Classification of congenital cataracts based on multidimensional phenotypes and its association with visual outcomes

●AIM:To establish a classification for congenital cataracts that can facilitate individualized treatment and help identify individuals with a high likelihood of different visual outcomes.●METHODS:Consecutive patients diagnosed with congenital cataracts and undergoing surgery between January 2005 and November 2021 were recruited.Data on visual outcomes and the phenotypic characteristics of ocular biometry and the anterior and posterior segments were extracted from the patients’medical records.A hierarchical cluster analysis was performed.The main outcome measure was the identification of distinct clusters of eyes with congenital cataracts.●RESULTS:A total of 164 children(299 eyes)were divided into two clusters based on their ocular features.Cluster 1(96 eyes)had a shorter axial length(mean±SD,19.44±1.68 mm),a low prevalence of macular abnormalities(1.04%),and no retinal abnormalities or posterior cataracts.Cluster 2(203 eyes)had a greater axial length(mean±SD,20.42±2.10 mm)and a higher prevalence of macular abnormalities(8.37%),retinal abnormalities(98.52%),and posterior cataracts(4.93%).Compared with the eyes in Cluster 2(57.14%),those in Cluster 1(71.88%)had a 2.2 times higher chance of good best-corrected visual acuity[<0.7 logMAR;OR(95%CI),2.20(1.25–3.81);P=0.006].●CONCLUSION:This retrospective study categorizes congenital cataracts into two distinct clusters,each associated with a different likelihood of visual outcomes.This innovative classification may enable the personalization and prioritization of early interventions for patients who may gain the greatest benefit,thereby making strides toward precision medicine in the field of congenital cataracts.

Characterization of N6-methyladenosine long non-coding RNAs in sporadic congenital cataract and age-related cataract

AIM:To characterize the N6-methyladenosine(m6A)modification patterns in long non-coding RNAs(lncRNAs)in sporadic congenital cataract(CC)and age-related cataract(ARC).METHODS:Anterior capsule of the lens were collected from patients with CC and ARC.Methylated RNA immunoprecipitation with next-generation sequencing and RNA sequencing were performed to identify m6A-tagged lncRNAs and lncRNAs expression.Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses and Gene Ontology annotation were used to predict potential functions of the m6A-lncRNAs.RESULTS:Large amount of m6A peaks within lncRNA were identified for both CC and ARC,while the level was much higher in ARC(49870 peaks)than that in CC(18688 peaks),yet those difference between ARC in younger age group(ARC-1)and ARC in elder age group(ARC-2)was quite slight.A total of 1305 hypermethylated and 1178 hypomethylated lncRNAs,as well as 182 differential expressed lncRNAs were exhibited in ARC compared with CC.On the other hand,5893 hypermethylated and 5213 hypomethylated lncRNAs,as well as 155 significantly altered lncRNA were identified in ARC-2 compared with ARC-1.Altered lncRNAs in ARC were mainly associated with the organization and biogenesis of intracellular organelles,as well as nucleotide excision repair.CONCLUSION:Our results for the first time present an overview of the m6A methylomes of lncRNA in CC and ARC,providing a solid basis and uncovering a new insight to reveal the potential pathogenic mechanism of CC and ARC.

Abnormal function of EPHA2/p.R957P mutant in congenital cataract

AIM:To identify genetic defects in a Chinese family with congenital posterior polar cataracts and assess the pathogenicity.METHODS:A four-generation Chinese family affected with autosomal dominant congenital cataract was recruited.Nineteen individuals took part in this study including 5 affected and 14 unaffected individuals.Sanger sequencing targeted hot-spot regions of 27 congenital cataract-causing genes for variant discovery.The pathogenicity of the variant was evaluated by the guidelines of American College of Medical Genetics and InterVar software.Confocal microscopy was applied to detect the subcellular localization of fluorescence-labeled ephrin type-A receptor 2(EPHA2).Co-immunoprecipitation assay was implemented to estimate the interaction between EphA2 and other lens membrane proteins.The mRNA and protein expression were analyzed by reverse transcription-polymerase chain reaction(qRT-PCR)and Western blotting assay,respectively.The cell migration was analyzed by wound healing assay.Zebrafish model was generated by ectopic expression of human EPHA2/p.R957P mutant to demonstrate whether the mutant could cause lens opacity in vivo.RESULTS:A novel missense and pathogenic variant c.2870G>C was identified in the sterile alpha motif(SAM)domain of EPHA2.Functional studies demonstrated the variant’s impact:reduced EPHA2 protein expression,altered subcellular localization,and disrupted interactions with other lens membrane proteins.This mutant notably enhanced human lens epithelial cell migration,and induced a central cloudy region and roughness in zebrafish lenses with ectopic expression of human EPHA2/p.R957P mutant under differential interference contrast(DIC)optics.CONCLUSION:Novel pathogenic c.2870G>C variant of EPHA2 in a Chinese congenital cataract family contributes to disease pathogenesis.

Novel MIP gene mutation causes autosomal-dominant congenital cataract

●AIM:To identify disease-causative mutations in families with congenital cataract.●METHODS:Two Chinese families with autosomaldominant congenital cataract(ADCC)were recruited and underwent comprehensive eye examinations.Gene panel next-generation sequencing of common pathogenic genes of congenital cataract was performed in the proband of each family.Sanger sequencing was used to valid the candidate gene mutations and sequence the other family members for co-segregation analysis.The effect of sequence changes on protein structure and function was predicted through bioinformatics analysis.Major intrinsic protein(MIP)-wildtype and MIP-G29R plasmids were constructed and microinjected into zebrafish single-cell stage embryos.Zebrafish embryonic lens phenotypes were screened using confocal microscopy.●RESULTS:A novel heterozygous mutation(c.85G>A;p.G29R)in the MIP gene was identified in the proband of one family.A known heterozygous mutation(c.97C>T;p.R33C;rs864309693)in MIP was found in the proband of another family.In-silico prediction indicated that the novel mutation might affect the MIP protein function.Zebrafish embryonic lens was uniformly transparent in both wild-type PCS2+MIP and mutant PCS2+MIP.●CONCLUSION:Two missense mutations in the MIP gene in Chinese cataract families are identified,and one of which is novel.These findings expand the genetic spectrum of MIP mutations associated with cataracts.The functional studies suggest that the novel MIP mutation might not be a gain-of-function but a loss-of-function mutation.

Epidemiology and molecular genetics of congenital cataracts

Congenital cataract is a crystallin severe blinding disease and genetic factors in disease development are important. Crystallin growth is under a combination of genes and their products in time and space to complete the coordination role of the guidance. Congenital cataract-related genes, included crystallin protein gene (CRYAA, CRYAB, CRYBA1/A3, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD, CRYGS), gap junction channel protein gene (GJA1, GJA3, GJA8), membrane protein gene (GJA3, GJA8, MIP, LIM2), cytoskeletal protein gene (BF-SP2), transcription factor genes (HSF4, MAF, PITX3, PAX6), ferritin light chain gene (FTL), fibroblast growth factor (FGF) and so on. Currently, there are about 39 genetic loci isolated to which primary cataracts have been mapped, although the number is constantly increasing and depends to some extent on definition. We summarized the recent advances on epidemiology and genetic locations of congenital cataract in this review.

Factors associated with strabismus after cataract extraction and primary intraocular lens implantation in congenital cataracts

AIM:To evaluate factors associated with the development of strabismus after cataract extraction and primary intraocular lens implantation.METHODS:The medical records of 122 patients,aged1.5mo to 9y,who had undergone cataract extraction with primary intraocular lens implantation between January1993 and August 2011 were reviewed.Fourteen patients(17 eyes)with strabismus before cataract surgery were excluded.Patients were divided into those with congenital bilateral cataracts(64 patients,128 eyes)and those with unilateral cataracts(44 patients,44 eyes).The associations between the development of strabismus and age at cataract surgery,pre-and post-cataract extraction corrected distance visual acuity(CDVA),interocular CDVA difference,nystagmus,surgical method,and secondary cataract were evaluated.RESULTS:Factors significantly associated with the development of strabismus included age at cataract surgery(≤1y),preoperative mean CDVA≤20/100,presence of nystagmus in the bilateral cataract group and postoperative interocular CDVA difference】20/70 in the unilateral group.Postoperative CDVA≤20/100 and preservation of posterior capsule,and presence of secondary cataract were significant factors in both groups.CONCLUSION:Children with congenital cataracts should be monitored carefully after cataract surgery for the development of strabismus,especially when they underwent surgery at age≤1y,and they have nystagmus,large postoperative interocular CDVA difference,poor preoperative and postoperative CDVA,preservation of the posterior capsule,or secondary cataract.

Changes of corneal central thickness of aphakia following congenital cataract surgery under the first six months of life

AIM: To observe the central corneal thickness (CCT) changes in infants and young children who had been undergone bilateral congenital cataract surgery, and to compare the changes with normal control group which was selected from healthy population. METHODS: A cross section case-control study contained 28 cases (56 eyes) of bilateral aphakia (aphakic group) due to congenital cataract surgery combining with posterior continuous curvilinear capsulorhexis and with anterior vitrectomy during 2-6 months after birth. Fourteen children (28 eyes) of age-sex matched with the aphalic group were selected as normal control group. CCT and intraocular pressure (TOP) were measured postoperatively and the results were compared between groups. RESULTS: The mean CCT was 653.5 +/- 82.4 mu m in the aphakic group and 579.6 +/- 39.2 mu m in the control group, with a significant difference (P=0.000). The mean value of TOP in aphakic group (22.0 +/- 1.6mmHg) was greater than that of control group (16.9 +/- 2.1mmHg), P=0.023. There was a negative correlation between age and CCT in normal control group (r=-0.531, P=0.026), and there was no correlation in bilateral aphakia group (r=-0.324, P=0.165). CONCLUSION: Aphakic children due to congenital cataract surgery have a greater CCT than normal children. It is necessary to consider CCT in evaluating IOP for children after congenital cataract surgery.

Use of high-throughput targeted exome sequencing in genetic diagnosis of Chinese family with congenital cataract

AIM： To identify disease-causing mutation in a congenital cataract family using enrichment of targeted genes combined with next-generation sequencing.· METHODS： A total of 371 known genes related to inherited eye diseases of the proband was selected and captured, followed by high-throughput sequencing. The sequencing data were analyzed by established bioinformatics pipeline. Validation was performed by Sanger sequencing.·RESULTS： A recurrent heterozygous non-synonymous mutation c.130 G A（p.V44M） in the GJA3 gene was identified in the proband. The result was confirmed by Sanger sequencing. The mutation showed co-segregation with the disease phenotype in the family but was not detected in unaffected controls.·CONCLUSION： Targeted exome sequencing is a rapid,high-throughput and cost-efficient method for screening known genes and could be applied to the routine gene diagnosis of congenital cataract.

Effect of low molecular weight heparin (enoxaparin) on congenital cataract surgery

AIM: To assess the efficacy of intracameral enoxaparin (a low-molecular-weight heparin) infusion, in variable doses on postoperative inflammatory response in congenital cataract surgery.METHODS: It is a prospective, randomized controlled trial. Eighty eyes of 53 children with congenital cataract were enrolled in this study. Every eye had primary posterior capsulorrhexis and intraocular lens (IOL) implantation after lens aspiration. The eyes were divided into 4 equal groups. In group 1 balanced salt solution (BSS) without enoxaparin was used as an irrigation solution. Whereas in group 2, 3 and 4, 40mg, 20mg and 10mg enoxaparin in 500mL BSS was used respectively. The inflammatory response in the anterior chamber was compared among the groups with slit-lamp biomicroscopy.RESULTS: The mean follow-up period was (17.75±3.95) months in group 1, (18.00±5.15) months in group 2, (19.20±5.47) months in group 3 and (18.65±5.16) months in group 4. Mean number of inflammatory cells in the anterior chamber in group 1 was significantly higher than that of group 2, 3, 4 (P <0.001). There was fibrin formation in the anterior chambers of 3 eyes in group 1 and one eye in group 4. There was synechiae formation in 3 eyes of group 1 and one eye of group 4. There was no significant difference among the groups by means of fibrin or synechiae formation (P>0.05). There were IOL precipitates in 4 eyes of group 1 and 2 eyes of group 4. IOL precipitate formation was significantly higher in group 1 than that of group 2 and 3 in which there was no IOL precipitate (P=0.048). There was IOL subluxation in only one eye of group 1, 3 and 4 while no subluxation was observed in group 2 (P>0.05). There was no statistically significant difference detected about IOL subluxation occurance in all 4 groups (P>0.05). CONCLUSION: Complications of cataract surgery in congenital cataract patients associated with postoperative inflammatory response found to be decreased with the use of enoxaparin in intraocular infusion solutions. Furthermore according to our results the anti-inflammatory effect of enoxaparin was dose dependant.

Expression of lens-related microRNAs in transparent infant lenses and congenital cataract

AIM：To identify the expression of lens-related micro RNAs（miRNAs）in the central epithelium of transparent infant lenses and congenital cataract. METHODS：Lens-related mi RNAs were retrieved from Pub Med database. The expression levels of these mi RNAs in transparent infant lenses and congenital cataract were determined by stem-loop reverse transcription-polymerase chain reaction（RT-PCR）. mi Randa algorithm was used to predict the target genes of these differentially expressed mi RNAs. The target m RNA was validated.RESULTS：Six lens-related mi RNAs were retrieved from screening Pub Med database. The most abundant mi RNA in transparent infant lenses according to stem-loop RT-PCR was mi R-184. miR-182 was up-regulated in congenital cataract. Contrarily,miR-204 and miR-124 was down-regulated.mi R-204 exhibited a more significant decrease in expression than mi R-124. In addition,Meis2 was predicted to be the target of mi R-204 using mi Randa algorithm. mi R-204mimic/antagomir transfection experiments suggested the negative correlation between the expression of mi R-204 and Meis2.CONCLUSION：The expression levels of miR-182,miR-204 and mi R-124 differ between the central epithelium of transparent infant lens and congenital cataract,suggesting their involvement in the pathogenesis of congenital cataract. miR-204 may act via silencing Meis2 to regulate lens development and congenital cataract formation.

Ocular development in children with unilateral congenital cataract and persistent fetal vasculature

AIM: To investigate the ocular development of patients who had unilateral congenital cataract(CC) combined with persistent fetal vasculature(PFV).METHODS: This cross-sectional, observational study included patients who had unilateral CC and PFV and those with isolated unilateral CC.Axial length(AL), keratometry, anterior chamber depth(ACD), lens thickness, and vitreous length were obtained.The ocular biometric parameters of the affected eyes of patients with CC and PFV were compared with the fellow eyes and with the affected eyes of patients with isolated CC.RESULTS: A total of 110 patients were included and divided into 4 groups: group 1(18 patients with CC and PFV, <24 mo), group 2(22 patients with CC and PFV, ≥24 mo), group 3(35 patients with CC, <24 mo), and group 4(35 patients with CC, ≥24 mo).The ALs of the affected eyes were shorter than those of the fellow eyes in group 1(20.02±1.06 vs 20.66±0.63 mm, P=0.025).While the ALs of the affected eyes were longer than those of the fellow eyes in group 2(23.18±2.00 vs 22.31±1.06 mm, P=0.044) and group 4(22.64±1.80 vs 22.02±1.01 mm, P=0.033).The keratometries of the affected eyes were steeper than those of the fellow eyes in group 2(44.78±1.66 vs 43.83±1.38 D,P=0.041) and group 4(43.76±1.91 vs 43.34±1.46 D, P=0.043).No difference of ACDs between two eyes was found in all groups(all P>0.05).CONCLUSION: Compared with the fellow eyes, the ALs of the eyes with unilateral CC and PFV are shorter in patients younger than 24 mo and longer in those older than 24 mo;the keratometries of the eyes with unilateral CC and PFV are steeper in patients older than 24 mo and similar with those younger than 24 mo.These findings provide further understanding of ocular development in patients with both CC and PFV.

A novel splice site mutation of CRYBA3/A 1 gene associated with congenital cataract in a Chinese family

AIM： To identify the disease-causing mutation responsible for the presence of congenital cataract in a Chinese family. METHODS： The study recruited a four-generation Chinese pedigree affected by autosomal dominant congenital cataract （ADCC）. Family history and the history of cataract extraction were recorded. Blood samples were collected from individuals for DNA extraction. Direct sequencing of congenital cataract-associated genes was performed. Single-strand conformational polymorphism and bioinformatic analysis were conducted to further study the mutation. RESULTS： Direct sequencing revealed a novel splice site mutation of c.30-2 A〉G in the CRYBA3/A1 gene. The mutation co-segregated within all affected individuals in the family and was not found in unaffected members or 100 unrelated normal controls. These results were further confirmed by single-strand conformational polymorphism and bioinformatic analysis using the Human Splicing Finder and MaxEnt online software and Annovar computer software. CONCLUSION： c,30-2 A〉G mutation of CRYBA3/A1 gene is a novel mutation and broadens the genetic spectrum of ADCC, KEYWORDS： splice site mutation; congenital cataract; CRYBA3/A1 gene

Clinical features of strabismus and nystagmus in bilateral congenital cataracts

AIM：To evaluate the prevalence,clinical features,and the factors affecting onset of strabismus and nystagmus in patients with bilateral congenital cataracts.METHODS：This study evaluated 116 eyes of 58 patients who underwent lens removal for the treatment of bilateral congenital cataracts between January 1999 and January 2011.The presence and type of strabismus and nystagmus were determined before and after surgery.Type of strabismus and final visual acuity were compared in patients with and without nystagmus.Patients were divided into three groups（orthotropia/orthotropia,orthotropia/strabismus,and strabismus/strabismus） according to their preoperative and postoperative ocular alignment.Age at cataract surgery and associations of nystagmus and primary intraocular lens（IOL） implantation with strabismus were analyzed.RESULTS：Six patients（10.3%） had strabismus preoperatively and an additional 11（19.0%） developed postoperative strabismus.Exotropia was more common than esotropia both preoperatively and postoperatively.Eighteen patients（31.0%） had postoperative nystagmus,with sensory nystagmus being the most common type.Of the 18 patients with nystagmus,10 had strabismus,with exotropia being more common than esotropia.Postoperative visual acuity was poor in patients with nystagmus.Age at cataract surgery and rate of primary IOL implantation were significantly lower,and postoperative nystagmus was more common,in the orthotropia/strabismus group than in the other two groups.CONCLUSION：Exotropia and sensory nystagmus are common in patients with bilateral congenital cataracts.Age at cataract surgery and rate of IOL implantation are lowerand nystagmus more common in patients with postoperative onset of strabismus.Nystagmus is associated with poor visual prognosis.

Novel mutations in CRYBB1/CRYBB2 identified by targeted exome sequencing in Chinese families with congenital cataract

AIM：To summarize the phenotypes and identify the underlying genetic cause of the CRYBB1 and CRYBB2 gene responsible for congenital cataract in two Chinese families.METHODS：Detailed family histories and clinical data were collected from patients during an ophthalmologic examination. Of 523 inheritable genetic vision systemrelated genes were captured and sequenced by targeted next-generation sequencing,and the results were confirmed by Sanger sequencing. The possible functional impacts of an amino acid substitution were performed with Poly Phen-2 and SIFT predictions.RESULTS：The patients in the two families were affected with congenital cataract. Sixty-five （FAMILY-1） and sixty two （FAMILY-2） single-nucleotide polymorphisms and indels were selected by recommended filtering criteria.Segregation was then analyzed by applying Sanger sequencing with the family members. A heterozygous CRYBB1 mutation in exon 4 （c.347T〉C, p.L116P） was identified in sixteen patients in FAMILY-1. A heterozygous CRYBB2 mutation in exon 5 （c.355G〉A, p.G119R） was identified in three patients in FAMILY-2. Each mutation cosegregated with the affected individuals and did not exist in unaffected family members and 200 unrelated normal controls.The mutation was predicted to be highly conservative and to be deleterious by both PolyPhen-2 and SIFT.CONCLUSION：TheCRYBB1 mutation（c.347T〉C）and CRYBB2 mutation （c.355G〉A） are novel in patients with congenital cataract. We summarize the variable phenotypes among the patients, which expanded the phenotypic spectrum of congenital cataract in a different ethnic background.

Efficacy of microcatheter-assisted trabeculotomy on secondary glaucoma after congenital cataract surgery

AIM: To evaluate efficacy of microcatheter-assisted trabeculotomy(MAT) in eyes with secondary glaucoma after congenital cataract surgery and explore its correlation with the different degree of trabeculotomy. METHODS: A retrospective analysis was conducted on patients who underwent the said procedure between September 2019 and September 2020. The patients were classified into two groups according to the degree of trabeculotomy(group 1: ≤240-degree;group 2: 240–360-degree). The intraocular pressure(IOP) and antiglaucoma drugs before and after operation was collected during the 12-month follow-up. RESULTS: Totally 27 eyes of 25 patients were included: 11(40.7%) eyes in group 1 and 16(59.3%) eyes in group 2. The mean IOP of all patients was 34.67±9.18 mm Hg preoperatively and 8.74±4.32, 9.95±5.65, 14.39±5.30, 16.02±4.37, 15.82±3.28, and 16.19±3.56 mm Hg 1 d, 1 wk, 1, 3, 6, and 12 mo after surgery, respectively. In all patients, there were significant differences in IOP at each time point(F=65.614, P<0.01). In each group, IOP after surgery was lower than that before surgery(all P<0.01), but there was no difference in the rate of IOP reduction between the two groups(P=0.246). Furthermore, the amount of anti-glaucoma medications reduced to 0.30±0.67(0–2) at 12 mo from 2.63±0.49(2–3) preoperatively(P<0.01), and there was no difference between the two groups(P>0.05). At the end of follow-up, the partial success rate was 81.8% in group 1 vs 93.75% in group 2(P=0.549). Various amount of intraoperative and postoperative hyphema occurred in all eyes, which spontaneously absorbed or cleaned through paracentesis and irrigation. No other serious complications was observed.CONCLUSION: MAT can effectively reduce IOP in patients with secondary glaucoma after congenital cataract surgery with a high success rate and safety. And it can be used as the first choice for the treatment of secondary glaucoma after surgery for congenital cataracts.

Commentary review:challenges of intraocular lens implantation for congenital cataract infants

As an indispensable part of congenital cataract surgery,intraocular lens(IOL)implantation in infantile patients has long-term positive impacts on visual rehabilitation,as well as postoperative complications inevitably.Timing of IOL implantation in infantile congenital cataract patients is not simply a point-in-time but a personalized decision that comprehensively takes age at surgery,risks of postoperative complications,and economic condition of family in consideration,and combines with choosing suitable IOL type and power.For infants with well-developed eyeballs and good systemic conditions,IOL implantation at six months of age or older is safe and effective.Otherwise,secondary IOL implantation may be a safer choice.

PVEP in Patients with Different Types of Congenital Cataract

The preoperative and postoperative PVEP in 79 eyes of 45 patients with three types of congenital namely lamellar cataract, nuclear cataract and total cataract was studied. The results showed that visual acuity of patients who could be cooperatively examined was improved significantly after operation. The examination of PVEP revealed that more abnormal wave-formes were found in total cataract group before operation. P1 latencies of low and medium spatial frequencies (140', 70', and 35') became much longe...

The Corneal Endothelium in Children after Congenital Cataract Surgery--A Comparison of Pre- and Post-Operative Results

Three months after surgery, the research group showed significantly statistical improvement in visual acuity, a statistically significant decrease in corneal endothelial cell density, a statistically significant increase in the percentage of 5 and 8 sided cells and a statistically significant decrease in the percentage of six sided cells. Central corneal thickness and the percentage of 4 and 7 and more than 8 sided did not change in a statistically significant way. Comparing the test group and control group, no statistically significant differences were detected in the examined parameters. The present study also shows that the cornea in the eyes with congenital cataract does not show statistically significant changes in the density and the morphology of the corneal endothelial cells and the thickness of the cornea and in terms of corneal thickness in comparison to the corneas of healthy eyes. Although in corneas undergoing cataract occurs statistically significant changes, the influence of the cornea does not affect the improvement in visual acuity which was also demonstrated in this study.

A Novel HSF4 Mutation in a Chinese Family with Autosomal Dominant Congenital Cataract

This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4（HSF4） gene in a Chinese family with autosomal dominant congenital cataract（ADCC）. All exons of HSF4 were amplified by PCR. Sequence analysis of PCR products was performed. Restriction fragment length polymorphism（RFLP） analysis was conducted to confirm the pathogenic mutation. The results showed that a C to T substitution occurred at nucleotide 331 in patients of this family, leading to the replacement of the amino acid arginine-111 with cysteine in exon 3. RFLP analysis showed that the amino acid change was co-segregated with all affected individuals. It was concluded that the new mutation of c.331C〉T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family.

A missense mutation S228P in the CRYBB1 gene causes autosomal dominant congenital cataract

Background Congenital cataract is a highly heterogeneous disorder at both the genetic and phenotypic levels. This study was conducted to identify disease locus for autosomal dominant congenital cataracts in a four generation Chinese family. Methods Family history and clinical data were recorded. All the members were genotyped with microsatellite markers which are close to the known genetic loci for autosomal congenital cataracts. Two-point Lod scores were obtained using the MLINK of the LINKAGE program package （vet 5.1）. Candidate genes were amplified by polymerase chain reaction （PCR） and direct cycle sequencing.Results The maximum Lod score of Zmax=2.11 was obtained with three microsatellite markers D22S258, D22S315, and D22S1163 at recombination fraction θ= 0. Haplotype analysis showed that the disease gene was localized to a 18.5 Mbp region on chromosome 22 flanked by markers D22S1174 and D22S270, spanning the β-crystallin gene cluster. A c.752T→C mutation in exon 6 of CRYBB1 gene, which resulted in a heterozygous S228P mutation in predicted protein, was found to cosegregate with cataract in the family.Conclusions This study identified a novel mutation in CRYBB1 gene in a Chinese family with autosomal dominant congenital cataract. These results provide strong evidence that CRYBB1 is a pathogenic gene for congenital cataract.