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Characterizing Homozygous Variants in Bardet-Biedl Syndrome-Associated Genes Within Iranian Families: Unveiling a Founder Variant in BBS2, c.471G>A

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Abstract

Bardet–Biedl syndrome (BBS) is a rare inherited ciliopathy disorder characterized by a broad spectrum of clinical symptoms such as retinal dystrophy, obesity, polydactyly, genitourinary and kidney anomalies, learning disability, and hypogonadism. The understanding of the variants involved in BBS-causing genes remains incomplete, highlighting the need for further research to develop a molecular diagnostic strategy for this syndrome. Singleton whole-exome sequencing (WES) was performed on sixteen patients. Our study revealed (1) nine patients carried eight homozygous pathogenic variants with four of them being novel (2) Specifically, a synonymous splicing variant (c.471G > A) in BBS2 gene in six patients with Baloch ethnicity. The identification of runs of homozygosity (ROH) calling was performed using the BCFtools/RoH software on WES data of patients harboring c.471G > A variant. The presence of shared homozygous regions containing the identified variant was confirmed in these patients. In-silico analysis predicted the effect of the c.471G > A variants on BBS2 mRNA splicing. This variant results in disrupted wild-type donor site and intron retention in the mature mRNA. (3) And a deletion of exons 14 to 17 in the BBS1 gene was identified in one patient by Copy-Number Variation (CNV) analysis using the ExomeDepth pipeline. Our results identified the founder variant c.471G > A in the BBS2 gene in the Baloch ethnicity of the Iranian population. This finding can guide the diagnostic approach of this syndrome in future studies.

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Notes

  1. G-protein-coupled receptors.

  2. Alstrom Syndrome Protein 1.

  3. Nephrocystin 4.

  4. Human Splicing Finder.

Abbreviations

BBS:

Bardet–Biedl syndrome

WES:

Whole exome sequencing

ROH:

Runs of homozygosity

CNV:

Copy-Number Variation

NGS:

Next-generation sequencing

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Acknowledgements

We express our gratitude to our patients and their families for their collaboration in this research, as well as to the colleagues who assisted us in this study.

Funding

This research was supported by Mashhad University of Medical Sciences and University of Social Welfare and Rehabilitation Sciences.

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Authors and Affiliations

  1. Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran

    Masoumeh Heidari Feizabadi, Zohreh Fattahi & Hamid Reza Khorram Khorshid

  2. Genetic Foundation of Khorasan Razavi, Mashhad, Iran

    Masoome Alerasool

  3. Faculty of Medicine, Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran

    Masoome Alerasool, Atieh Eslahi, Shima Farokhi & Majid Mojarrad

  4. Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran

    Emran Esmaeilzadeh

  5. Diabetes Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Mohammad Yahya Vahidi Mehrjardi

  6. RP Eye Patients Supporting Institute, Tehran, Iran

    Mitra Saket

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  1. Masoumeh Heidari Feizabadi
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  2. Masoome Alerasool
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MHF, MA, AE, EE, MYVM, MS, ZF, HRKK, MM. The first draft of the manuscript was written by SF and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Majid Mojarrad.

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Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Research Ethics Committee of University of Social Welfare and Rehabilitation Science, Tehran, Iran (Date: 2021-12-27/No: IR.USWR.REC.1400.235).

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Informed consent to participate in this research was obtained from all the patient’s parents.

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Informed consent for publication of the results was obtained from all the patient’s parents.

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Feizabadi, M.H., Alerasool, M., Eslahi, A. et al. Characterizing Homozygous Variants in Bardet-Biedl Syndrome-Associated Genes Within Iranian Families: Unveiling a Founder Variant in BBS2, c.471G>A. Biochem Genet (2024). https://doi.org/10.1007/s10528-023-10637-w

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