ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000012.11) (NC_000012.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15489854 Hellemans et al. (2004): Describes loss-of-function variants identified in three families with variable expressivity for osteopoikilosis, Buschke-Ollendorf syndrome, and melorheostosis, as well as in three unrelated individuals with osteopoikilosis. Two nonsense variants were reported, along with three frameshift variants and one splice-site variant that results in exon 6 skipping and a frameshift were reported; all were believed to result in loss-of-function. The reported variants in the 3 families were shown to segregate with all affected relatives in each kindred (>7 segregations across all 3 families). Of note, the paper also reports a case of an individual with osteopoikilosis, microcephaly, ectopic kidneys, and learning disabilities who was found to have a microdeletion enccompassing LEMD3 as well as a number of other genes.
17087626 Mumm et al. (2007): Describes 4 additional variants, including one nonsense variant (L478X) in a 3 generation family with osteopoikilosis, another nonsense variant (R655X) in a family with osteopoikilosis and melorheostosis, another nonsense (Y441X) variant in a family with Buschke-Ollendorf syndrome and lastly a 2 base insertion resulting in a frameshift in a family with Buschke-Ollendorf syndrome.
19438932 Zhang et al. (2009): Describes a W855X variant described in a boy with Buschke-Ollendorf syndrome that was inherited from his father with osteopoikilosis.

Haploinsufficiency phenotype comments:

Loss-of-function variants in LEMD3 are associated with osteopoikilosis, Buschke-Ollendorf syndrome, and melorheostosis with many more publications beyond those presented here supporting haploinsufficiency for LEMD3. Variable expressivity has been reported, with members of the same family exhibiting each of these different phenotypes. To date, variants in LEMD3 have not been observed in individuals with isolated melorheostosis (see Gnoli et al. 2019 PMID: 31129707).

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