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. 2025 Jan 7;18(1):4.
doi: 10.1186/s12920-024-02078-0.

Whole-exome sequencing uncovers the genetic basis of hereditary concomitant exotropia in ten Chinese pedigrees

Wenhua Duan  1 , Taicheng Zhou  2 , Xiaoru Huang  3 , Dongqiong He  4 , Min Hu  2
Affiliations

Whole-exome sequencing uncovers the genetic basis of hereditary concomitant exotropia in ten Chinese pedigrees

Wenhua Duan et al. BMC Med Genomics. .

Abstract

Purpose: To explore possible pathogenic genes for concomitant exotropia using whole-exome sequencing.

Methods: In this study, 47 individuals from 10 concomitant exotropia (including intermittent exotropia and constant exotropia) pedigrees were enrolled. Whole-exome sequencing was used to screen mutational profiles in 25 affected individuals and 10 unaffected individuals. Sanger sequencing and in silico analysis were performed for all participants. Two target genes were used to capture the sequences of 220 sporadic samples.

Results: All 10 concomitant exotropia pedigrees presented autosomal dominant inheritance with childhood onset (3.35 ± 1.51 years old). Eleven different missense variants were identified among seven potential pathogenic genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that cosegregated with pedigree members. All variants were predicted to be deleterious and had low frequencies in the general population. Distinct variants of COL4A2 were present in three pedigrees, and distinct variants of SYNE1 were present in two pedigrees. Fifteen variants in AUTS2 and four variants in GTDC2 were identified in 220 patients with sporadic concomitant exotropia using a target-capture sequencing approach.

Conclusion: This is the first study to explore the genetic mechanism of concomitant exotropia and identify seven associated genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that may be candidate genes causing concomitant exotropia. More samples and in-depth studies are needed to verify these findings.

Keywords: Concomitant exotropia; Genetics; Strabismus.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was performed in accordance with the Declaration of Helsinki. It was reviewed by the research unit’s professional ethics committee, and informed consent was obtained and signed by the investigator. Our study was approved by the Ethics Committee of The Affiliated Hospital of Yunnan University (The Second People’s Hospital of Yunnan Province), No. 20180774. Informed written consent was obtained from all the participants and the legal guardians of the children. Consent for publication: Written informed consent was obtained from the patients or their guardians (parents), and they consented to the publication of their medical information. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Workflow for genetic variant detection and validation in concomitant exotropia pedigrees
Fig. 2
Fig. 2
Pedigrees of 10 families with exotropia. Excluded participants are marked with an “X”. Affected individuals are represented by symbols with a black fill, with border colors indicating the type of exotropia: intermittent exotropia (IXT) is marked by a red border, and constant exotropia (CXT) is marked by a green border. Unaffected individuals are shown as unfilled symbols. Individuals with unknown diagnostic status are shaded in gray. Males are depicted as squares, and females are depicted as circles. Arrows indicate the probands
Fig. 3
Fig. 3
Venn diagrams showing the overlap of genes between family-specific genes and the Human Phenotype Ontology (HPO) strabismus gene list. (A) Venn diagram depicting the overlap of identified genes among Families 1 (F1), 8 (F8), and 9 (F9) with the HPO strabismus gene list (HP:0000486). (B) Venn diagram showing the overlap of genes among Families 3 (F3) and 6 (F6) with the HPO strabismus gene list (HP:0000486)
Fig. 4
Fig. 4
Chromatograms showing nucleotide sequences for wild-type (WT) and mutated (variant) alleles for each gene. Each panel compares the WT sequence (top) from an unaffected individual with the mutated sequence (bottom) from an affected pedigree member. The arrows indicate the nucleotide position of each variant
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