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Phenotype puzzle: the role of novel LMBRD1 gene variant in Cbl deficiency causing Dyskeratosis Congenita-like clinical manifestations

Journal of Human Genetics volume 70, pages 207–213 (2025)Cite this article

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Abstract

Cobalamin (Cbl) metabolism deficiencies are a heterogeneous group (CblA, CblB, CblC, CblD, CblE, CblF, CblG) of autosomal recessive disorders. CblF deficiency occurs due to mutations in LMBRD1 gene, causing variable phenotype, including neurological, haematological, developmental and dermatological defects. Here, we describe a 15-year-old male, presented with clinical features of Dyskeratosis Congenita (DC) such as dystrophic nails, skin discoloration with additional clinical features of uniform reticulate-brown hued hyperpigmentation, developmental delay, mild intellectual disability, mucositis and anemia. Genomic analysis using high throughput next generation sequencing (NGS) identified a novel splice site deletion (c.562+4_562+7del) in the LMBRD1 gene resulting in Cbl deficiency. cDNA sequencing elucidated exon 6 skipping as a consequence of a novel deletion, resulting in significant structural alterations of LMBD1 protein, which was further validated by in-silico computational analysis. Computational modeling and docking studies revealed a reduced interaction affinity between the LMBD1 protein and its partner protein ABCD4. These alterations contribute to a disrupted cascade mechanism in cobalamin (Cbl) metabolism resulting in development of variable clinical phenotypes. In our case, the proband was treated with intravenous hydroxocobalamin therapy and follow up showed a significant improvement in clinical symptoms of skin hyperpigmentation, angular cheilitis and aphthous ulcers. Hence the genomic analysis is essentially important for the appropriate genetic counseling and management of the disease.

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Data availability

The novel variant identified in the present study has been submitted in ClinVar database under the submission ID SUB13687835 (https://submit.ncbi.nlm.nih.gov/subs/clinvar_file/SUB13687835/overview) (ClinVar accession ID: VCV002572168.1).

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Acknowledgements

This work was supported by ICMR-National Institute of Immunohaematology. We thank resident doctors from hematology department of KEM hospital for clinical diagnosis and treatment of subject. We thank the subject and his family for their cooperation and participation in the study. Thanks also due to Council of Scientific and Industrial Research for providing fellowship to AS.

Funding

This study was performed with the financial support by the intramural grant from ICMR-National Institute of Immunohaematology, India under grant no. [ICMR/NIIH/15-2019]. The research was supported by fellowship grant by Council of Scientific and Industrial Research (CSIR) NET-JRF awarded to AS. The funding body played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

Author information

Authors and Affiliations

  1. Department of Cytogenetics, ICMR-National Institute of Immunohaematology, 13th floor, New Multi-storeyed building, KEM hospital Campus, Parel, Mumbai, 400012, Maharashtra, India

    Anjali Shah, Merin George, Somprakash Dhangar, Jagdeeshwar Ghatanatti & Babu Rao Vundinti

  2. Department of Hematology, 10th Floor, New Multistoried Building, KEM Hospital, Parel, Mumbai, 400012, Maharashtra, India

    Santosh Khuba & Chandrakala Shanmukhaiah

  3. School of Biotechnology and Bioinformatics, D Y Patil Deemed to be University, Plot no. 50, Sector 15, CBD Belapur, Navi Mumbai, 400614, Maharashtra, India

    Selvaa Kumar C

Authors
  1. Anjali Shah
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  2. Santosh Khuba
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  3. Selvaa Kumar C
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  8. Babu Rao Vundinti
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Contributions

AS collected clinical history and performed laboratory work. CS and SK carried out clinical diagnosis, treatment and follow up. AS and SK has equally contributed. AS and MG performed molecular work, genetic analysis along with family screening and follow up. AS, SK and BRV contributed to conception and designing of the work. SKC performed sequence and structure based computational analysis of mutant LMBD1 protein. AS, SK, SKC reviewed a literature and drafted a manuscript. BRV and CS performed general supervision of the overall research work. AS deposited variant on ClinVar database. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Babu Rao Vundinti.

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The authors have no competing interests.

Ethical approval and consent participation

The study was approved by the “Institutional Ethics Committee on human subjects” of ICMR-National Institute of Immunohaematology (Ethics approval number: NIIH/IEC/22-2019). All procedures performed in studies involving human participants were as per the ethical standards of the institutional review board of the institute and with the 1964 declaration of Helsinki (DoH) and its later amendments or comparable ethical standards.

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Written informed consent was obtained from the participant’s mother to use images and other personal or clinical details.

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Shah, A., Khuba, S., Kumar C, S. et al. Phenotype puzzle: the role of novel LMBRD1 gene variant in Cbl deficiency causing Dyskeratosis Congenita-like clinical manifestations. J Hum Genet 70, 207–213 (2025). https://doi.org/10.1038/s10038-025-01320-6

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