A novel DNAH11 variant segregating in a sibship with heterotaxy and implications for genetic counseling

BACKGROUND: Isomerism or heterotaxy syndrome is the loss of normal asymmetry of the internal thoraco‐abdominal organs in the left‐right axis and is associated with cardiovascular malformations. Mutations within DNAH11 can be associated with primary ciliary dyskinesia and heterotaxy syndromes. METHODS: We report a family of healthy, nonconsanguinous parents with subsequent pregnancies demonstrating a novel likely pathogenic variant in DNAH11 segregating in a sibship with varied presentations. RESULT: The first affected pregnancy presented with right atrial isomerism. Further DNA testing identified three variants in DNAH11 related to primary ciliary dyskinesia: a maternally inherited heterozygous variant of unknown significance (VUS) c.2772G>A (p.Met924Ile), a maternally inherited novel likely pathogenic variant c.11662C>T (p.Arg3888Cys) as well as a paternally inherited pathogenic c.1648delA variant (p.Arg550GlyfsX16). The second pregnancy inherited the same variants including the pathogenic and likely pathogenic DNAH11 variants and presented with left isomerism and extracardiac abnormalities. CONCLUSION: We present a novel likely pathogenic variant (c.11662C>T) in DNAH11 that has manifested in heterotaxy with variability in phenotypes for subsequent pregnancies of common parents. This report demonstrates that sibship illustrates potential variability in phenotypes associated with the same pathogenic variants within a family and highlights the difficulty in genetic counseling due to the variation in clinical presentation.