Novel Mutation in CRYBB3 Causing Pediatric Cataract and Microphthalmia

Abstract

Up to 25% of pediatric cataract cases are inherited, with half of the known mutant genes belonging to the crystallin family. Within these, crystallin beta B3 (CRYBB3) has the smallest number of reported variants. Clinical ophthalmological and genetic-dysmorphological evaluation were performed in three autosomal dominant family members with pediatric cataract and microphthalmia, as well as one unaffected family member. Peripheral blood was collected from all participating family members and next-generation sequencing was performed. Bioinformatics analysis revealed a novel missense variant c.467G>A/p.Gly156Glu in CRYBB3 in all family members with childhood cataract. This variant is classified as likely pathogenic by ACMG, and no previous descriptions of it were found in ClinVar, HGMD or Cat-Map. The only other mutation previously described in the fifth exon of CRYBB3 is a missense variant that causes a change in amino acid from the same 156th amino acid to arginine and has been associated with pediatric cataract and microphthalmia. To the best of our knowledge, this is the first time the c.467G>A/p.Gly156Glu variant is reported and the second time a mutation in CRYBB3 has been associated with microphthalmia.

A novel hemizygous CD40L mutation of X-linked hyper IgM syndromes and compound heterozygous DOCK8 mutations of hyper IgE syndromes in two Chinese families

“…No association between HIES and congenital malformation of eyes and no correlation between congenital microphthalmia and DOCK8 mutations were reported until now after searching the relevant studies previously published. Congenital microphthalmia was associated with the mutations of CRYBB3, FOXE3 and PAX6, none of which was detected by WES analysis in this patient [41][42][43]. Therefore, we recommended the couple to seek genetic counseling positively before their next pregnancy.…”

Effect of clinical whole exome sequencing in aetiological investigation and reproductive risk prediction for a couple with monogenic inherited diseases

“…Additionally, different variants in β-crystallin genes can cause different types of cataracts, including variants in the β-B3 crystallin gene ( CRYBB3 ; OMIM 123630), which cause Cataract 22 (OMIM 609741). As of 3 October 2022, the Cat-Map website has included data on 10 CRYBB3 gene variant loci, including 7 AD genetic loci: c.75 + 1G>A ( Chen and Zhu, 2021 ), c.224G>A ( Rodríguez-Solana et al, 2023 ), c.466G>A ( Taylan Sekeroglu et al, 2020 ), c.467G>A ( Zin et al, 2021 ), c.531G>T ( Fernández-Alcalde et al, 2021 ), c.581T>A ( Xu et al, 2021 ), and c.634T>C ( Fan et al, 2020 ), as well as 1 AR genetic locus, c.493G>C ( Iqbal et al, 2020 ).…”

Genome Sequencing Provides Novel Insights into Mudflat Burrowing Adaptations in Eel Goby Taenioides sp. (Teleost: Amblyopinae)

“…Beta-crystallin B3 is one important form of β-crystallins that are necessary for lens transparency and eye development of vertebrates [ 33 , 37 ]. Mutations or abnormal expression in CRYBB3 would lead to severe developmental disorders of eye development, such as poor vision [ 38 ], cataract [ 35 ], corneal degeneration [ 39 ], or some form of microphthalmia (syndrome with unusual smaller eyes) [ 39 , 40 ] in Humans. Such gene losses in genome may change the visual perception or eye development in animals, and may be implicated in the evolution of small vestigial eyes in Taenioides sp, though the causative effect of these presumed gene losses still awaits further investigation.…”