To analyze the clinical and molecular genetic characteristics of a Chinese family with congenital cataract-microcornea syndrome.

The method of pedigree investigation was adopted.A Chinese Han family with congenital cataract-microcornea syndrome was recruited in Xiamen Eye Center of Xiamen University.All the family members received detailed ophthalmologic examination including the best corrected visual acuity, intraocular pressure measurement by handheld applanation tonometry, slit lamp biomicroscopy, color fundus photography, B-scan ultrasonography, corneal diameter, anterior segment optical coherence tomography, ultrasound biomicroscopy, corneal endoscopy, and corneal topography.Genomic DNA was extracted from peripheral venous blood from some patients and unaffected family members.Targeted high-throughput DNA sequencing was performed on the proband.The sequencing chip contained 188 known pathogenic genes related to lens abnormalities.Suspected pathogenic genes were verified by Sanger sequencing in phenotypically normal family members to identify the co-segregation and the disease-causing gene.Bioinformatics analysis was performed to analyze the pathogenicity of variants by REVEL.Conserved protein domains were analyzed by InterPro.Physicochemical property of the mutant protein was analyzed by ProtParam.The deleteriousness of the protein was predicted by PolyPhen-2.Homology of the variants in pathogenic gene was analyzed by NCBI website to compare the conservation among various species.This study followed the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Xiamen Eye Center of Xiamen University (No.XMYKZX-LW-2009-003).Written informed consent was obtained from each subject prior to entering the study cohort.

There were 39 members of 4 generations in this family including 11 patients with an autosomal dominant inheritance pattern.Clinical features of the patients included congenital cataract and microcornea.No obvious abnormality was found in ophthalmic and general examination.A heterozygous mutation c. 61C>T in the CRYAA gene was found, resulting in the mutation of the amino acid from arginine to tryptophan (p.Arg21Trp) at position 21, consistent with co-segregation.The number of cationic cluster in the mutant protein decreased, and the hydrophilicity and stability were reduced.The variant was predicted to be deleterious and was highly conserved in multiple species.

A novel heterozygous mutation c.61C>T p. Arg21Trp in CRYAA gene is considered as the causal gene of this family.It is the first time this variant has been reported in China.

Cataract-microcornea syndrome; Pedigree; Genetic testing; Mutation; CRYAA gene