ORPHA: 3449; DO: 0050475;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q24.3 | ?Weill-Marchesani syndrome 3, recessive | 614819 | Autosomal recessive | 3 | LTBP2 | 602091 |
A number sign (#) is used with this entry because of evidence that Weill-Marchesani syndrome-3 (WMS3) is caused by homozygous mutation in the LTBP2 gene (602091) on chromosome 14q24. One such family has been reported.
Weill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, and lens abnormalities (Faivre et al., 2002).
For a general phenotypic description and a discussion of genetic heterogeneity of WMS, see 277600.
Haji-Seyed-Javadi et al. (2012) studied a large consanguineous Iranian family in which a brother and sister and their cousin had Weill-Marchesani syndrome, whereas 3 older sibs of the brother and sister displayed some features of WMS without meeting diagnostic criteria for the disorder. The proband was a 17-year-old boy who had ectopia lentis, myopia, elevated intraocular pressure, shallow anterior chamber, microspherophakia, short stature, brachydactyly, joint stiffness, and pulmonary and aortic stenosis. His 19-year-old sister also showed all of these features. In addition, 3 sibs had no eye findings but displayed some of the other features of WMS: a 30-year-old sister had brachydactyly, joint stiffness, and pulmonary and aortic stenosis; a 36-year-old brother had brachydactyly, joint stiffness, and pulmonary stenosis; and a 22-year-old sister had pulmonary and aortic stenosis. Their 37-year-old female cousin displayed all of the eye findings as well as brachydactyly and joint stiffness, but did not have pulmonary or aortic stenosis.
The transmission pattern of WMS3 in the Iranian family reported by Haji-Seyed-Javadi et al. (2012) was consistent with autosomal recessive inheritance.
Haji-Seyed-Javadi et al. (2012) screened the LTBP2 gene for sequence variations in 30 unrelated Iranian probands with ectopia lentis (see 129600), which was isolated in 13, associated with WMS in 4, and associated with Marfan syndrome (MFS; 154700) in 13. The proband of a large consanguineous Iranian family with ectopia lentis and WMS was found to be homozygous for a missense mutation (V1177M; 602091.0012), which was also identified in 2 more affected family members, as well as in 3 relatives with WMS-like features. Analysis of FBN1 (134797), ADAMTS10 (608990), and ADAMTS17 (607511) in 2 family members, 1 diagnosed with WMS and 1 with WMS-like features, revealed no disease-causing variations. Whole-genome homozygosity mapping on DNA from 5 affected and 4 unaffected family members confirmed that the only homozygous region segregating with affected status was an interval bordered by SNPs rs8017852 and rs7150688, containing the LTBP2 gene. Haji-Seyed-Javadi et al. (2012) also identified heterozygosity for a nonsense mutation in LTBP2 in a proband with ectopia lentis associated with Marfan syndrome; the proband and his MFS-affected daughter, who did not carry the LTBP2 mutation, were both found to also carry a mutation in the FBN1 gene. However, the proband's mother and brother, who had mitral valve prolapse (MVP) and primary closed angle glaucoma and MVP, myopia, and mild pectus excavatum, respectively, had the LTBP2 mutation but not the FBN1 mutation. Haji-Seyed-Javadi et al. (2012) concluded that the FBN1 mutation was highly likely to be the major cause of the ectopia lentis-Marfan syndrome phenotype in the pedigree, but that LTBP2 also contributed to disease status. No disease-associated mutation was identified in the 13 probands with isolated ectopia lentis; however, the authors thought that it remained a plausible candidate gene and suggested that larger cohorts be screened.
Faivre, L., Megarbane, A., Alswaid, A., Zylberberg, L., Aldohayan, N., Campos-Xavier, A. B., Bacq, D., Legeai-Mallet, L., Bonaventure, J., Munnich, A., Cormier-Daire, V. Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3-p13.2. Hum. Genet. 110: 366-370, 2002. [PubMed: 11941487] [Full Text: https://doi.org/10.1007/s00439-002-0689-3]
Haji-Seyed-Javadi, R., Jelodari-Mamaghani, S., Paylakhi, S. H., Yazdani, S., Nilforushan, N., Fan, J.-B., Klotzle, B., Mahmoudi, M. J., Ebrahimian, M. J., Chelich, N., Taghiabadi, E., Kamyab, K., Boileau, C., Paisan-Ruiz, C., Ronaghi, M., Elahi, E. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix. Hum. Mutat. 33: 1182-1187, 2012. [PubMed: 22539340] [Full Text: https://doi.org/10.1002/humu.22105]