HKUMed Researchers Discover Novel Gene Implicated in Rare Heterotaxy Syndrome

Rare Daily Staff

Researchers in the department of Pediatrics and Adolescent Medicine at The University of Hong Kong have discovered a novel gene, CC2D1A, which is associated with human heterotaxy, a spectrum of congenital disease that disrupts the arrangement of internal organs.

It is the first time that CC2D1A is reported to be associated with heterotaxy in the literature. The findings have been published in the academic journal, Circulation: Genomic and Precision Medicine.

The placement of organs in the human body is asymmetrical. For example, heart and spleen are on the left side of the body, whereas most of the liver is on the right side. Heterotaxy, also known as situs ambiguous, is a class of human congenital disorders that are characterized by the failure to establish normal left-right asymmetry, resulting in the abnormal arrangement of internal organs on the wrong side of the body. Patients with heterotaxy have congenital birth defects that can affect multiple organs, including the heart, lungs, liver, spleen, stomach, and intestines. The estimated incidence at birth is around 1 in 10,000, and is more common in Asians than in Caucasians. Approximately 90 percent of heterotaxy patients have complex congenital heart defects. Patients with heterotaxy have poor prognosis, with overall survival of less than 50 percent by the age of 10.

More than 20 genes have already been reported to cause heterotaxy. Some of these genes are related to the formation of cilia, which are hair-like projections that stick out from the cell’s surface. Cilia defects may cause abnormal flow of signals that guide the left-right axis formation at the embryonic development, resulting in heterotaxy.

The division of Pediatric Cardiology, Department of Pediatrics and Adolescent Medicine, The University of Hong Kong (HKUMed), has been taking care of this group of patients in Hong Kong for a long time. However, the genetic causes of these patients remained unknown.

The research team used whole exome sequencing technology to identify the disease-causing mutations in 26 patients with heterotaxy, but no pathogenic mutations could be identified in known genes associated with heterotaxy. The researchers then tried to identify new genes not previously associated with heterotaxy. By comparing the mutations identified in patients with controls, they found a significant enrichment of CC2D1A damaging variants in patients.

The CC2D1A gene produces a protein with 951 amino acids, and has been reported to be involved in regulating signaling pathways, immune response, and synapse maturation. CC2D1A has been reported to be associated with intellectual disability in humans, but not heterotaxy. In collaboration with Alvin Ma Chun-hang, assistant professor, Department of Health Technology and Informatics, The Hong Kong Polytechnic University, the function of this gene was further examined on a zebrafish model using gene editing on the cc2d1a gene to create an abnormal protein that lost its functions.

Zebrafish with cc2d1a mutation showed disarrangements in heart and digestive systems, suggesting that the normal left-right asymmetry was disrupted. In addition, defective ciliary was also observed, resulting in fewer and shorter cilia. More importantly, injections of wild type cc2d1a to the edited fertilized egg can rescue the abnormal organ arrangement and ciliary defects. The result demonstrated that mutations in cc2d1a disrupt the establishment of left-right axis formation, and the disease mechanism of heterotaxy resulted from abnormal function of cilia.

“Surprisingly, mutations in Caucasian patients with heterotaxy cannot be found in our local patients. It shows that we have to perform the genetic study at our own capacity to discover the unique disease-causing mutations in Chinese or Asians,” said Brian Chung Hon-Yin, clinical associate professor, Department of Pediatrics and Adolescent Medicine, HKUMed. “Our study provides the first evidence on the association of the CC2D1A gene with human heterotaxy, which will facilitate the genetic diagnosis of heterotaxy patients more precisely in Hong Kong.”

The findings of the study have significant implications in the understanding of the genetics of heterotaxy in Hong Kong, making pre-implantation genetic diagnosis of CC2D1A in families with a history of heterotaxy possible.

Photo: Brian Chung Hon-yin, clinical associate professor, Department of Pediatrics and Adolescent Medicine, HKUMed