Submission Details

GDAP1 was first reported in relation to Charcot-Marie-Tooth Disease in 2002 (Baxter et al., PMID: 11743579, Cuesta et al., PMID: 11743580). Variants in this gene are inherited in both autosomal recessive and autosomal dominant fashions, with phenotypes presenting as a spectrum of severity depending on the specific mutation and number of alleles present in trans. The phenotypes associated with GDAP1 variants include both axonal, intermediate, and demyelinating neuropathy (based on the nerve conduction velocities), with the clinical features of symmetric muscle weakness, atrophy of feet and hands, reduced to normal motor and sensory nerve conduction studies, mild sensory loss, areflexia, vocal cord paresis, and pes cavus.

GDAP1 is also expressed in peroxisomes as a tail-anchored protein and is thought to function as a peroxisomal fission factor and to be involved in regulating peroxisome morphology (PMID: 30669311). GDAP1 is also reported to increase cellular glutathione-s-transferase in neuronal cells, decrease reactive oxygen species production and protect against oxidative stress (PMID: 26848201). Experimentally, GDAP1 knockdown was shown to result in more cells with elongated peroxisomes, due to the decrease in fission. No peroxisome biochemical functions were measured. Re-introduction of wild-type GDAP1 and CMT-related GDAP1 N-terminal variants into knockdown cells restored peroxisomal morphology, while CMT-related C-terminal variants of GDAP1 did not (PMID: 23628762). This gene has been included in a few sequencing panels testing for peroxisomal disorders, but till date, no GDAP1 variants have been reported in patients showing a peroxisome biogenesis disorder phenotype, to the best of our knowledge.

At least 10 unique variants have been reported in humans, including nonsense, missense, and frameshift variants. Evidence supporting this gene-disease relationship includes case-level data, segregation and experimental data. Variants in this gene have been reported in at least 15 probands in at least 5 publications (PMIDs:11743579, 15805163, 11743580, 12499475, 18492089). Variants in this gene segregated with disease in 19 additional family members across three different families. This gene-disease relationship is supported by expression studies, functional studies, and animal models. GDAP1 has been shown to be predominantly expressed in neural tissue, with expression in both neurons and Schwann cells (PMIDs: 11743580, 16172208). Functional studies have revealed that GDAP1 overexpression increases mitochondrial fragmentation, while GDAP1 knockdown increased mitochondrial fusion, therefore confirming the role of GDAP1 as a mitochondrial fission-inducing factor (PMID: 16172208). In a drosophila model, both overexpression and knockdown of the fly ortholog, Gdap1, was shown to result in neuromuscular degeneration and alterations of mitochondrial morphology and dynamics (PMID: 25122658). A Gda1 knockout mouse model resulted in late onset hypomyelinating peripheral neuropathy with changes in mitochondrial morphology and dynamics (PMID: 24480485). In summary, GDAP1 is DEFINITIVELY associated with recessive and dominant Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on June 9, 2020.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, it was determined that variants in this gene result in a spectrum of the similars pathophysiology and lead to similar phenotypes underlying the disease entities: (1) Charcot-Marie-Tooth disease, axonal, type 2K (MIM:607831), (2) Charcot-Marie-Tooth disease, axonal, with vocal cord paresis (MIM:607706), (3) Charcot-Marie-Tooth disease, recessive intermediate, A (MIM:608340), (4) Charcot-Marie-Tooth disease, type 4A (MIM:214400). Therefore, all of the disease entities have been lumped into one disease entity, Charcot-Marie-Tooth Disease.