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

BMC Medical Genomics volume 18, Article number: 4 (2025) Cite this article

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.

Peer Review reports

Introduction

Strabismus is one of the most common eye diseases, affecting approximately 2.4–4.6% of children of different races and regions [1, 2]. Strabismus can affect a patient’s vision, binocular vision function, appearance, balance control, job selection, and quality of life [3,4,5].

Concomitant exotropia is a common type of concomitant strabismus. In Asians, concomitant exotropia is more common than esotropia is, with an incidence of 1–2% in children [6]. Patients with concomitant exotropia are likely to be undiagnosed because they usually have unaffected corrected visual acuity and eye movement. Families with a history of hereditary concomitant exotropia often have multiple affected members; if the optimal intervention period is missed, the stereoscopic vision of affected patients cannot be effectively improved and restored [7]. The pathogenesis of concomitant exotropia is attributed to genetic, environmental (external) and microenvironmental (internal) factors [8]. Risk factors for concomitant exotropia in childhood include heredity, ametropia, astigmatism, ethnic origin, low birth weight (< 1500 g), the presence of hypoxia at birth, and smoking by pregnant women [9, 10].

In recent years, an increasing number of clinical observations have shown that concomitant strabismus has a clear familial tendency [11,12,13], suggesting that hereditary factors play a very important role in unexplained concomitant exotropia. Research on familial exotropia continues to grow, with some genetic susceptibility genes already identified. For example, Min et al. used whole-exome sequencing to examine a two-generation family with concomitant exotropia, identifying AHI1 c.3257 A > G and NEB c.914 A > G as potential causal variants [14]. Similarly, Gong et al. studied a three-generation Chinese family in which both a 7-year-old girl and her mother had intermittent exotropia, identifying PAX3 c.434G > T (p.R145L) as a potential causative variant [15]. These results expand our understanding of the relevant genetic etiology of concomitant exotropia. However, there have been few studies on concomitant exotropia, which include small genetic pedigrees and insufficient sample sizes, and its specific pathogenic genes and mechanisms are still unclear. In addition, some genetic research on concomitant strabismus has not distinguished between esotropia and exotropia [16, 17], which may increase the difficulty of identifying pathogenic genes. To date, we have conducted genetic studies on specific concomitant exotropia populations to explore possible pathogenic genes.

The aim of this study was to identify potential pathogenic genes associated with concomitant exotropia through whole-exome sequencing and analysis of variant profiles in ten Chinese families.

Patients and methods

Sample collection and diagnostic procedures

All patients were from Yunnan, China. The patients we identified were limited to those with concomitant exotropia, including both intermittent and constant exotropia. The patients were defined as individuals from pedigrees with at least two affected members. All patients underwent a careful slit-lamp examination by an experienced ophthalmologist to rule out any ocular diseases, including eye movement-related disorders such as nystagmus. Patients with any of these ocular diseases or with nervous system or other systemic diseases were excluded from the study. The proband and available pedigree members were examined for best corrected visual acuity, Hirschberg corneal reflex test, angle of deviation at near (33 cm) and far (5 m) distances using the prism and alternate cover test, stereopsis, ocular appearance and fundus photography. The prism test was performed after 1 h of monocular coverage (full break of binocular fusion). Affected members with concomitant exotropia were defined as having a horizontal misalignment of 10.00 or more diopters in the prism test at either near or far distances from the primary position. Unaffected individuals were defined as having unaffected corneal reflection and stereopsis. Finally, 47 participants (32 affected and 15 unaffected) from 10 pedigrees were included in the study.

Whole-exome sequencing and data analysis

Peripheral blood was obtained from all 47 participants and collected for DNA extraction (AP-MN-BL-GDNA-250, Axygen, USA). Whole-exome sequencing was used to screen the mutational profiles of 25 affected individuals and 10 unaffected individuals. Exome capture was performed using the Agilent SureSelect Human All Exon V6 capture kit (Santa Clara, CA, USA). Sequencing was conducted on the DNBSEQ high-throughput sequencing platform developed by BGI Technology Services Co., Ltd. (BGI-Shenzhen, China).

We used 1 µg of genomic DNA to construct whole-genome libraries. All the clean data from each sample were subsequently mapped to the human reference genome (HG19) [18]. We strictly followed the recommended best practices for variant analysis with the Genome Analysis Toolkit (GATK) to ensure accurate variant calling. Base quality score recalibration and duplicate read marking were performed using GATK [19]. The sequencing depth and coverage for each individual were calculated based on the alignments. The GATK HaplotypeCaller tool was used to detect single-nucleotide polymorphisms (SNPs) and insertion-deletions (InDels) simultaneously.

To narrow down candidate variants, the main filtering criteria included the following: (1) population frequency in databases, selected from databases with less than 0.005 variant frequencies; (2) prediction of pathogenicity, using programs such as SIFT, PolyPhen2, MutationTaster, MutationAssessor, FATHMM, PROVEAN and CADD [20], to determine whether the variant was harmful (a variant was considered harmful if more than half of the prediction tools indicated harmful effects); and (3) segregation analysis, for which the corresponding genetic model (autosomal dominant, AD/autosomal recessive, AR) of the pedigree was selected, with clear typing, and the number of sequencing case/control samples was fully consistent.

The online software Wayne (VENNY2.1, https://bioinfogp.cnb.csic.es/tools/venny/index.html) was used to explore the candidate genes that were consistent between different pedigrees and the genes in each pedigree that intersected with the Human Phenotype Ontology (HPO, https://hpo.jax.org/app/) for strabismus (HP:0000486, strabismus).

Sanger sequencing

Sanger sequencing was performed on all 47 individuals for segregation analysis. Primers were designed (https://www.ncbi.nlm.nih.gov/tools/primer-blast/) for the candidate genes of each pedigree, PCR was performed (ABI, American), and then first-generation Sanger sequencing was used to validate the candidate variants (genes and primer information are shown in Table 2).

Variant validation

Based on information provided for family members and appropriate gene size, a special full-exon panel for AUTS2 and GTDC2 was designed (by BGI Technology Services Co., Ltd.) for capture sequencing to search for other possible variants.

Results

Figure 1 shows the workflow of exome sequencing analysis from sample collection, validation of variants in concomitant exotropia pedigrees, exon capture and sequencing of the target gene, and variant validation.

Fig. 1
figure 1

Workflow for genetic variant detection and validation in concomitant exotropia pedigrees

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Pedigree information

Forty-seven individuals from 10 pedigrees were included in this study. All patients were from Yunnan, China. Among the 32 affected patients, 43.75% were male, and 56.25% were female.

Figure 2 shows the pedigrees of the ten studied Chinese families

Fig. 2
figure 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

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Among the 10 concomitant exotropia pedigrees, there were 5 intermittent exotropia pedigrees (F1, F2, F4, F5, and F10), 2 constant exotropia pedigrees (F3 and F6), and 3 pedigrees with mixed intermitted and constant exotropia (F7, F8, and F9). Among the 47 individuals, 11 were diagnosed with constant exotropia, 21 with intermittent exotropia, and 15 were unaffected. All pedigrees showed autosomal dominant inheritance (Fig. 2).

The available clinical findings of the studied members of the pedigrees are summarized in Table 1.

Table 1 Clinical data (10 concomitant exotropia pedigrees, 32 affected and 15 unaffected)
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Table 2 Lists the Sanger sequencing-verified genes that achieved coisolation in each pedigree (including primers, product size, and annealing temperature)
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Except for participants who were unsure of the exact age of onset, the mean onset age of concomitant exotropia in pedigrees was 3.35 ± 1.51 years (26 patients). All the participants had unaffected corrected visual and eye movements. Stereopsis (unaffected: 40 s of arc) was impaired to varying degrees in 25 (78.1%) affected patients.

Genetic analysis in concomitant exotropia pedigrees

Exome sequencing was performed on 47 individuals from 10 concomitant exotropia pedigrees. After removing low-quality reads, we obtained an average of 86,196,646 clean reads (12,929,496,900 bps). The clean reads of each sample had high Q20 and Q30 values, indicating high sequencing quality. The average GC content was 50.78%. Duplicate reads accounted for approximately 14.85% of the total mapped reads, and the average sequence read depth was 107.79×. On average, per sequenced individual, the whole genome, excluding gap regions, was covered by at least 1 read. We identified an average of 131,079 SNPs, 99.18% of which were represented in dbSNP and 92.7% of which were annotated in the 1000 Genomes Project database. The number of novel InDels was 2,991.

In total, we identified 11 different missense variants among 7 potential pathogenic genes, which cosegregated with pedigree members (Table 3: Candidate genes and variants). Among these genes, 5 genes (COL4A2, SYNE1, AUTS2, HERC2, and CDH3) intersected with the Human Phenotype Ontology (HPO) strabismus gene list (HP:0000486).

Table 3 Shows chromosome and variant details of the target genes
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Figure 3 shows the overlap of genes between some family-specific genes and the Human Phenotype Ontology (HPO) strabismus gene list.

Fig. 3
figure 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)

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In a multipedigree study of the same hereditary disease, Venn diagram comparison was able to help us quickly identify possible cosegregated genes. All candidate SNPs identified by whole-exome sequencing were verified by Sanger sequencing (the results are shown in Fig. 4).

Fig. 4
figure 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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Figure 4 shows the nucleotide sequences of the cosegregated genes for each pedigree.

Verification of candidate genes in sporadic cases

In accordance with the results of Sanger sequencing and previous data analysis, AUTS2 and GTDC2 were selected for validation in sporadic concomitant exotropia samples and an unaffected population. In the validation of the expanded sample, the c.979 C > T (p.R327C) variant in AUTS2 was not detected in 496 sporadic concomitant exotropia samples or 239 unaffected samples, and the c.1181G > A (p.R394Q) variant in GTDC2 was not detected in 422 sporadic concomitant exotropia samples or 239 unaffected samples (Table 4). The capture sequencing results revealed that in 220 sporadic concomitant exotropia samples, 15 variants in AUTS2 were captured (Table 5), and 4 variants were captured in GTDC2 (Table 6).

Table 4 Shows that AUTS2 and GTDC2 were validated in sporadic concomitant exotropia samples and an unaffected population. The AUTS2 c.979C > T (p.R327C) variant was not detected in 496 sporadic samples or 239 unaffected samples. The GTDC2 c.1181G > A (p.R394Q) variant was not detected in 422 sporadic samples or 239 unaffected samples.
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Table 5 A full-exon panel of AUTS2 was designed for capture sequencing in 220 sporadic concomitant exotropia samples to search for other possible variants. Table 5 shows that in 220 sporadic concomitant exotropia samples, 15 variants were captured (including 12 SNP variant sites and 3 Indels) in AUTS2
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Table 6 A full exon panel of GTDC2 was designed for capture sequencing in 220 sporadic concomitant exotropia samples to search for other possible variants. Table 6 shows that in 220 sporadic concomitant exotropia samples, 4 SNP variant site variants in GTDC2 were captured.
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Discussion

This is the first study to explore the genetic mechanism of concomitant exotropia. Eleven different missense variants were identified among seven potential pathogenic genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that cosegregated with pedigree members.

Concomitant strabismus is characterized by an angle of deviation (magnitude of ocular misalignment) that remains the same in all directions of gaze, whichever eye is fixed [21]. Concomitant exotropia includes intermittent exotropia and constant exotropia [22]. Intermittent exotropia in infancy tends to rapidly progress to the constant phase [23]. Intermittent exotropia is more likely to develop into constant exotropia when there are decreases in binocular function and the stability of the eye movement control system [24]. In our study, there were 5 intermittent exotropia pedigrees, 2 constant exotropia pedigrees and 3 mixed pedigrees (both intermittent and constant strabismus members in one pedigree). Intermittent exotropia mostly occurs in children and has a higher incidence in patients with concomitant exotropia and a more pronounced inheritance tendency [22], which is consistent with our research.

The familial nature of isolated or nonsyndromic strabismus has been recognized in the medical literature since Hippocrates [25]. Cantolino and Von Noorden reported that there may be a hereditary component to microtropia, the minor form of strabismus [26]. Pedigree studies suggest that there is a strong genetic component to the etiology of concomitant strabismus, with approximately 30% of probands with strabismus having a pedigree member or close relative with strabismus [11]. To date, most progress in understanding the genetics of strabismus has been made in cases of incomitant strabismus [27,28,29,30,31]. Only a few studies have been performed on concomitant exotropia, and no distinction has been made between concomitant exotropia and esotropia [17, 32].

In this study, we limited the subjects to pedigrees with concomitant exotropia to exclude the interference of other types of strabismus, such as esotropia. Our results revealed that the onset age of individuals in pedigrees was earlier (3.35 ± 1.51 years, 26 cases) than that of individuals with sporadic (6.19 ± 5.45 years, 377 cases) concomitant exotropia. The results revealed that genetic factors play important roles in the early onset of concomitant exotropia. The main refraction of individuals in these pedigrees was myopia, with no significant differences in morbidity or diopter measurements compared with those with sporadic concomitant exotropia.

Based on whole-exome sequencing performed in a subset of members and Sanger sequencing performed in all participants, 47 individuals from 10 concomitant exotropia pedigrees were subjected to in silico analysis. We identified 11 different missense variants among 7 potential pathogenic genes that cosegregated with pedigree members. All variants had a low frequency (< 5%) in the general population and could affect the secondary and tertiary structures of proteins.

Four variants of the COL4A2 gene cosegregated in three pedigree members. COL4A2 (collagen type IV alpha 2 chain) is a protein-coding gene associated with brain small vessel disease and intracerebral hemorrhage [33]. Among its related pathways are the integrin pathway and nervous system development [34]. Interestingly, ophthalmic diseases associated with COL4A2 variants include keratoconus, ocular anterior segment dysgenesis, and nonarteritic anterior ischemic optic neuropathy [35]. Neri et al. described a novel COL4A2 variant that presented with epilepsy and cortical development malformations, and the phenotype included strabismus [36]. In our study, this gene was screened in all three pedigrees with different variant sites.

SYNE1 was the pedigree coisolation gene in F3 (c.6992 C > A(p. A2331D)) and F6 (c.1838 C > T(p.S613F)). SYNE1 (spectrin repeat-containing nuclear envelope protein 1) encodes a spectrin repeat-containing protein that is expressed mainly in skeletal and smooth muscle [37]. Current studies have revealed that diseases associated with SYNE1 include spinocerebellar ataxia [38], autosomal recessive 8 [39] and arthrogryposis multiplex congenita [40]. The SYNE1 gene is highly expressed in the skeletal muscle and nervous systems. Research has also suggested that the Klarsicht/ANC-1/Syne homolog (KASH)-domain-containing protein SYNE1 plays crucial roles in anchoring both synaptic and nonsynaptic myonuclei, which are important for proper motor neuron innervation [41]. In our study, pedigrees F3 and F6 presented different variants in the SYNE1 gene that caused different amino acid changes.

AUTS2 was the pedigree coisolation gene in F4, and the variant (c.979 C > T (p.R327C)) was not detected in 496 sporadic concomitant exotropia samples or 239 unaffected samples (Table 4). A total of 220 sporadic samples were subsequently used for capture sequencing to search for other possible variants. The results revealed 15 variants (including 12 SNPs and 3 Indels) at multiple sites in AUTS2 (Table 5). Among them, three samples had the same SNP site variant (c.2600 A > G (p.K867R)). Therefore, AUTS2 may be a pathogenic gene that causes hereditary concomitant exotropia. AUTS2 (activator of transcription and developmental regulator) is a protein-coding gene; it has been implicated in neurodevelopment and is a candidate gene for numerous neurological disorders [42], including intellectual disability, developmental delay, and autism spectrum disorders [43]. This finding is consistent with neurogenic factors related to the pathogenesis of strabismus.

GTDC2 is known as POMGNT2 (protein O-linked mannose N-acetylglucosaminyltransferase 2 (beta 1,4)), the pedigree coisolation gene in F10 (c.1181G > A (p.R394Q)). The variant was not detected in 422 sporadic concomitant exotropia samples or 239 unaffected samples (Table 4). Subsequent capture and sequencing results revealed that four different SNP variants were acquired from 220 sporadic samples (Table 6). The results revealed that GTDC2 has a variety of variants associated with concomitant exotropia, and it could be an underlying pathogenic gene. GTDC2 is a protein-coding gene associated with muscular dystrophy–dystroglycanopathy [44]. This finding is consistent with muscular factors related to the pathogenesis of strabismus.

HERC2 (HECT and RLD domain containing E3 ubiquitin protein ligase 2), CDH3 (cadherin 3), and LOXHD1 (lipoxygenase homology PLAT domains 1) are protein-coding genes. Diseases associated with HERC2 include intellectual developmental disorders [45], autosomal recessive diseases and skin/hair/eye pigmentation [46]. Diseases associated with CDH3 include ectodermal dysplasia, ectrodactyly, and macular dystrophy syndrome [47]. Diseases associated with LOXHD1 include deafness, autosomal recessive 77 and autosomal recessive nonsyndromic sensorineural deafness [48] and late-onset Fuchs’ corneal dystrophy [49]. LOXHD1 is also expressed in skeletal muscle, such as extraocular muscle [50].

Concomitant exotropia is a genetically heterogeneous disorder involving extraocular muscles [51] and neurophysiological [52] causes. Any factor that causes either of these changes may lead to this disease. Among the candidate genes we identified, COL4A2, SYNE1, HERC2, and AUTS2 are related to nervous system development, and CDH3, LOXHD1, and GTDC2 are related to muscle development.

Conclusions

Concomitant exotropia is characterized by genetic heterogeneity, presumably with numerous genes involved in its pathophysiology. This is the first study exploring the genetic mechanism of concomitant exotropia, and 7 candidate genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2, and CDH3) that may be candidate genes causing concomitant exotropia were identified. Among these genes, 5 genes (COL4A2, SYNE1, AUTS2, HERC2, and CDH3) intersected with the HPO strabismus gene list (HP:0000486).

The limitation of this study is that the genes that cosegregated in pedigrees have not been thoroughly studied at the levels of mRNA transcription and protein translation, including in animal model experiments. Larger sample sizes and functional studies are needed to validate these findings and explore the mechanisms by which these genes may contribute to concomitant exotropia. With the discovery of an increasing number of genes and loci, we can better understand the genetic mechanisms that cause strabismus, such as concomitant exotropia. Soon, genetic testing for strabismus may allow for earlier diagnosis or prenatal diagnosis and even lead to the development of new therapeutic options. Currently, there is no particularly effective treatment for concomitant exotropia, and surgical intervention is recommended for constant and frequent intermittent exotropia [53]. We hope that further studies of pathogenic genes will lead to new insights, potentially guiding the development of more effective treatments for concomitant strabismus.

Data availability

The relevant data were generated during this study and included in this article. Requests for data from this study should be made to the corresponding author, Wenhua Duan (drduanwh@163.com). 

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Acknowledgements

The authors thank the patients and all family members for their participation in this study. The experiment was completed in the central laboratory of the Affiliated Hospital of Yunnan University.

Funding

This study was supported by the Leading the Charge of Yunnan Province Health System (L-2018018), the Yunnan University “Double first-class” construction - Children Low Vision Prevention and Control Innovation Team (CY22624106), the Kunming University of Science and Technology medical joint project (KUST-KH2022036Y), and the Science and Technology plan project of the First People’s Hospital of Yunnan Province (2024-KHRCBZ-B06).

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Authors and Affiliations

  1. The First People’s Hospital of Yunnan Province (The Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan Province, China

    Wenhua Duan & Dongqiong He

  2. The Affiliated Hospital of Yunnan University (The Second People’s Hospital of Yunnan Province), Kunming, Yunnan Province, China

    Taicheng Zhou & Min Hu

  3. Yunnan University, Kunming, Yunnan Province, China

    Xiaoru Huang

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  1. Wenhua Duan
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  2. Taicheng Zhou
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  3. Xiaoru Huang
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  4. Dongqiong He
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  5. Min Hu
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Contributions

WD and XH carried out the experiments. WD and TZ drafted the manuscript. TZ and MH designed this study. MH, DH and WD funded this study. All the authors have read and approved the final manuscript. Wenhua Duan and Taicheng Zhou contributed equally to this work as co-first authors.

Corresponding author

Correspondence to Wenhua Duan.

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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.

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Written informed consent was obtained from the patients or their guardians (parents), and they consented to the publication of their medical information.

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The authors declare no competing interests.

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Duan, W., Zhou, T., Huang, X. et al. Whole-exome sequencing uncovers the genetic basis of hereditary concomitant exotropia in ten Chinese pedigrees. BMC Med Genomics 18, 4 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12920-024-02078-0

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BMC Medical Genomics

ISSN: 1755-8794

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