Isolated Nonsyndromic Congenital Heart Defects via the ZFPM2 (FOG2) Gene

Congenital heart defects (CHDs) are the most common birth defect occurring in 6-10 per 1000 live births and are a major cause of infant morbidity and mortality (Hoffman et al. J Am Coll Cardiol 39:1890-1900, 2002; Oyen et al. Circulation 120:295-301, 2009). Congenital heart diseases arise due to defects in cardiac morphogenesis during embryonic development, which leads to structural malformations in the heart and great vessels. Conotruncal heart defects (CTDs) are a class of outflow tract abnormalities that includes tetralogy of Fallot (TOF), double outlet right ventricle (DORV), truncus arteriosus (TA), interrupted aortic arch (IAA), and transposition of the great arteries (TGA). CTDs are common, occurring in over 10% of patients with CHDs (Oyen et al. 2009).

CHDs have genetic and non-genetic causes. The majority of patients with CHDs are thought to have a complex, multifactorial etiology. CHDs can be caused by single gene or chromosomal abnormalities, exposure to teratogens, and other unknown mechanisms. Non-cardiac malformations are found in roughly 20% of patients with CHDs and chromosomal abnormalities account for ~ 7% of patients with CHDs (Eskedal et al. Cardiol Young 14:600-607, 2004; Oyen et al. Circulation 120:295-301, 2009). Monogenic non-syndromic CHD are caused by variants in regulators of heart development (reviewed by Bruneau Nature 451:943-948, 2008). Autosomal dominant nonsyndromic CHDs can occur due to variants in the zinc finger transcription factor ZFPM2 (FOG2). ZFPM2/FOG2 is expressed during early heart development and acts as a coregulator of GATA4 (Tevosian et al. Cell 101:729-739, 2000). The majority of documented causative variants in ZFPM2 (FOG2) are de novo missense variants (Tan et al. Clin Genet 2011). In addition to TOF and DORV, a de novo nonsense variant in ZFPM2 (FOG2) was identified in a patient with nonsyndromic congenital diaphragmatic hernia (Ackerman et al. PloS Genet 1:58-65, 2005).

Variants in ZFPM2 (FOG2) have been reported in 13-15% of patients with DORV and less than 1% of patients with tetralogy of Fallot (De Luca et al. Clin Genet 80:184-190, 2011; Tan et al. Clin Genet 2011).

This test provides full coverage of all coding exons of the ZFPM2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).