Clinical and genetic characteristics of Chinese patients with familial or sporadic pediatric cataract

Abstract

Background: Pediatric cataract is a clinically and genetically heterogeneous disease which is a significant cause of lifelong visual impairment and treatable blindness. Our study aims to investigate the genotype spectrum in a group of Chinese patients with pediatric cataract.

Methods: We enrolled 39 families with pediatric cataract from October 2015 to April 2016. DNA samples of the probands were analyzed by target next-generation sequencing. Variants were validated using Sanger sequencing in the probands and available family members.

Results: In our cohort of 39 cases with different types of pediatric cataract, 23 cases were found to harbor putative pathogenic variants in 15 genes: CRYAA, CRYBA1, CRYBA4, CRYBB1, CRYGC, CRYGD, MIP, GCNT2, IARS2, NHS, BCOR, BFSP2, FYCO1, MAF, and PAX6. The mutation detection rates in the familial and sporadic cases were 75 and 47.8%, respectively. Of the 23 causative variants, over half were novel.

Conclusions: This is a rare report of systematic mutation screening analysis of pediatric cataract in a comparably large cohort of Chinese patients. Our observations enrich the mutation spectrum of pediatric cataract. Next-generation sequencing provides significant diagnostic information for pediatric cataract cases, especially when considering sporadic and subtle syndromal cases.

Keywords: Next-generation sequencing; Nystagmus; Pediatric cataract; Variant.

Fig. 1

Mutation spectrum of familial and sporadic pediatric cataract cases. The mutation detection rates in the familial and sporadic cases were 75 and 47.8%, respectively. Mutations were found in 15 different genes, with high-penetrance mutations distributed in crystallins, MIP, GCNT2, IARS2, and NHS

Fig. 2

Pedigree and variants identified in crystallin genes These schematics show the encoded domain structure of CRYAA (a), CRYBA1 (b), CRYBA4 (c), CRYBB1 (d), CRYGC (e), and CRYGD (f). Mutations found in this study are illustrated above the schematics, with novel variants indicated in red characters. Probands are indicated by arrows, ^+/− indicates heterozygous individuals, ^−/− indicates individuals testing negative. WT: wild type, MT: mutant type

Fig. 3

Pedigree and variants in transcription factor genes MAF and PAX6. The schematics show the encoded domain structure of MAF or PAX6, and the variants are illustrated above the schematics. MAF c.950A > G; p.(Glu317Gly) was identified in sporadic case #11 (a). PAX6 c.113G > A p.(Arg38Gln) was identified in family #12 (b). Patients II1 and II2 from family #12 inherited the same PAX6 allele from their unaffected mother. Allele specific PCR demonstrated that the variant was present in the asymptomatic mother. Probands are indicated by arrows. ^+/− indicates heterozygous individuals, ^−/− for individuals testing negative, ^{−/G > A} indicates a mosaic case besides the normal sequence “G” also chromosomes are found containing “A”. WT: Wild Type, MT: Mutant Type

Fig. 4

Pedigree and variants in BFSP2, FYCO1, GCNT2, and MIP. These schematics show the encoded domain structure of BFSP2 (a), exonic and protein domain structure of FYCO1 (b), encoded protein domain structure of GCNT2 (c) and MIP (d). Mutations found in this study are illustrated above the schematics, with novel variants indicated in red characters. Probands are indicated by arrows, ^+/− indicates heterozygous individuals, ^−/− for individuals testing negative. WT: wild type, MT: mutant type, W1: Wild Type 1, W2: Wild Type 2, M1: Mutant Type 1, M2: Mutant Type 2

Fig. 5

Pedigree and variants in BCOR, IARS2, and NHS. These schematics show the encoded domain structure of BCOR (a), IARS2 (b), and NHS (c). BCOR and NHS are X-linked genes. The variants found in this study are illustrated above the schematics. Probands are indicated by arrows. A dotted circle indicates an obligate X-linked carrier. ^+/− indicates heterozygous individual, ^−/− indicates individual testing negative, ^+/0 indicates hemizygote testing positive, ^−/0 indicates hemizygote testing negative. W1: Wild Type 1, W2: Wild Type 2, W3: Wild Type 3, M1: Mutant Type 1, M2: Mutant Type 2, M3: Mutant Type 3