Heterotaxy, Situs Inversus and Kartagener's Syndrome Panel

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder affecting the function of motile cilia (Leigh et al. 2009. PubMed ID: 19606528). The hallmark features of PCD are neonatal respiratory distress, chronic coughing, and recurrent sinus or ear infections; 80-100% of all PCD patients have one or more of these symptoms. In 40-50% of individuals with PCD, the major visceral organs are reversed from their normal positions, also called situs inversus (Sutherland and Ware. 2009. PubMed ID: 19876930; Zariwala et al. 2019. PubMed ID: 20301301). Kartagener’s syndrome is a condition defined by the symptomatic triad of situs inversus, sinusitis, and bronchiectasis. Patients with PCD can also have abnormal orientation of some organs but not others, a condition called situs ambiguus or heterotaxy (Kennedy et al. 2007. PubMed ID: 17515466). Heterotaxy syndrome results from a failure to properly establish left-right asymmetry during embryogenesis. This results in an abnormal arrangement of thoracic or abdominal visceral organs or both, 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. Aside from cardiac malformations, common defects 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 in 10,000 live births (Lin et al. 2000. PubMed ID: 11256661).

The majority of PCD patients have neonatal symptoms and around half have situs inversus, but despite these signs, diagnosis is often delayed (Collins et al. 2014. PubMed ID: 26237387). This prevents early onset of regular airway clearance therapy, aggressive management of infections, monitoring and treatment of hearing impairment, and genetic counselling for the family. Genetic testing at an early age is helpful in all these respects.

Both PCD and heterotaxy are genetically heterogeneous. PCD can be caused by pathogenic variants in at least 50 genes, and heterotaxy is caused by pathogenic variants in at least 40 genes (Zariwala et al. 2019. PubMed ID: 20301301). In addition, the INVS/NPHP2 and ANKS6 genes have been associated with situs inversus or heterotaxy, either with or without biliary complications (Schön et al. 2002. PubMed ID: 11935322; Otto et al. 2003. PubMed ID: 12872123; Hoff et al. 2013. PubMed ID: 23793029). Thus, a common thread among all these genes is the association of laterality defects.

ACVR2B, FOXH1, LEFTY2, NKX2-5, and NODAL are associated with autosomal dominant laterality defects, PKD1L1 and DNAH6 are associated with autosomal recessive laterality defects, FOXJ1, DNAAF6/PIH1D3, and ZIC3 are associated with X-linked or autosomal dominant PCD and heterotaxy, and AK7, ODAD2/ARMC4, ANKS6, CCDC103, ODAD1/CCDC114, CCDC39, CCDC40, ODAD3/CCDC151, CFAP300, CFAP53, CFAP298, DNAAF1, DNAAF2, DNAAF3, DNAAF5 (HEATR2), DNAH1, DNAI1, DNAI2, DNAH5, DNAH9, DNAH11, DNAL1, DNAAF4 (previously called DYX1C1), GAS2L2, GAS8, HYDIN, INVS, LRRC6, LRRC56, MMP21, NME8, SPAG1, TTC12, ODAD4/TTC25, and ZMYND10 are associated with autosomal recessive PCD with or without laterality defects. SMAD2 is associated with autosomal dominant congenital heart defects with or without heterotaxy. 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. 2007. PubMed ID: 17924340). Two truncating variants in GDF1 were found to cause classic heterotaxy in one Finnish family. Heterozygous carriers were asymptomatic (Kaasinen et al. 2010. PubMed ID: 20413652). De novo variants have been reported in the FOXJ1, DNAAF6 and ZIC3 (Wallmeier. 2019. PubMed ID: 31630787; Paff et al. 2017. PubMed ID: 28041644; Wessels et al. 2010. PubMed ID: 20452998). Copy number variants have been documented in the ODAD2, CCDC40, DNAAF1, DNAAF2, DNAH11, DNAH5, DNAAF4, LEFTY2, NKX2-5, NODAL, SPAG1, OFD1, DNAAF6, ZIC3, and ZMYND10 genes (Human Gene Mutation Database).

See individual gene summaries for information about molecular biology of gene products and spectra of pathogenic variants.

Congenital heart defects and heterotaxy are clinically and genetically heterogeneous. Clinical sensitivity for the primary ciliary dyskinesia portion of this test has been reported to be ~80% (Zariwala et al. 2019. PubMed ID: 20301301). Clinical sensitivity for the entire test is unknown at this time.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 91% coverage of all coding exons of the genes 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 coverage as ≥20X NGS reads or Sanger sequencing.

Due to technical difficulties, only exons 1-5 and 85-86 of the HYDIN gene are included in this panel.

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).