ATL3

Inheritance Pattern: AD

Disease ID:MONDO:0014286

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014286

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0014286

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0018213

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0014286

Submitter: ClinGen

ATL3 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2014 (Kornak et al., PMID: 24459106). ATL3 encodes for the endoplasmic reticulum (ER) membrane shaping protein, atlastin 3. Two recurrent missense variants, Y192C and P338R, have been reported in five autosomal dominant families from four different publications (PMIDs: 24459106, 34090020, 24736309, 30680846). All reported cases are described with axonal sensory neuropathy (HSN). Clinical presentation includes sensory disturbances in the distal parts of the lower limbs, painless injuries and foot ulcerations. Case-level variant and experimental evidence support the gene-disease relationship. Expression of the ATL3 mutant Y192C in cell culture led to protein aggregates and disruption of the endoplasmic reticulum network (PMID: 24459106). Expression of both mutants, Y192C and P338R, caused disruption of the ER connectivity and loss of ER fusion efficiency in transfected cells (PMID: 29768202). In situ hybridization analysis in mouse tissues show high expression of ATL3 in dorsal root ganglion (DRG), in line with the major site of the pathology (PMID:24459106). ATL3 can physically interact with ATL1, which has also been associated with HSN (PMID: 24459106). In addition, ATL3 performs a biochemical function shared with ATL1 in ER structure maintenance (PMID: 27619977). Analysis of patient fibroblasts revealed abnormal ER network and altered mitochondrial distribution and dynamics (PMIDs: 29768202 and 30339187). Although there is strong genetic and experimental supporting evidence available, the lack of additional families and an animal model limits the final classification to MODERATE. **Recuration Update**: One additional publication was curated, providing new genetic evidence supporting the association between ATL3 and autosomal dominant hereditary sensory neuropathy type 1F. Pyromali et al. (2023; PMID: 37371660) reported the first structural variant involving ATL3, identifying a heterozygous 3.2 kb in-frame deletion encompassing exons 11 and 12 (c.(1036-861_1539+329del), p.(Ala346_Gln513del)) in a 68-year-old man with late-onset hereditary sensory neuropathy. The patient presented with a phenotype highly consistent with ATL3-associated disease, including progressive distal sensory neuropathy affecting the lower limbs, paresthesia, hypoesthesia, areflexia, pes cavus, and abnormal sensory nerve conduction studies. A comprehensive 93-gene peripheral neuropathy panel did not identify any pathogenic single-nucleotide variants or small insertions/deletions. Sural nerve biopsy demonstrated severe rarefaction of myelinated fibers, demyelinating–remyelinating changes, and abnormal endoplasmic reticulum morphology consistent with the known cellular role of ATL3. The deletion preserves the reading frame and was proposed to produce a truncated protein capable of exerting a dominant-negative effect, although this mechanism was not experimentally confirmed. No segregation analysis or de novo testing was available. Based on the highly specific phenotype and supporting pathological findings, this proband was conservatively scored as 0.5 point for genetic evidence. A second publication by Mohammadi et al. (2023; PMID: 36856139) reported a heterozygous early nonsense variant (p.Arg6Ter) in two families with sensory neuropathy. However, because the established disease mechanism for ATL3-associated hereditary sensory neuropathy is dominant-negative missense variation rather than haploinsufficiency, and the authors acknowledged that loss-of-function is not an established pathogenic mechanism for ATL3, these families were not included as additional case-level evidence. Together, these publications contributed 0.5 additional genetic evidence point, providing modest support for the ATL3–autosomal dominant hereditary sensory neuropathy type 1F gene-disease relationship.