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First description of novel compound heterozygous mutations in HYCC1: clinical evaluations and molecular analysis in patient with hypomyelinating leukodystrophy-5 with retrospective view

Journal of Human Genetics volume 70, pages 75–85 (2025)Cite this article

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Abstract

Hypomyelinating leukodystrophy-5 (HLD5) is a rare autosomal recessive hypomyelination disorder characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system, caused by mutations in the HYCC1 gene. Here we report a 23-year-old girl with HLD5 from unrelated families. Molecular analysis was performed using sequence screening of the HYCC1 gene. In addition, in silico prediction tools and molecular investigation were used to predict the structural effect of the mutations. Results showed a novel compound heterozygous mutation in the HYCC1 gene. Moreover, in silico tools and 3D structural modeling revealed that c.521C > A (p.Ala174Glu) and c.652C > G (p.Gln218Glu) mutations could affect the structure, stability, and conformational analyses in the N-ter domain of the Hyccin protein. We also, we compared the phenotype of our patient with those of previously reported cases with HLD5 syndrome and our findings indicate the absence of reliable genotype-phenotype correlations. To the best of our knowledge, this is the first report describing a Tunisian HLD5 patient with compound heterozygous mutations (c.521C > A (p.Ala174Glu) and c.652C > G (p.Gln218Glu)) in HYCC1 gene.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank patients and her family for their cooperation in the present study. We also thank the doctors of NeuroPediatrics Service in the CHU Hedi Chaker of Sfax for their help and availability.

Funding

This work was supported by the Ministry of Higher Education and the Scientific Research in Tunisia.

Author information

Authors and Affiliations

  1. Laboratory of Molecular and Functional Genetics, Faculty of Science of Sfax University, Sfax, Tunisia

    Abir Ben Issa, Boudour Khabou & Faiza Fakhfakh

  2. Research Laboratory (LR19ES15), Sfax Medical School, Sfax University, Sfax, Tunisia

    Abir Ben Issa, Fatma Kamoun, Wafa Bouchaala & Chahnez Triki

  3. Faculty of Medicine of Sfax, Sfax University, Sfax, Tunisia

    Abir Ben Issa, Fatma Kamoun, Wafa Bouchaala & Chahnez Triki

  4. Child Neurology Department, Hedi Chaker Hospital, Sfax, Tunisia

    Fatma Kamoun, Wafa Bouchaala & Chahnez Triki

Authors
  1. Abir Ben Issa
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  2. Fatma Kamoun
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  3. Boudour Khabou
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  4. Wafa Bouchaala
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  5. Faiza Fakhfakh
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  6. Chahnez Triki
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Contributions

Abir Ben Issa: conceptualization, methodology, software, formal analysis, and writing the original draft. Fatma Kamoun: clinical investigations. Boudour Khabou: software and bioinformatic analysis. Wafa Bouchaala: clinical review and editing. Faiza Fakhfakh: revised the final version of the manuscript. Chahnez Triki: clinical investigations.

Corresponding author

Correspondence to Abir Ben Issa.

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Competing interests

The authors declare no competing interests.

Ethical approval

The study was conducted in accordance with the principles stated in the Declaration of Helsinki-Ethical Principles for Medical Research Involving Human Subjects, Helsinki, Finland, 1964, and as amended in Fortaleza, Brazil, 2013. The study design was approved by the committee on research ethics of the University of Sfax, Tunisia.

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Informed consent for publication of this study was obtained from all patients and/or families involved.

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Ben Issa, A., Kamoun, F., Khabou, B. et al. First description of novel compound heterozygous mutations in HYCC1: clinical evaluations and molecular analysis in patient with hypomyelinating leukodystrophy-5 with retrospective view. J Hum Genet 70, 75–85 (2025). https://doi.org/10.1038/s10038-024-01300-2

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