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

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.