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A novel homozygous ZNF469 variant causing brittle cornea syndrome is associated with corneal ectasias in heterozygous carriers

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Abstract

Aim

To describe a family segregating a novel truncating ZNF469 homozygous mutation causing brittle cornea syndrome type 1 in a male patient and associated with corneal ectasia in his two heterozygous young children.

Methods

A 49-year-old affected male and his 12- and 8-year-old, apparently healthy, siblings underwent phenotypic and genetic assessment. An Oculus Pentacam Scheimpflug topographer system was employed for keratometries and central corneal thickness measurements. Exome sequencing was performed in DNA from the index case with subsequent Sanger sequencing confirmation of the ZNF469 gene causal variant in his relatives.

Results

The index case had a history of bilateral keratoglobus, corneal perforations, bilateral hypoacusia, and skeletal anomalies. His two children exhibited topographic anomalies compatible with keratoconus suspects as well as mild skeletal anomalies. Genetic analysis identified a novel homozygous c.2340delC variant in the ZNF469 gene, which predicts a p.(Arg781Glufs*19) truncated protein. Sanger sequencing identified heterozygosity for the c.2340delC variant in DNA from both siblings.

Conclusion

Our results expand the mutational spectrum associated with brittle cornea syndrome and provide the first demonstration of early corneal anomalies in subjects carrying monoallelic ZNF469 variants.

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Funding

No funding was received for this research.

Author information

Authors and Affiliations

  1. Department of Genetics, Institute of Ophthalmology “Conde de Valenciana”, 14, Col. Obrera, Cuauhtemoc, 06800, Mexico City, CP, Mexico

    Rocío Arce-González, Oscar Francisco Chacon-Camacho, Vianey Ordoñez-Labastida & Juan Carlos Zenteno

  2. Carrera de Médico Cirujano, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, Mexico

    Oscar Francisco Chacon-Camacho

  3. Cornea Department, Institute of Ophthalmology “Conde de Valenciana”, Mexico City, Mexico

    Enrique O. Graue-Hernandez & Alejandro Navas-Pérez

  4. Biochemistry Department, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico

    Juan Carlos Zenteno

  5. Faculty of Medicine, Autonomous University of the State of Morelos, UAEM, Leñeros S/N, Los Volcanes, 62350, Cuernavaca, Morelos, Mexico

    Vianey Ordoñez-Labastida

Authors
  1. Rocío Arce-González
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  5. Alejandro Navas-Pérez
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  6. Juan Carlos Zenteno
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Contributions

OFCC and RAG wrote the paper. RAG, VOL, ANV and EOGH examined and collected patient’s information. RAG made figures. JCZ collected patients’ information; revised and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Juan Carlos Zenteno.

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Conflict of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or nonfinancial interest in the subject matter or materials discussed in this manuscript.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institute of Ophthalmology “Conde de Valenciana Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Arce-González, R., Chacon-Camacho, O.F., Ordoñez-Labastida, V. et al. A novel homozygous ZNF469 variant causing brittle cornea syndrome is associated with corneal ectasias in heterozygous carriers. Int Ophthalmol 43, 807–815 (2023). https://doi.org/10.1007/s10792-022-02481-5

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  • DOI: https://doi.org/10.1007/s10792-022-02481-5

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