Heterotaxy and Situs Inversus Panel

Content Review: May 2021 Last Update:
  • Use to detect variants in genes known to cause laterality defects such as situs inversus, heterotaxy, or complex congenital heart defects.
  • Regions of low coverage and reported variants are confirmed by Sanger sequencing as necessary.

Laterality defects, such as heterotaxy and situs inversus, are developmental defects characterized by the abnormal placement of the abdominal (visceral) organs. Situs inversus totalis involves the complete transposition of all visceral organs, while heterotaxy (situs ambiguus) is used to describe any deviation from the standard placement of organs in the abdomen. Laterality defects can also impact the left-right symmetry in the heart, and many individuals with heterotaxy have congenital heart defects. These conditions are clinically and genetically heterogeneous and have been associated with pathogenic variants in a number of different genes that are involved in both early embryo development and pathways related to left-right patterning. Clinical symptoms are variable and depend on the function of the organs involved.

Disease Overview

Symptoms/Associated Disorders

Symptoms vary depending on the organs involved and may include cyanosis or other complications of congenital heart disease, digestive problems due to intestinal malrotation, or immunologic disorders due to abnormal spleen function. 

Primary ciliary dyskinesia (Kartagener syndrome) is an associated disorder caused by abnormalities of the motile cilia, which leads to sinopulmonary disease, infertility, and, in 50% of cases, situs inversus. For more information, see the Primary Ciliary Dyskinesia Panel Test Fact Sheet.

Epidemiology/Prevalence

Heterotaxy syndrome affects approximately one in 10,000 individuals and is causative of about 3% of cases of congenital heart defects.

Genetics

Etiology

Pathogenic germline variants in genes associated with left-right symmetry in early embryo development

Penetrance

Varies; some associated genes exhibit reduced penetrance

Inheritance

Varies; see Genes Tested table

Test Interpretation

Clinical Sensitivity

Variable, dependent on phenotype/condition

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a heritable laterality defect.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
    • Regulatory region and deep intronic variants
    • Large deletions/duplications in any of the tested genes
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • ANKS6(NM_173551) exon(s) 1
      • ARMC4(NM_001290020) exon(s) 9
      • ARMC4(NM_001290021) exon(s) 13
      • ARMC4(NM_001312689) exon(s) 4
      • ARMC4(NM_018076) exon(s) 9
      • CCDC103(NM_001258397) exon(s) 4
      • CCDC114(NM_001364171) exon(s) 3
      • CCDC114(NM_001364171) partial exon(s) 4(Chr19:48822049-48822069)
      • CCDC40(NM_001243342) exon(s) 18
      • CFAP298(NM_001350335) partial exon(s) 5(Chr21:33975399-33975450)
      • CFAP298(NM_001350337) partial exon(s) 6(Chr21:33974534-33974561)
      • DNAAF5(NM_017802) exon(s) 1
      • DNAI2(NM_001353167) exon(s) 13
      • GATA6(NM_005257) partial exon(s) 2(Chr18:19751812-19751963)
      • PKD1L1(NM_138295) partial exon(s) 8(Chr7:47955029-47955060)
      • SPAG1(NM_001374321) partial exon(s) 11(Chr8:101225456-101225529)
      • SPAG1(NM_003114) partial exon(s) 11(Chr8:101225456-101225529)
      • SPAG1(NM_172218) partial exon(s) 11(Chr8:101225456-101225529)
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
    • Low-level somatic variants

Genes Tested

Gene Name MIM # Associated Disorder Inheritance Pattern

ANKS6

615370

Nephronophthisis

AR

ARL2BP

615407

Retinitis pigmentosa with or without situs inversus

AR

ARMC4

615408

PCD

AR

CCDC103

614677

PCD

AR

CCDC114

615038

PCD

AR

CCDC151

615956

PCD

AR

CCDC39

613798

PCD

AR

CCDC40

613799

PCD

AR

CFAP298

615494

PCD

AR

CFAP53

614759

Visceral heterotaxy

AR

CRELD1

607170

Atrioventricular septal defect, partial, with heterotaxy syndrome

AD

DNAAF1

613190

PCD

AR

DNAAF2

612517

PCD

AR

DNAAF3

614566

PCD

AR

DNAAF4

608706

PCD

AR

DNAAF5

614864

PCD

AR

DNAH1

603332

PCD

AR

DNAH11

603339

PCD

AR

DNAH5

603335

PCD

AR

DNAI1

604366

PCD

AR

DNAI2

605483

PCD

AR

DNAL1

610062

PCD

AR

FOXH1

603621

Congenital heart defects (multiple types)

AD

GATA4

600576

Congenital heart defects (multiple types)

AD

GATA6

601656

Congenital heart defects (multiple types)

AD

INVS

243305

Nephronophthisis

AR

LRRC6

614930

PCD

AR

MMP21

608416

Visceral heterotaxy

AR

NKX2-5

600584

Congenital heart defects (multiple types)

AD

NME8

607421

PCD

AR

NODAL

601265

Visceral heterotaxy

AD

PIH1D3

300933

PCD

XLR

PKD1L1

609721

Visceral heterotaxy

AR

SPAG1

603395

PCD

AR

ZIC3

300265

Visceral heterotaxy, Congenital heart defects

XLR

ZMYND10

607070

PCD

AR

AD, autosomal dominant; AR, autosomal recessive; PCD, primary ciliary dyskinesia; XLR, X-linked recessive

Additional Resources