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.

Figure 1

Gypsy PCG kindred, with recently identified relatedness between separately recruited families, PCG 3 and PCG 18. The two branches of family 3 have different CYP1B1 mutations, and none of these is shared by the affected subject in family 18.

Figure 2

Double CYP1B1 and LTBP2 mutants in (a) family PCG 16 and (b) family PCG 27. Dark shaded symbols indicate PCG affected individuals and dashed symbol (16-7) indicates late-onset angle closure glaucoma.

Figure 3

Geographic distribution of the p.R299X and p.E387K alleles in Bulgaria, indicating places of residence of affected subjects and of carriers identified among population controls. The map outline is taken from http://www.worldatlas.com.

Figure 4

Founder mutation haplotypes on independent chromosomes carrying: (a) CYP1B1 p.E387K and (b) LTBP2 p.R299X. The genetic distances follow the DeCode map. The positions of rs57778725 and of the two mutations are interpolated from the physical distances and positions relative to the DeCode STRs. The conserved (presumably ancestral) haplotypes are highlighted in grey. Asterisks (^*) denote potential mutations, rather than recombinations. M denotes mutant allele.