Relevance to Autism

LEMD3 was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were two damaging de novo missense variants (defined as having a REVEL score > 0.5). Subsequent gene-based meta-analysis involving de novo variant enrichment, transmission disequilibrium testing (TDT) of rare, inherited LoFs from unaffected parents to affected offspring, and comparisons of loss-of-function variants in cases vs population controls in this report found that LEMD3 exhibited an nominal enrichment of rare inherited loss-of-function variants preferentially transmitted to affected offspring compared to unaffected offspring (6:2; p = 0.02).

Molecular Function

This locus encodes a LEM domain-containing protein. The encoded protein functions to antagonize transforming growth factor-beta signaling at the inner nuclear membrane. Two transcript variants encoding different isoforms have been found for this gene. Mutations in this gene have been associated with osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.

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