HKU discovers CC2D1A mutations specific to local heterotaxy patients

Researchers at the Department of Paediatrics and Adolescent Medicine, University of Hong Kong (HKU), have discovered a unique association between CC2D1A mutations and heterotaxy in Chinese or Asian patients.

Heterotaxy, also known as situs ambiguous, is a class of human congenital disorders that are characterized by a failure to establish normal left-right (L-R) asymmetry and by the misplacement of one or more organs during embryonic development. [Eur J Hum Genet 2006;14:17-25]

“The genetic basis of heterotaxy has been studied for decades, but is still poorly characterized. Although most cases of heterotaxy are sporadic, Mendelian inheritance and familial occurrence have also been reported,” wrote the researchers. “Our study is the first to identify seven rare, damaging exonic missense variants of CC2D1A in six out of 26 [23 percent] patients with heterotaxy using whole-exome sequencing.” [Circ Genom Precis Med 2020;13(6):e003000]

The researchers performed whole-exome sequencing and copy number variant analyses on 26 local patients with heterotaxy. In spite of the advances in genetic sequences and the discovery of a number of gene contributors to the heterotaxic phenotype, which include components of the nodal signalling pathway, cilia or flagella associated protein-coding genes, no pathogenic mutations were identified in these genes in the current cohort. [Nat Genet 2015;47:1260-1263]

“Surprisingly, mutations in Caucasian patients with heterotaxy could not be found in our local patients. It shows that we have to perform our own genetic research to discover the unique disease-causing mutations in Chinese or Asians. The evidence from our study will facilitate genetic diagnosis of heterotaxy patients more precisely in Hong Kong,” said Dr Brian Chung of the Department of Paediatrics and Adolescent Medicine at HKU.

To determine genes with significant enrichment in heterotaxy, SNP-set Kernel Association Test was performed in the 26 heterotaxy cases and in 130 local controls with no known cardiac or laterality defects. “Among them, only one gene, CC2D1A, showed statistical significance [p=0.0379],” reported the researchers. Seven occurrences of the rare mutations in CC2D1A were identified in six out of the 26 cases, with one patient harbouring two different mutations simultaneously.

“To functionally evaluate the candidate mutations in vivo, we used a zebrafish model, as the cc2d1a gene is highly conserved between humans and this species,” explained the researchers. The knockout zebrafish model with cc2d1a mutations exhibited obvious heterotaxy and ciliopathy phenotypes, providing evidence of cc2d1a’s importance in L-R axis formation during embryonic development. “Despite the heterogeneity of genetic causes, the role of cilia in breaking the L-R symmetry and hence the pathogenesis of heterotaxy is crucial,” commented the researchers.

To date, the only human disease reported to be associated with CC2D1A is autosomal recessive nonsyndromic intellectual disability. [J Med Genet 2006;43:203-210] “Personal communication with Dr L Basel-Vanagaite, the first author of [the aforementioned] study, confirmed that none of the autosomal recessive nonsyndromic intellectual disability patients or the carrier parents had laterality defects … To the best of our knowledge, our study is the first to suggest an association of CC2D1A with heterotaxy,” stated the researchers.

“Heterotaxy research in Hong Kong is important as clinical management continues to be challenging,” said Professor Yiu-Fai Cheung of the Department of Paediatrics and Adolescent Medicine at HKU. With the genetic cause identified, preimplantation genetic diagnosis of CC2D1A in families with family history could be possible.