ClinGen Dosage Sensitivity Curation Page

LETM1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000004.11) (NC_000004.12)

Haploinsufficiency phenotype comments:

LETM1 is typically deleted as part of the Wolf-Hirschhorn syndrome. Though it is believed to be one of the critical dosage-sensitive genes contributing to the Wolf-Hirschhorn phenotype, particularly the development of seizures (see PMIDs 10486213, 17696124), there are no reports demonstrating that loss of function mutations in LETM1 alone cause a specific phenotype in humans. Furthermore, there are some patients with larger deletions encompassing LETM1 that do no develop siezures. Within the paper PMID:21729882, there is a single patient with a focal deletion of 54kb involving LETM1. The patient did not exhibit features of Wolf-Hirschhorn syndrome (including facial features), but rather presented at one year of age with microtia, renal agenesis, Duane anomaly, and a congenital heart defect. Parental studies were not described and seizures were not mentioned, but at the age of presentation may not be ruled-out. Also note the phenoytpe of this patient is different enough from those with larger deletions that are associated with Wolf-Hirschhorn syndrome, that it is possible the LETM1 deletion is not related to the phenotype of this patient. It is important to note that, though the current ISCA Haploinsufficiency rating for specific LETM1 is 0, deletions involving the larger Wolf-Hirschhorn region have a haploinsufficiency rating of 3. Given the expected critical role in WHS syndrome, any deletion involving LETM1 should be considered carefuly for pathogenicity, particularly when seizures are present.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Duplications encompassing LETM1 (along with other genes) have been reported in association with intellectual disability and congenital anomalies (PMID:21815251; PMID:20197130). No reports have been found, however, linking duplications involving only the LETM1 gene to specific phenotypes in humans.