Heterotaxy, Visceral, 6, Autosomal

A number sign (#) is used with this entry because of evidence that autosomal visceral heterotaxy-6 (HTX6) is caused by homozygous mutation in the CCDC11 gene (614759) on chromosome 18q21.

For a discussion of the genetic heterogeneity of visceral heterotaxy, see HTX1 (306955).

Clinical Features

Perles et al. (2012) reported 2 brothers, born of consanguineous Arab-Muslim parents, with variable manifestations of visceral heterotaxy. The younger brother, aged 14 years, presented with congenital heart disease and severe cyanosis. Echocardiography showed a complex cardiovascular defect and abdominal situs abnormalities. He died after corrective surgery. Radiographs showed midline liver and inverted stomach and spleen. His heart malformation included dextrocardia, a complete unbalanced atrioventricular canal defect with single atrium and common atrioventricular valve, hypoplastic left ventricle with bulboventricular foramen, double outlet right ventricle with transposition of the great arteries, severe pulmonary stenosis, right aortic arch, abnormal systemic venous return, and total anomalous pulmonary venous drainage. In contrast, his 17-year-old, apparently healthy brother was found to have situs inversus totalis with normal cardiac anatomy and function. He had no respiratory symptoms, and sperm count, structure, and motility were normal. Light microscopy examination of a nasal sample showed beating ciliated cells, and electron microscopy showed normal ciliary ultrastructure with typical 9:2 doublet microtubules, excluding a ciliary defect.

Narasimhan et al. (2015) reported a patient (OP-1069-II1), born of consanguineous parents, with situs inversus totalis. He had mild respiratory symptoms, including recurrent cough and sinusitis, but normal nasal nitric oxide levels. Further clinical details were not provided.

Inheritance

The transmission pattern of heterotaxy-6 in the family reported by Perles et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

By homozygosity mapping followed by candidate gene analysis of 2 brothers with heterotaxy-6, Perles et al. (2012) identified a homozygous splice site mutation in the CCDC11 gene (614759.0001).

In a patient, born of consanguineous parents, with HTX6, Narasimhan et al. (2015) identified a homozygous truncating mutation in the CCDC11 gene (R41X; 614759.0002). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing, was found in heterozygous state in the unaffected father. CCDC11 was undetectable in patient respiratory cilia, consistent with a loss of function, but patient respiratory cilia showed no morphologic defects.

Animal Model

In zebrafish embryos, Narasimhan et al. (2015) found expression of ccdc11 in the cilia in Kupffer vesicle (KV), in the floor plate of the spinal cord, and in the pronephric ducts. Ccdc11 localized along the axoneme of cilia in pronephric kidney tubules but localized exclusively to the ciliary base in KV and motile cilia in the neural tube. Visualization studies indicated that ccdc11 was required for proper cilia motility in the spinal canal and KV, but not for motility in the pronephric cilia. Ultrastructural studies of the KV showed a reduction in the numbers of outer dynein arms in zebrafish with morpholino knockdown of ccdc11. Morpholino knockdown of ccdc11 resulted in phenotypes consistent with defective motile cilia, including curved body axis, hydrocephalus, edema, and abnormalities in left-right asymmetry. There were no obvious defects in the gross morphology of motile cilia. The findings indicated that ccdc11 activity is differentially required for distinct cilia types.