Submission Details

TOR1AIP1 encodes TorsinA-interacting protein 1, which is also known as lamina-associated polypeptide 1 (LAP1). LAP1 localizes to the inner nuclear membrane, where it interacts with emerin and lamins, playing a crucial role in maintaining the structural integrity of the nuclear envelope. In humans, alternative start site usage produces two LAP1 isoforms, LAP1B and LAP1C, which lacks 122 amino acids from the N-terminus of LAP1B. While the functions of the two isoforms have not been completely characterized, distinct expression patterns are recognized, with LAP1B expressed at higher levels in skeletal muscle and LAP1C more highly expressed during the early stages of differentiation (PMID: 37108075).

TOR1AIP1 was first reported in relation to autosomal recessive muscular dystrophy, cardiomyopathy, and respiratory involvement in 2014 (Kayman-Kurekci et al., PMID: 24856141). Variants in TOR1AIP1 have subsequently been reported in individuals with additional features like congenital myasthenic syndrome as well as more severe multisystemic disease including hearing loss, cataract, skin abnormalities, growth anomalies, dystonia, cerebellar atrophy, neurodevelopmental delays, hypotonia, and progeroid features (PMID: 24856141, 27342937, 32873274, 33405017, 34164833, 33215087, 32055997, 30723199, 25425325). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in inheritance pattern or underlying molecular mechanism but identified differences in phenotype linked to isoform specificity: variants causing biallelic loss of only LAP1B seem to result in muscle-specific presentations, whereas loss of both LAP1B and LAP1C function is related to more severe syndromic disease. Given the evidence for the genotype-phenotype correlation and the distinct genetic testing context for each end of the spectrum, we opted to curate the muscle-specific, often adult-onset phenotypes as TOR1AIP1-related myopathy (MONDO:0100582; includes MIM #617072) and the multi-systemic, often early-onset presentations as TOR1AIP1-related multisystem disorder (MONDO:0100591; completed in collaboration with the Syndromic Disorders GCEP). Both of these entities, along with any intermediate phenotypes that may be recognized in the future, can be considered part of the broader spectrum of TOR1AIP1-related nuclear envelopathy (MONDO:0100604).

The evidence for TOR1AIP1-related multisystem disorder includes case-level and experimental data. Six variants (2 nonsense, 2 frameshift, and 2 missense) reported in eight probands from three publications (PMID: 32055997, 30723199, 25425325) are included in the curation. The c.961C>T p.(Arg321Ter) variant has been identified as a founder variant in five Palestinian families and was scored only once (3 pts), resulting in a total genetic evidence score of 9 points. The mechanism of pathogenicity appears to be loss of function affecting both the LAP1B and LAP1C isoforms. Experimental evidence (3 pts) includes a role in the nuclear envelope shared with other genes associated with similar phenotypes, including a direct interaction with A- and B-type lamins and torsin A (PMID: 28854936, 8324822, 9305626, 9305626); disrupted nuclear membrane organization and cell motility in patient cells, which can be partially rescued by expression of WT LAP1B or LAP1C (PMID: 307231990); recapitulation of cardiac defects observed in human patients in mice with cardiac- or striated muscle-specific conditional knockout of LAP1 (PMID: 24859316); and perinatal lethality and nuclear envelope abnormalities in homozygous knockout mice (PMID: 20457914).

In summary, there is definitive evidence supporting the relationship between TOR1AIP1 and autosomal recessive TOR1AIP1-related multisystem disorder. This relationship 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 Muscular Dystrophies and Myopathies GCEP on November 12, 2024 and by the Syndromic Disorders GCEP on April 2, 2025 (SOP Version 11).