ERLIN2

Inheritance Pattern: AR

Disease ID:MONDO:0700309

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0012639

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012639

Submitter: ClinGen

*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).

Inheritance Pattern: AD

Disease ID:MONDO:0957788

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0700309

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0012639

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0011663

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012639

Submitter: ClinGen

*ERLIN2* was first reported in relation to autosomal recessive hereditary spastic paraplegia 18 in 2011 (Alazami AM et al., PMID:21796390). Autosomal recessive 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 dominant hereditary spastic paraplegia 18 has been curated separately. Eight variants (4 missense, 2 splice site, 2 frameshift) that have been reported in ten probands in eight publications (PMIDs: 28832565, 32147972, 27824013, 21796390, 23109145, 23085305, 21330303, 32042907) are included in this curation. Ample segregation data is available with variants in *ERLIN2* segregating in 16 individuals across four families resulting in a summed LOD score of 14.7. More evidence may be available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. In summary, there is definitive evidence supporting the relationship between *ERLIN2* and autosomal recessive hereditary spastic paraplegia 18. 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 Amyotrophic Lateral Sclerosis Spectrum Disorders GCEP on the meeting date Name of Month, Date, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0012639

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0017232

Submitter: Orphanet