DNAH11 variants and its association with congenital heart disease and heterotaxy syndrome

Sida Liu,Shuolin Li,Wei Sheng,Guoying Huang,Weicheng Chen,Xiaojing Ma,Yongkun Zhan,Duan Ma

doi:10.1038/s41598-019-43109-6

Abstract

Congenital heart diseases (CHDs) are the most common types of birth defects, affecting approximately 1% of live births and remaining the leading cause of mortality. CHD patients often show a higher incidence of heterotaxy syndrome. However, the exact aetiology of CHD and heterotaxy syndrome remains unclear. In this study, targeted sequencing and Sanger sequencing were performed to analyze the exonic regions of 37 primary ciliary dysfunction (PCD)- related candidate genes in 42 CHD patients with heterotaxy syndrome. Variants affecting protein-coding regions were filtered according to databases of known variants and predicted in silico using functional prediction program. Thirty-four potential disease-causing heterozygous variants in 11 genes were identified in the 19 CHD patients with heterotaxy syndrome (45.2%, 19/42). The DNAH11 gene showed the highest mutation rate (16.7%; 14 of 84 alleles) among the CHD patients with heterotaxy. Fisher’s exact test revealed a significant association of DNAH11 variants with CHD and heterotaxy (P = 0.0001). In families, six different compound heterozygous variants of DNAH11 were validated in family 1-5031 (p.W802X/p.M282I), family 2-5045 (p.T3460K/p.G4425S), family 3-5065 (p.G447R/p.L1157R), family 4-5130 (p.I2262T/p.D3800H), family 5-5707 (p.S1823fs/p.F2759L/p.R4395X) and family 6-5062 (p.D3610V/p.I243V). These findings suggest that the DNAH11 variants are significantly associated with CHD and heterotaxy syndrome and that compound heterozygous DNAH11 variants may be the common genetic cause of the development of familial CHD and heterotaxy syndrome.

Highlights

Congenital heart diseases (CHDs) are the most common types of birth defects, affecting approximately 1% of live births and remaining the leading cause of mortality[1]
An overwhelming majority of previous studies related to DNAH11 have focused on primary cilia dysfunction (PCD) and situs inversus totalis, and few studies have concentrated on heterotaxy and CHD
To investigate the role of gene variants in CHD/heterotaxy diseases, we carried out targeted sequencing on the exonic regions of the following 37 PCD-related candidate genes in 42 CHD patients with heterotaxy: ABCC4, ARMC4, C21orf[59], CCDC39, CCDC40, CCDC65, CCDC114, CCDC151, CCNO, DNAAF1, DNAAF2, DNAFF3, DNAAF5, DNAH5, DNAH8, DNAH11, DNAI1, DNAI2, DNAL1, DRC1, DYX1C1, HEATR2, HYDIN, LRRC6, NAT10, NME8, PTGES, PTGES2, PTGES3, PTGER4, PTGS1, PTGS2, RSPH1, RSPH4A, RSPH9, SPAG1 and ZMYND10

Summary

Introduction

Congenital heart diseases (CHDs) are the most common types of birth defects, affecting approximately 1% of live births and remaining the leading cause of mortality[1]. CHD and heterotaxy syndrome have been shown to be associated with primary cilia dysfunction (PCD) or cilia dysfunction (CD). PCD is considered to be a monogenic heterogeneous recessive disorder, while CHD and heterotaxy syndrome are multiple-gene complex inherited diseases[5]. Studies have shown that mutations in genes causing PCD may be associated with the development of heterotaxy and/or CHD syndrome. 50% of PCD patients exhibit heterotaxy associated with complex CHDs6. PCD-related genes in heterotaxy are thought to be responsible for the function of motile cilia in LR patterning, and CHD/heterotaxy patients show increased airway CD similar to that seen in PCD patients[7]. Researchers have shown that CHD and heterotaxy syndromes are multiple, complex, inherited diseases caused by numerous genes that are responsible for inherited and sporadic cases[8]. An overwhelming majority of previous studies related to DNAH11 have focused on PCD and situs inversus totalis, and few studies have concentrated on heterotaxy and CHD

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