Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts

Vanita Berry,Roy A Quinlan,Nikolas Pontikos,Michel Michaelides,Anthony T Moore,Alex Ionides

doi:10.1038/s41433-021-01711-x

Abstract

BackgroundLens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies.MethodsUsing whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing.ResultsFamily A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470–477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case.ConclusionsWe have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

Highlights

Cataract the opacification of the eye lens is the most common, but treatable cause of blindness in the world
● We have identified novel heterozygous mutations in PAX6 and PITX3 in two English families with autosomal-dominant congenital nuclear cataract
Our study extends the mutation spectrum associated with the transcriptional factors essential to lens development to the benefit of patients through the improved genetic counselling this knowledge delivers

Summary

Introduction

Cataract the opacification of the eye lens is the most common, but treatable cause of blindness in the world (https://www.who.int/ publications-detail/world-report-on-vision). Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies. METHODS: Using whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing. CONCLUSIONS: We have identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

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Discussion

Conclusion