Identification of a compound heterozygous mutation in GDAP1 gene in a consanguineous South Indian family with Charcot–Marie–Tooth (CMT) Disease
Abstract Background Charcot–Marie–Tooth (CMT) is a clinically, electro-physiologically, and genetically heterogenous group of muscle disease which is also known as hereditary motor and sensory neuropathy. Autosomal recessive forms of CMT type 4A have been reported with either homozygous or compound...
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| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
SpringerOpen
2025-05-01
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| Series: | Egyptian Journal of Medical Human Genetics |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s43042-025-00718-3 |
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| Summary: | Abstract Background Charcot–Marie–Tooth (CMT) is a clinically, electro-physiologically, and genetically heterogenous group of muscle disease which is also known as hereditary motor and sensory neuropathy. Autosomal recessive forms of CMT type 4A have been reported with either homozygous or compound heterozygous mutations in a gene that encodes ganglioside-induced differentiation-associated protein-1 (GDAP1). GDAP1 is located on 8q21, and plays a major role in ganglioside differentiation and Schwann cell function, as well as regulates neuronal and axonal development. Case presentation In this study, we recruited a consanguineous south Indian family with an affected patient, an unaffected sibling, and the mother. The patient was affected with progressive weakness in the lower and upper limbs, atrophy of small muscles of the foot and hands, club shaped hands, steppage gait, hoarseness, and decreased muscle tone. His nerve biopsy examination revealed peripheral nerve demyelination and nerve conduction testing confirmed a reduction in nerve activities, while MRI showed mild degenerative changes in the cervical spine. Further, targeted exome sequencing (TES) and copy number variation analysis were performed on the patient. TES identified a compound heterozygous mutation that includes a missense mutation and a 3’UTR mutation (NM_018972.4: c.413A > G:p.His138Arg; g.74488790C > A:c.*29C > A, respectively) in GDAP1. The missense change is not reported in available public databases, while the UTR variant is seen only in the South Asian population in gnomAD (allele frequency = 0.00002). Multiple in silico prediction tools show that the missense mutation is damaging. Subsequently, in silico protein modeling, phylogenetic conservation analysis, and the impact of the mutation on the canonical transcript have also been performed. The compound heterozygous mutation was confirmed in the patient by PCR-Sanger sequencing and was shown to segregate within the family. Conclusions The combined results support the fact that these two mutations in GDAP1 link the genotype–phenotype correlation in the family. This will help the family in genetic testing, counseling, and early diagnosis. Our findings support expanded phenotypic characterization along with the genetic spectrum of GDAP1 mutations in CMT type4A in the Indian population. |
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| ISSN: | 2090-2441 |