Five novel ZEB1 mutations including a 0.34 Mb deletion detected by whole genome sequencing in patients with posterior polymorphous corneal dystrophy type 3

Abstract

Purpose : To report on clinical and molecular genetic findings in six families diagnosed with posterior polymorphous corneal dystrophy.

Methods : Ocular examination, Sanger sequencing of ZEB1 coding regions in all probands and whole genome sequencing in one proband was performed. Sanger sequencing was used to verify breakpoints and for segregation within the families.

Results : Five novel heterozygous ZEB1 mutations were detected confirming a diagnosis of PPCD type 3; a deletion chr10.hg19:31,476,839_31,812,954, and point mutations c.646G>T, p.(Glu216*); c.1669C>T, p.(Gln557*); c.2577del, p.(Val860*); c.1918C>T, p.(Gln640*). In addition, de novo occurrence of a previously reported mutation c.689_690del; p.(His230Arg*7) was found in one patient. Clinical variability ranged from minimal corneal findings in one asymptomatic carrier with bilateral uncorrected visual acuity of 1.0, to a more severe phenotype, observed in 6 (60%) eyes out of 10 with best corrected visual acuity of < 0.5. Non-keratoconic corneal steepening (mean keratometry ≥ 46.75 D) was detected in 5 (56%) eyes out of 9. Endothelial cell density was decreased in all 5 eyes with available measurements (range 751-1584 cells/mm2). One 23-year-old male had cloudy corneas at 6 weeks of age and marked corneal shape asymmetry with a mean keratometry of 39.8 D in the right eye and 50.5 D in the left eye. Except for hydrocele in one male, no other systemic findings were noted.

Conclusions : PPCD3 may be associated with impaired postnatal corneal development. The occurrence of recurrent mutations in ZEB1 is rare, to date only two have been documented, and the proportion of patients with PPCD3 is currently underestimated.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.