ERLIN2 was first reported in relation to autosomal dominant hereditary spastic paraplegia 18 in 2018 (Rydning SL et al., PMID:29528531). Autosomal dominant hereditary spastic paraplegia 18 is a pure or complex form of hereditary spastic paraplegia characterized by spastic paraparesis, most prominent in the lower limbs, and unsteady gait. Onset usually occurs within the first decade of life, although patients have been reported with later onset. Some patients additionally present with increased deep tendon reflexes, amyotrophy, cerebellar ataxia, flexion contractures of the knees and intellectual disability.
Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, inheritance pattern and phenotypic variability between HSP18 and ALS. Therefore, both disease entities have been lumped into a single curation under the term hereditary spastic paraplegia 18 for the purpose of this curation. It is recognized that HSP18 can convert to ALS. Autosomal recessive hereditary spastic paraplegia 18 has been curated separately.
Seven variants, all missense, that have been reported in nine probands in seven publications (PMIDs:32042907, 34734492, 32094424, 34536826, 32147972, 29528531, 38607533) are included in this curation. The mechanism of pathogenicity appears to be loss of function.
This gene-disease relationship is also supported by a mouse model that demonstrates that an autosomal dominant missense variant in ERLIN2 disrupts axonogenesis in the mouse (PMID:37752894). Limited points are awarded to this evidence because it does not recapitulate the human phenotype but does demonstrate ERLIN2 having a role in a relevant pathway.
In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ClinGen Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on the meeting date Name of April 24, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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