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. 2023 Jun 29:10:1190162.
doi: 10.3389/fmolb.2023.1190162. eCollection 2023.

Identification of novel compound heterozygous variants in the DNAH1 gene of a Chinese family with left-right asymmetry disorder

Lamei Yuan  1   2   3   4 , Xuehui Yu  1   2 , Heng Xiao  1   2 , Sheng Deng  5 , Hong Xia  6 , Hongbo Xu  2 , Yan Yang  4 , Hao Deng  1   2   3   4
Affiliations

Identification of novel compound heterozygous variants in the DNAH1 gene of a Chinese family with left-right asymmetry disorder

Lamei Yuan et al. Front Mol Biosci. .

Abstract

Most internal organs in humans and other vertebrates exhibit striking left-right asymmetry in position and structure. Variation of normal organ positioning results in left-right asymmetry disorders and presents as internal organ reversal or randomization. Up to date, at least 82 genes have been identified as the causative genetic factors of left-right asymmetry disorders. This study sought to discover potential pathogenic variants responsible for left-right asymmetry disorder present in a Han-Chinese family using whole exome sequencing combined with Sanger sequencing. Novel compound heterozygous variants, c.5690A>G (p.Asn1897Ser) and c.7759G>A (p.Val2587Met), in the dynein axonemal heavy chain 1 gene (DNAH1), were found in the proband and absent in unaffected family members. Conservation analysis has shown that the variants affect evolutionarily conserved residues, which may impact the tertiary structure of the DNAH1 protein. The novel compound heterozygous variants may potentially bear responsibility for left-right asymmetry disorder, which results from a perturbation of left-right axis coordination at the earliest embryonic development stages. This study broadens the variant spectrum of left-right asymmetry disorders and may be helpful for genetic counseling and healthcare management for the diagnosed individual, and promotes a greater understanding of the pathophysiology.

Keywords: DNAH1; genetic analysis; left-right asymmetry disorder; novel variant; whole exome sequencing.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Genetic analysis of the left-right (L-R) asymmetry disorder pedigree and the representative computed tomography (CT) image of the proband. (A) Pedigree analysis of the L-R asymmetry disorder family. Squares and circles indicate males and females, respectively; open symbols indicate unaffected family members; the arrow indicates the proband; the symbol with a slash indicates a deceased member. (B) CT image of the proband showed the stomach and spleen were right-sided, and the liver was left-sided. (C) Heterozygous DNAH1 c.5690A>G (p.Asn1897Ser) variant in the proband (II:2). (D) Heterozygous DNAH1 c.7759G>A (p.Val2587Met) variant in the proband (II:2).
FIGURE 2
FIGURE 2
Conservation analyses of the dynein axonemal heavy chain 1 p.Asn1897 and p.Val2587 amino acid residues.
FIGURE 3
FIGURE 3
Cartoon model of the dynein axonemal heavy chain 1 (DNAH1) protein structure visualized by PyMOL based on the SWISS-MODEL. The asparagine (N) and mutated serine (S) at position 1897 and the valine (V) and mutated methionine (M) at position 2587 are indicated with ball-and-stick models.
See this image and copyright information in PMC

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Grants and funding

This study was supported by the National Natural Science Foundation of China (Grant Nos. 81670216, 81873686, and 81800219), Natural Science Foundation of Hunan Province (Grant Nos. 2020JJ4830, 2020JJ3057, and 2022JJ30922), Hunan Provincial Innovation Foundation for Postgraduate (Grant No. CX20210375), Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (Grant No. YX202109), and Distinguished Professor of the Lotus Scholars Award Program of Hunan Province, China.

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