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SLC4A11 mutations causative of congenital hereditary endothelial dystrophy (CHED) progressing to Harboyan syndrome in consanguineous Pakistani families

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Abstract

Background

Autosomal recessive corneal hereditary endothelial dystrophy (CHED) is a rare congenital disorder of cornea. Mutations in SLC4A11 gene are associated with CHED phenotype. CHED is also an early feature of Harboyan syndrome. The aim of the present study was to identify genetic mutations in the SLC4A11 gene in CHED cases belonging to inbred Pakistani families. Furthermore, all homozygous mutation carriers were investigated for hearing deficit.

Methods and results

This study included consanguineous CHED families presented at Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan from June 2018 to September 2018. DNA was extracted from blood samples. Direct sequencing of SLC4A11 gene was performed. All identified variants were evaluated by in silico programs i.e., SIFT, PolyPhen‐2, and MutationTaster. Pathogenicity of the two identified splice site variants was analyzed by Human Splicing Finder and MaxEnt Scan. Screening of five CHED families revealed a total of three previously un reported (p.Arg128Gly, c.2241-2A > T and c.1898-2A > C in family CHED19, CHED22 and CHED26 respectively) and two already reported homozygous disease causing variants (p.Arg869Cys and p.Val824Met in family CHED24 and CHED25 respectively) as predicted by mutation taster. All of these variants segregated with disease phenotype and were not detected in controls.

Conclusion

Affected individuals of the five CHED families screened in this study had the disease due to SLC4A11 mutations and progressing to Harboyan syndrome. Identification of previously unreported mutations aid to heterogeneity of SLC4A11 and CHED pathogenesis as well as helped to provide genetic counseling to affected families.

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Data availability

All data relevant to the study are included in the manuscript.

Code availability

Not applicable.

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Acknowledgements

We thank patients and their families for their participation in this study. We are grateful to Dr. Muhammad Asif Naeem from National Centre of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan, for audiometric analysis of selected cases.

Funding

This study was financially supported (in part) by the University Research Fund (URF) for the year 2018–2019, Quaid-i-Azam University, Islamabad, Pakistan and access to Scientific Instrumentation Program (ASIP), Higher Education Commission, and Islamabad, Pakistan (20-2(10)/ASIP/R&D/HEC/17/000530(CAMB)/18).

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Authors and Affiliations

  1. Department of Zoology, Faculty of Biological Sciences, Quaid-i-Azam University, University Road, Islamabad, 45320, Pakistan

    Sabika Firasat,  Dur-e-Shawar,  Nousheen, Bushra Noreen, Rutaba Gul & Kiran Afshan

  2. Cornea Department, Pakistan Institute of Ophthalmology (PIO), Al-Shifa Trust Eye Hospital, Jhelum Road, Rawalpindi, Pakistan

    Wajid Ali Khan

  3. Al-Shifa School of Public Health, Pakistan Institute of Ophthalmology (PIO), Al-Shifa Trust Eye Hospital, Jhelum Road, Rawalpindi, Pakistan

    Ume Sughra

  4. Al-Shifa Research Centre, Pakistan Institute of Ophthalmology (PIO), Al-Shifa Trust Eye Hospital, Jhelum Road, Rawalpindi, Pakistan

    Ume Sughra

  5. Genetics Division, Department of Livestock Production, University of Veterinary and Animal Sciences, Ravi Campus, Pattoki, Pakistan

    Haiba Kaul

  6. Department of Zoology, Lahore College for Women University, Lahore, Pakistan

    Shagufta Naz

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  1. Sabika Firasat
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  2. Dur-e-Shawar
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Contributions

SF, HK and SN contributed to the study conception and design. WAK and US performed clinical analysis. BN, N and DeS collected data. DeS, N, BN and RG performed experiments. DeS, N and SF did data analysis and prepared the first draft of the manuscript. KA, HK and SN commented on previous versions of the manuscript. All authors read and approved the content and submission of the final manuscript.

Corresponding author

Correspondence to Sabika Firasat.

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Conflict of interest

We have no conflict of interest.

Consent to participate

Written informed consent was obtained from all the participants included in this study. Furthermore, it is confirmed that written informed consents were signed by the parents/legally authorized representatives of the subjects of the study, who are all minors.

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Not applicable.

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Bioethical Committee (BEC) of Quaid-i-Azam University, Islamabad, Pakistan approved this study.

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Firasat, S., Dur-e-Shawar, Khan, W.A. et al. SLC4A11 mutations causative of congenital hereditary endothelial dystrophy (CHED) progressing to Harboyan syndrome in consanguineous Pakistani families. Mol Biol Rep 48, 7467–7476 (2021). https://doi.org/10.1007/s11033-021-06765-4

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