Identification of pathogenic genetic variants in patients with acquired early-onset bilateral cataracts using next-generation sequencing.

Background: Acquired early-onset bilateral cataracts can result from systemic etiologies or genetic disorders.

Methods: In this observational study, we analyzed individuals 18 months to 35 years of age with acquired bilateral cataracts via a next-generation sequencing panel of 66 genes to identify disease-causing genetic variants.

Results: Of 347 patients enrolled, 313 (90.2%) were <19 years (median, 8 years). We identified 74 pathogenic or likely pathogenic variants in 69 patients. Of the variants, we observed 64 single nucleotide variants (SNV) in 24 genes and 10 copy number variants (CNV) of varying size and genomic location. SNVs in crystallin genes were most common, accounting for 27.0% of all variants (20 of 74). Of those, recurrent variants included known cataract-causing variants CRYBA1 c.215+1G>A, observed in 3 patients, and CRYBA1 c.272_274delGAG, CRYBB2 c.463C>T and c.562C>T, and CRYAA c.62G>A, each observed in 2 patients. In 5 patients, we identified CNV deletions ranging from 1.32-2.41 Mb in size associated with 1q21.1 microdeletion syndrome. Biallelic variants in CYP27A1 were identified in two siblings, one as part of targeted follow-up family testing, who were subsequently diagnosed with cerebrotendinous xanthomatosis, a rare but treatable autosomal recessive disease that often presents with acquired early-onset bilateral cataracts.

Conclusions: This study demonstrates the utility of genetic testing in individuals with acquired early-onset bilateral cataracts to help clarify etiology. Identification of causative genetic variants can inform patient management and facilitate genetic counseling by identifying genetic conditions with risk of recurrence in families.