ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

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Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11577371 Schwarze et al. (2001) studied 4 patients with EDS IV who presented with vascular aneurysm or rupture and were found to be functionally haploinsufficient for a COL3A1 allele due to nonsense mutations. They noted that in contrast to individuals with null mutations in COL1A1 and COL2A1, who have milder phenotypes than those caused by mutations that alter protein sequence, the consequence of haploinsufficiency of COL3A1 appears to result in a severe vascular phenotype, which events often occurring by the third decade of life. The authors suggested that the major effect of many of these dominant mutations may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.
24922459 Pepin et al. (2014) reviewed clinical records for details of vascular, bowel, and organ complications in 1,231 individuals (630 index cases and 601 relatives) with vascular EDS. Missense and splice site mutations accounted for more than 90% of the 572 alterations that the authors identified in COL3A1. Median survival was 51 years but was influenced by gender (lower in men) and by the type of mutation. Among the 410 unique mutation sites identified by Pepin et al. (2014), 69 had more than 1 family with the same mutation. Among these, 4 sites (c.1662+1G-A, IVS24+1G-A (32), c.547G-A, p.Gly183Ser, p.Gly16Ser in the triple helical domain (18), c.755G-T, p.Gly252Val, c.1347+1G-A, IVS20+1G-A (9), and Gly85Val in the triple helical domain (8)) accounted for 30% of recurrent mutations. There were 17 additional sites with more than 2 unrelated families with the same mutation. By mutation type, Pepin et al. (2014) found that survival was highest among patients with null mutations; second, by more severe and splice acceptor site mutations; third, by glycine substitution mutations; and fourth, by splice donor site mutations.
24650746 Shalhub et al (2014, PMID: 24650746) compared the phenotypes of 69 EDS patients with mutations that either resulted in abnormal protein production (MINimal in 59 individuals) or reduced protein productions (HI, haploinsufficient in 9 individuals). The authors found that HI patients had later onset of vascular events, similar to Liestritz, and that those events involved aortic disease with a higher frequency than the MIN cohort. Bruising and translucent skin was not as prevalent in the HI group.

Haploinsufficiency phenotype comments:

Plancke et al. (2009) reported a 10-year-old French girl, born of consanguineous parents, with EDS type IV who was found to carry a homozygous truncating mutation in the COL3A1 gene (479dupT). The patient's unaffected parents were each heterozygous for the mutation, suggesting autosomal recessive inheritance. The mutation was shown to result in nonsense-mediated decay. The lack of phenotype in the parents was discussed by Plancke et al. (2009) in light of the study by Schwarze et al. (2001, PMID: 19455184), who reported a severe phenotype resulting from haploinsufficiency for COL3A1 due to truncating mutations. Plancke et al. (2009) noted that heterozygous Col3a1-null mice have no phenotype (Liu et al., 1997), similar to the parents of their French patient. Plancke et al. (2009) also noted that the nonsense-mediated mRNA process is inefficient and, in the cases of Schwarze et al. (2001), could have resulted in the production of a small amount of protein with dominant-negative effects. Leistritz et al. (2011, PMID: 21637106) reviewed the clinical and family histories of medical complications in 54 individuals from 19 families with COL3A1-null mutations consisting of frameshift and nonsense mutations. Compared with individuals with missense or exon-skipping mutations, they found that life span of individuals with null mutations was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. Families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incident, had a complication and only 30% had minor clinical features of vascular Ehlers-Danlos syndrome type IV. Leistritz et al. (2011) concluded that null mutations of COL3A1 have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.

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