 microdeletion syndrome's cardiac phenotype.

Purpose of the Study:

  • To investigate the genetic basis of TA in non-consanguineous families.
  • To explore the role of NKX2-6 variants in congenital heart defects (CHD).
  • To identify novel genetic etiologies for truncus arteriosus (TA).

Main Methods:

  • Genetic sequencing of NKX2-6 in two siblings with TA.
  • Analysis of two in-house cohorts with conotruncal defects (CTD) for NKX2-6 variants.
  • Assessment of variant impact on the NKX2-6 protein's homeobox domain.

Main Results:

  • Two siblings with TA presented with compound heterozygous NKX2-6 variants.
  • No additional cases of biallelic NKX2-6 variants were found in conotruncal defect (CTD) cohorts.
  • Identified variants likely lead to a truncated NKX2-6 protein, disrupting its function.

Conclusions:

  • Biallelic loss of function in NKX2-6 represents a rare genetic cause of truncus arteriosus (TA).
  • This finding expands the known genetic spectrum of congenital heart defects (CHD).
  • NKX2-6 dysfunction may contribute to other forms of CHD beyond TA.

Keywords:
NKX2-6autosomal recessivecongenital heart diseasetruncus arteriosus

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