Heterotaxy

Heterotaxy is congenital in origin and typically recognised prenatally on detailed cardiac and visceral imaging, or in the neonatal period when complex congenital heart disease prompts evaluation. The cardinal feature is failure of normal left-right organ patterning during embryogenesis, with phenotypes classically grouped as right isomerism (asplenia type) and left isomerism (polysplenia type). Cardiac malformations are the principal driver of morbidity and mortality across the heterotaxy spectrum, with right isomerism conferring substantially poorer outcomes than left isomerism. Extracardiac involvement is frequent and typically includes asplenia or polysplenia, biliary tract anomalies, and intestinal malrotation. Both syndromic and non-syndromic presentations occur: non-syndromic forms are restricted to laterality defects and cardiac anomalies, while syndromic forms overlap most prominently with primary ciliary dyskinesia, in which laterality defects accompany chronic otosinopulmonary disease and are reported in 10% of affected individuals.

The incidence of heterotaxy is approximately 1 to 1.5 per 10,000 live births.

A large number of genes have been associated with heterotaxy, and submicroscopic microdeletions and microduplications represent a further important mechanistic class. The genetic forms can be grouped into left-right axis signaling, motile-ciliopathy genes, and chromosomal contributors. Examples include ZIC3-related X-linked heterotaxy (zinc-finger transcription factor; X-linked form), DNAH5-related primary ciliary dyskinesia with laterality defect (axonemal outer-arm dynein heavy chain), and pathogenic copy-number variants recurrent in heterotaxy cohorts.

The genetic conditions associated with heterotaxy follow heterogeneous inheritance patterns. Reported modes across the spectrum include autosomal dominant, autosomal recessive, and X-linked inheritance. De novo variants and chromosomal events also contribute, and the inheritance pattern is determined at the level of the identified entity rather than heterotaxy as a whole.

Molecular genetic testing has the following clinical role:

• Where heterotaxy is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Saba TG, Geddes GC, Ware SM, Schidlow DN, Del Nido PJ, Rubalcava NS, et al. A multi-disciplinary, comprehensive approach to management of children with heterotaxy. Orphanet journal of rare diseases. 2022;17(1):351. doi: 10.1186/s13023-022-02515-2. PMID: . PMCID: PMC9463860.