ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
20127487 Gupta et al 2010 describe a deletion in LMNA in a patient with dilated cardiomyopathy, and the deletion caused less LMNA expression in cardiomyocytes. They identified a partial LMNA deletion (9 of 12 3? exons; exons 3-12, RefSeq NM_170707.3) in a patient with dilated cardiomyopathy by MLPA and qPCR. Functional studies on cardiomyocytes included immunostaining, which showed reduced lamin A/C levels, and electron microscopy, which showed intracellular and nuclear abnormalities, supportive of a loss-of-function due to the deletion. The authors propose haploinsufficiency as the mechanism of pathogenicity based on the extent of the deletion, functional studies and supportive data from the literature.
12854972 MacLeod et al (2003) identified a novel 2 base-pair deletion c.908_909delCT, causing a frameshift and truncated LMNA/C in a proband with history of paroxysmal atrial fibrillation, sick sinus syndrome, dilated cardiomyopathy. Per discussion: "It is presently unknown whether autosomal dominant lamin A/C mutations impart their phenotype through dominant negative or haploinsufficient mechanisms. The majority of reported LMNA mutations are missense. In this case, the mutant protein is thought to be expressed and to act through a dominant interfering mechanism. A smaller number of LMNA mutations are frameshifting and are expected to create truncated lamin A and C. In at least one case, a nonsense mutation at amino acid position 6 was described [11]. This mutation is effectively a null allele and therefore, dominant mutations, at least in this case, would be expected to arise from haploinsufficiency of lamin A/C."
12920062 Sebillion et al (2003) identified an insertional mutation (28insA) that led to a stop codon and an aberrant truncated protein of 38 amino acids in a family affected by dilated cardiomyopathy with conduction defects*. mRNA expression analysis was performed by signal intensity measurement of a RE-digested cDNA product prepped from total RNA extraction from patient lymphoblastoid cell lines; this analysis showed a reduction or loss of mutant fragment compared to wild-type. In vitro cell transfection experiments showed a significant decrease in transfection efficiency for the 28insA cDNA, suggestive of reduced mRNA expression or stability leading to reduction of protein. The authors suggest this mutation may act via haploinsufficiency. *Note: the authors found no mutation in LMNA in cases with isolated dilated cardiomyopathy.

Haploinsufficiency phenotype comments:

LMNA encodes Lamins A and C, produced by alternative splicing of transcripts encoded by this gene. Lamin A/C are intermediate filament proteins that localize to the inner nuclear membrane and nucleoplasm where they function in structural support, DNA organization and function. Mutations in LMNA are associated with a wide range of disorders (neuromuscular, cardiac, lipodystrophy and premature aging), some of which have overlapping and variably present clinical phenotypes. LMNA-associated phenotypes include both autosomal dominant and recessive inheritance patterns. A large number (>400) of disease-associated LMNA variants have been reported; the vast majority are sequence-level alterations and are predominantly missense mutations. However frameshift, nonsense, and intragenic deletions and duplications, which are capable of resulting in a loss-of-function, are also reported. Thus LMNA haploinsufficiency is a possible mechanism of pathogenicity, although it is not apparently the predominant mechanism. As yet, whole gene deletion of LMNA has not been reported in association with clinical phenotypes. Although the presence of >2 independent publications with numerous loss-of-function-type variants, some of which include supportive functional data, provide evidence in support of LMNA haploinsufficiency, due to the extensive clinical heterogeneity, inheritance patterns, mutational spectrum, and lack of reports of whole gene deletions, the haploinsufficiency score given here is 2.

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

Triplosensitivity phenotype comment:

As of 11-13-15, there is no evidence for triplosensitivity of LMNA, it is overall not tested and publications of whole gene duplications of LMNA were not found.