Identification and Functional Characterization of Mutation in FYCO1 in Families with Congenital Cataract

Abstract: Congenital cataract (CC) causes a third of the cases of treatable childhood blindness
worldwide. CC is a disorder of the crystalline lens which is established as clinically divergent and
has complex heterogeneity. This study aimed to determine the genetic basis of CC. Whole blood was
obtained from four consanguineous families with CC. Genomic DNA was extracted from the blood,
and the combination of targeted and Sanger sequencing was used to identify the causative gene. The
mutations detected were analyzed in silico for structural and protein–protein interactions to predict
their impact on protein activities. The sequencing found a known FYCO1 mutation (c.2206C>T;
p.Gln736Term) in autosomal recessive mode in families with CC. Co-segregation analysis showed
affected individuals as homozygous and carriers as heterozygous for the mutation and the unaffected
as wild-type. Bioinformatics tools uncovered the loss of the Znf domain and structural compactness
of the mutant protein. In conclusion, a previously reported nonsense mutation was identified in
four consanguineous families with CC. Structural analysis predicted the protein as disordered and
coordinated with other structural proteins. The autophagy process was found to be significant for the
development of the lens and maintenance of its transparency. The identification of these markers
expands the scientific knowledge of CC; the future goal should be to understand the mechanism of
disease severity. Ascertaining the genetic etiology of CC in a family member facilitates establishing
a molecular diagnosis, unlocks the prospect of prenatal diagnosis in pregnancies, and guides the
successive generations by genetic counseling.