Heterotaxy, Visceral 4 (HTX4) via the ACVR2B 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 and/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, double outlet right ventricle, transposition of the great arteries, 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). Heterotaxy, visceral 4 (HTX4; OMIM 613751) is inherited in an autosomal dominant manner caused by variants in ACVR2B. ACVR2B encodes for the NODAL coreceptor activin A receptor, type IIB. Two heterozygous missense variants in ACVR2B have been identified in patients with heterotaxy. Both missense variants are in conserved amino acids (p.R40H, p.V494I). The p.R40H variant resides within the region of NODAL ligand binding, perhaps interfering with signal transduction (Kosaki et al. Am J Med Genet 82:70-76, 1999; Ma et al. Cardiol Young 1-8, 2011).

Variants in the ACVR2B gene are estimated to cause ~2% of all cases of heterotaxy (Kosaki et al. Am J Med Genet 82:70-76, 1999).

This test provides full coverage of all coding exons of the ACVR2B 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).