Heterotaxy and Conotruncal Heart Defects via the GDF1 Gene

Heterotaxy syndrome or situs ambiguus results from a failure to properly establish left-right asymmetry during embryogenesis resulting in an abnormal arrangement of thoracic or abdominal visceral organs, including the heart, lungs, liver, spleen, intestines, and stomach. Affected patients frequently have significant morbidity and mortality due to a wide variety of cyanotic congenital heart defects. Common defects besides cardiac malformations include asplenia or polysplenia, left-sided liver, right-sided stomach, gastrointestinal malrotation, and altered lung lobation. Classic heterotaxy (cardiac malformations and visceral laterality defects) has an estimated prevalence of 1:10,000 live births (Lin et al. Genet Med 2:157-172, 2000).

Heterotaxy is a heterogeneous genetic disorder. Variants in at least 7 genes (NODAL, ZIC3, CFC1, FOXH1, LEFTY2, GDF1, and ACVR2B) involved in NODAL signaling have been proposed to cause heterotaxy or congenital heart defects (CHDs). These proteins play an essential role in establishing left-right patterning during organogenesis, including the heart and great vessels (reviewed by Hamada et al. Nat Rev Genet 3:103-113, 2002). Defects in NODAL signaling factors are also found in 5-10% of patients with isolated CHDs without heterotaxy, including tetralogy of Fallot (TOF), double outlet right ventricle (DORV), transposition of the great arteries (TGA), and cardiac septal defects (Roessler et al. Am J Hum Genet 83:18-29, 2008; Mohapatra et al. Hum Mol Genet 18:861-871, 2009). GDF1 (growth differentiation factor 1; OMIM 602880) encodes a NODAL-related signaling molecule that is important for left-right patterning of the heart (Rankin et al. Nat Genet 24:262-265, 2000). Heterozygous nonsense and missense variants in GDF1 were identified in individuals with conotruncal heart defects (TOF, DORV, TGA) without visceral laterality defects (Karkera et al. Am J Hum Genet 81:987-994, 2007). Two truncating variants in GDF1 were found to cause classic heterotaxy in one Finnish family with heterozygous carriers being asymptomatic (Kaasinen et al. Hum Mol Genet 19:2747-2753, 2010).

Variants in the GDF1 gene are estimated to cause ~2% of all cases of CHD (Karkera et al. Am J Hum Genet 81:987-994, 2007).

This test provides full coverage of all coding exons of the GDF1 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).