Posterior polymorphous corneal dystrophy is associated with TCF8 gene mutations and abdominal hernia

Abstract

Mutations in the two-handed zinc-finger homeodomain transcription factor gene (TCF8) have been associated with posterior polymorphous corneal dystrophy (PPCD) and extraocular developmental abnormalities. We performed screening of TCF8 in 32 affected, unrelated probands, affected and unaffected family members of probands identified with a TCF8 mutation, and in 100 control individuals. Eight different pathogenic mutations were identified in eight probands: four frameshift (c.953_954insA, c.1506dupA, c.1592delA, and c.3012_3013delAG); three nonsense (Gln12X, Gln214X, Arg325X); and one missense (Met1Arg). Screening of TCF8 in affected and unaffected family members in six families demonstrated that each identified mutation segregated with the disease phenotype in each family; two probands did not have additional family members available for analysis. None of the eight TCF8 mutations was identified in 200 control chromosomes. The prevalence of hernias of the abdominal region in affected individuals with PPCD associated with TCF8 mutations was significantly higher than the prevalence in both individuals with PPCD not associated with a TCF8 mutation and in unaffected individuals. Therefore, PPCD is associated with TCF8 mutations in one quarter of affected families in this study, or about one third of all PPCD families that have been screened thus far. In these families, the presence of apparently causative TCF8 mutations is associated with abdominal and inguinal hernias.

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

“…[9][10][11][12][14][15][16][17] In this study, we show that heterozygous deletions of the ZEB1 gene cause PPCD3, verifying that haploinsufficiency of ZEB1 is the mechanism of disease.…”

“…[2][3][4] The proportion of PPCD cases attributed to mutations in ZEB1 has been reported to be between 9 and 34%. [9][10][11][12][14][15][16][17] Our results demonstrate that the number of cases with PPCD3 is underestimated, because standard screening techniques do not detect deletions spanning such large regions. We have therefore developed an assay for the rapid and reliable detection of ZEB1 deletions using qRT-PCR.…”

“…20,24 PPCD often presents in small nuclear families or as an isolated case such that linkage to a specific genomic region is not conclusive, or is confounded by incomplete penetrance in some cases, so a substantial proportion of patients currently lack a molecular diagnosis. [9][10][11][12][14][15][16][17] In this study we demonstrate that, in some of these cases, PPCD can be attributed to heterozygous deletions at the ZEB1 locus, providing insights into the molecular diagnosis of previously unexplained PPCD cases and verifying haploinsufficiency as the mechanism of disease for PPCD3.…”

“…[9][10][11][12][13][14][15][16][17] There are regional variations in the contribution of these PPCD subtypes, and the proportion attributed to ZEB1 mutations (PPCD3) has been reported to be 9% in New Zealand, 20% in the Czech Republic, 30% in the United Kingdom and Canada, and 34% in the United States. [9][10][11][12][13][14][15][16][17] In contrast to other PPCD subtypes, PPCD3 is often associated with corneal steepening. 16,18 Systemic features such as inguinal hernias have also been described.…”

“…16,18 Systemic features such as inguinal hernias have also been described. 9,10,16 There is a substantial variability in disease onset and presentation even among affected members of the same family. 19 PPCD3 can arise as a result of de novo mutations, and some individuals with a pathogenic mutation in ZEB1 do not exhibit clinical signs of the disease indicating either incomplete, or age-related, penetrance.…”