Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease

Defective left-right (LR) pattering results in a spectrum of laterality disorders including situs inversus totalis (SIT) and heterotaxy syndrome (Htx). Approximately, 50% of patients with primary ciliary dyskinesia (PCD) displayed SIT. Recessive variants in DNAH9 have recently been implicated in patients with situs inversus. Here, we describe six unrelated family trios and 2 sporadic patients with laterality defects and complex congenital heart disease (CHD). Through whole exome sequencing (WES), we identified compound heterozygous mutations in DNAH9 in the affected individuals of these family trios. Ex vivo cDNA amplification revealed that DNAH9 mRNA expression was significantly downregulated in these patients carrying biallelic DNAH9 mutations, which cause a premature stop codon or exon skipping. Transmission electron microscopy (TEM) analysis identified ultrastructural defects of the outer dynein arms in these affected individuals. dnah9 knockdown in zebrafish lead to the disturbance of cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle (KV). By generating a Dnah9 knockout (KO) C57BL/6n mouse model, we found that Dnah9 loss leads to compromised cardiac function. In this study, we identified recessive DNAH9 mutations in Chinese patients with cardiac abnormalities and defective LR pattering.

Automated summary

This study identified recessive DNAH9 mutations in Chinese patients with cardiac abnormalities and defective left-right patterning. Whole exome sequencing and transmission electron microscopy were used to confirm the presence and effects of these mutations.