Dataset Information

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population.

ABSTRACT: Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for ?70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations--p.R299X/LTBP2 and p.E387K/CYP1B1.

SUBMITTER: Azmanov DN

PROVIDER: S-EPMC3062003 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population.

Azmanov Dimitar N DN Dimitrova Stanislava S Florez Laura L Cherninkova Sylvia S Draganov Dragomir D Morar Bharti B Saat Rosmawati R Juan Manel M Arostegui Juan I JI Ganguly Sriparna S Soodyall Himla H Chakrabarti Subhabrata S Padh Harish H López-Nevot Miguel A MA Chernodrinska Violeta V Anguelov Botio B Majumder Partha P Angelova Lyudmila L Kaneva Radka R Mackey David A DA Tournev Ivailo I Kalaydjieva Luba L

European journal of human genetics : EJHG 20101117 3

Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/Gypsy founder po ...[more]

PMID: 21081970

Similar Datasets

Project description:PURPOSE:The CYP1B1 gene encodes an enzyme that is a member of the cytochrome P450 superfamily. Mutations in CYP1B1 have been mainly reported in recessive pediatric ocular phenotypes, such as primary congenital glaucoma (PCG) and congenital glaucoma with anterior segment dysgenesis (CG with ASD), with some likely pathogenic variants also identified in families affected with adult-onset primary open angle glaucoma (POAG). METHODS:We examined CYP1B1 in 158 pediatric patients affected with PCG (eight), CG with ASD (22), CG with other developmental ocular disorders (11), juvenile glaucoma with or without additional ocular anomalies (26), and ASD or other developmental ocular conditions without glaucoma (91); in addition, a large cohort of adult patients with POAG (193) and POAG-negative controls (288) was examined. RESULTS:Recessive pathogenic variants in CYP1B1 were identified in two PCG pedigrees, three cases with CG and ASD, and two families with CG and other ocular defects, such as sclerocornea in one patient and microphthalmia in another individual; neither sclerocornea nor microphthalmia has been previously associated with CYP1B1. Most of the identified causative mutations are new occurrences of previously reported pathogenic alleles with two novel variants identified: a c.1325delC, p.(Pro442Glnfs*15) frameshift allele in a family with PCG and a c.157G>A, p.(Gly53Ser) variant identified in a proband with CG, Peters anomaly, and microphthalmia. Analysis of the family history in the CYP1B1-positive families revealed POAG in confirmed or presumed heterozygous relatives in one family with PCG and two families with ASD/CG; POAG was associated with the c.1064_1076del, p.(Arg355Hisfs*69) allele in two of these pedigrees. Screening of an unrelated POAG cohort identified the same c.1064_1076del heterozygous allele in one individual with sporadic POAG but not in age- and ethnicity-matched POAG-negative individuals. Overall, there was no significant enrichment for mutant alleles in CYP1B1 within the POAG cases compared to the controls. CONCLUSIONS:In summary, these data expand the mutational and phenotypic spectra of CYP1B1 to include two novel alleles and additional developmental ocular phenotypes. The contribution of CYP1B1 to POAG is less clear, but loss-of-function variants in CYP1B1, especially c.1064_1076del, p.(Arg355Hisfs*69), may be associated with an increased risk for POAG.

Dataset Information

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population.

Publications

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets