ESCRS - PP20.15 - Variants In The Znf469 Gene In Families With Brittle Cornea Syndrome And Keratoconus

Variants In The Znf469 Gene In Families With Brittle Cornea Syndrome And Keratoconus

Published 2025 - 43rd Congress of the ESCRS

Reference: PP20.15 | Type: Free paper | DOI: 10.82333/f8df-yg44

Authors: Adi Einan-Lifshitz* 1 , Malachy Nemet 2 , Anat Maytal 1 , Noa Cohen-Sinai 3 , Shir Cohen 1

1Department of Ophthalmology, Shamir Medical Center,Beer Yaakov,Israel, 2School of Medicine, Faculty of Medical and Health Sciences, Tel Aviv University,Tel Aviv,Israel, 3Bnai Zion Medical Center,Haifa,Israel

Purpose

We recruited a four-generation BCS1 family and two keratoconus families to explore pathogenic ZNF469variants.

Setting

Brittle cornea syndrome 1 (BCS1) is a rare autosomal recessive disorder characterized by corneal and sclera thinning and fragility that is caused by zinc finger protein 469 (ZNF469) gene mutation. Keratoconus is another disease related to corneal thinning. Several reports have linked ZNF469 variants and keratoconus. 

Methods

This study included 11 members from a family with BCS1, 2 families with keratoconus, 368 sporadic keratoconus patients and 325 unrelated healthy controls. Whole exome sequencing of DNA from peripheral blood and cross species conservation analysis was used to investigate and verify ZNF469 variants.

Results

A new homozygous frameshift mutation c. 6727del (p.Asp2243Thr fs*8) in ZNF469 was detected in the BSC1 family. Two ZNF469 heterozygous variants g.88494671G > A (c.793G > A, p.G265S, rs754776767) were detected in keratoconus family 1 and a heterozygous missense variant g.88498262G > A (c.4384G > A, p.D1462 N, rs577890057) was found in keratoconus family 2. Based on the American College of Medical Genetics and Genomics guidelines, rs577890057 and rs754776767 were predicted to be variants of uncertain significance. c. 6727del (p. Asp2243Thr fs*8) in ZNF469 was identified to be pathogenic.

Conclusions

We identified a new homozygous frameshift mutation and two heterozygous missense variations in ZNF469 in the three families. Our findings extend the spectrum of ZNF469 variants associated with keratoconus.