X-linked Heterotaxy (HTX1) via the ZIC3 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 and/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, 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). X-linked heterotaxy 1 (HTX1; OMIM 306955) is due to variants (missense, nonsense, frameshifts) in the zinc finger transcription factor ZIC3. Although males are most commonly affected, there are reports in the literature of symptomatic heterozygous females (Gebbia et al. Nature 17:305- 308, 1997; Ware et al. Am J Hum Genet 74:93-105, 2004; Chhin et al. Hum Mutat 28:563-570, 2007). Patients with isolated CHDs without any evidence for heterotaxy have also been found to harbor variants in ZIC3 (Megarbane et al. Eur J Hum Genet 8:704-708, 2000). A 1.3 Mb deletion of Xq26.3 including the ZIC3 locus has been found to segregate in an Italian family with heterotaxy (Chung et al. Am J Hum Genet 155A:1123-1128, 2011).

Variants in the ZIC3 gene are estimated to cause >75% of familial X-linked cases of heterotaxy, ~1% of sporadic cases of heterotaxy, and ~1% of cases with isolated CHDs without laterality defects (Ware et al. Am J Hum Genet 74:93-105, 2004).

This test provides full coverage of all coding exons of the ZIC3 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).