Determining the genetic basis of familial Keratoconus by autozygosity mapping and whole exome sequencing

Abstract

Purpose: Keratoconus (KC) is a non-inflammatory, progressive thinning of the cornea resulting in a conically shaped protrusion. The conical distortion of the cornea results in irregular astigmatism and myopia leading to visual impairment requiring corneal transplantation in severe cases. The incidence of KC is around 1/2000. KC genetics is poorly understood. This project aims to identify the genetic causes of KC using a cohort of familial KC cases.

Methods: Our cohort consists of 6 Lebanese Druze families, 3 Lebanese Christian Maronite families and 5 Asian Pakistani families; all belonging to ethnic backgrounds where consanguinity and endogamy are common. Patients from consanguineous families were subjected to autozygosity mapping. At least one member of each family was analysed by whole exome sequencing on the Illumina Genetic Analyser.

Results: We identified a large region of homozygosity shared by siblings with KC on chromosome 3q27-29 in one Lebanese Druze family. Our whole exome sequencing strategy also highlighted apparent enrichment of heterozygous variants for ZNF469 (Zinc Finger Protein 469) in the 12 KC patients that were analysed so far. Further 12 KC patients are in the process of analysis.

Conclusions: The analyses of exome sequencing at the potential new locus and elsewhere are ongoing. The identification of heterozygous ZNF469 variant enrichment in recessive families was unexpected. A fuller analysis of these findings may provide new insights into KC pathogenicity.

Keywords: 574 keratoconus • 539 genetics