Variants in the gene in families with Brittle cornea syndrome and keratoconus.

Background: 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 () gene mutation. Keratoconus is another disease related to corneal thinning. Several reports have linked variants and keratoconus. We recruited a four-generation BCS1 family and two keratoconus families to explore pathogenic variants.

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 variants.

Results: A new homozygous frameshift mutation c. 6727del (p.Asp2243Thr fs*8) in was detected in the BSC1 family. Two 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 was identified to be pathogenic.

Conclusions: We identified a new homozygous frameshift mutation and two heterozygous missense variations in in the three families. Our findings extend the spectrum of 9 variants associated with keratoconus.