Posterior polymorphous corneal dystrophy 3 is associated with agenesis and hypoplasia of the corpus callosum

Abstract

Posterior polymorphous corneal dystrophy (PPCD) is a dominantly inherited disorder of the corneal endothelium that has been associated with mutations in the zinc-finger E-box binding homeobox 1 gene (ZEB1) gene in approximately one-third of affected families. While the corneal dystrophies have traditionally been considered isolated disorders of the corneal endothelium, we have recently identified two cases of maldevelopment of the corpus callosum in unrelated individuals with PPCD. The proband of the first family was diagnosed shortly after birth with agenesis of the corpus callosum and several other developmental abnormalities. Karyotype, FISH and whole genome copy number variant analyses were normal. She was subsequently diagnosed with PPCD, prompting screening of the ZEB1 gene, which identified a novel deletion (c.449delG; p.(Gly150Alafs*36)) present in the heterozygous state that was not identified in either unaffected parent. The proband of the second family was diagnosed several months after birth with thinning of the corpus callosum and PPCD. Whole genome copy number variant analysis revealed a 1.79 Mb duplication of 17q12 in the proband and her father and brother, neither of whom had PPCD. ZEB1 sequencing identified a novel deletion (c.1913-1914delCA; p.(Ser638Cysfs*5)) present in the heterozygous state, which was also identified in the proband’s affected mother. Thus, we report the first two cases of the association of PPCD with a developmental abnormality of the brain, in this case maldevelopment of the corpus callosum. Keywords: agenesis, corpus callosum, PPCD3, ZEB1, ZEB2, corneal dystrophy

Agenesis of the corpus callosum, developmental delay, autism spectrum disorder, facial dysmorphism, and posterior polymorphous corneal dystrophy associated with ZEB1 gene deletion

“…Chromosome 10p11 deletion has not been reported previously in association with ACC and is not known to overlap any loci associated with syndromes including ACC as a feature (Bedeschi et al, ; Dobyns, ; Heide et al, ; Jang, Roldan, Frausto, & Aldave, ; Paul et al, ). In previous cases with cytogenetically visible chromosome 10p deletion containing p11.22, the patients were not reported to have ACC (Schinzel, ).…”

“…In previous cases with cytogenetically visible chromosome 10p deletion containing p11.22, the patients were not reported to have ACC (Schinzel, ). Jang et al, () reported two unrelated cases with agenesis/hypoplasia of corpus callosum and PPCD3. Sequencing of ZEB1 identified frameshift mutations in the gene in both probands (Jang et al, ).…”

“…Jang et al, () reported two unrelated cases with agenesis/hypoplasia of corpus callosum and PPCD3. Sequencing of ZEB1 identified frameshift mutations in the gene in both probands (Jang et al, ). Taking into consideration the similarities in the expression patterns of ZEB1 and ZEB2 genes as well as previous association of mutations in ZEB2 with ACC in Mowat–Wilson syndrome, the authors suggested that ZEB family of transcription factors may play a role in brain as well as ocular involvement and ZEB1 mutations might be the cause of ACC and PPCD3 in both of their probands.…”

Identification of Six Novel Mutations inZEB1and Description of the Associated Phenotypes in Patients with Posterior Polymorphous Corneal Dystrophy 3

“…Nonocular phenotypes, associated with ZEB1 mutations have been reported previously, most commonly the presence of hernia (Krafchak et al., ; Aldave et al., ; Lechner et al., ; Liskova et al., ; Jang et al., ). In this study, there was a self‐reported history of umbilical hernia in the twins from family C24, and umbilical hernia in the father of the proband from family B3.…”

“…Patients with PPCD3 also have a higher rate of abdominal hernia compared to the normal population (Krafchak et al., ). In one study, maldevelopment of the corpus callosum was noted in two PPCD3 probands (Jang et al., ).…”