Autosomal Dominant Congenital Cataract Research Articles

Four mutations identified in Chinese families with autosomal dominant congenital cataracts by next-generation sequencing.

Congenital cataracts, which can arise due to a combination of factors like environmental influences and genetic predisposition, significantly impact children's visual health globally. The occurrence rate of congenital cataracts varies from 0. 63 to 9.74 per 10,000 births. There are 7.4 instances per 10,000 children, with the highest occurrence seen in Asia. Symptoms of the disease include clouding of the lens and visual impairment. Timely identification of the condition plays a crucial role in the management and outlook of pediatric patients. This investigation aimed to discover causative mutations in four separate Chinese family lineages. The detailed clinical data and family history of four Chinese families with autosomal dominant congenital cataracts were carefully documented. Examination of the Whole Exome Sequencing was utilized to identify the genetic anomalies present in the familial cases. Subsequent validation of the identified mutations was carried out using PCR and Sanger sequencing. Following this, various computational predictive programs were utilized to evaluate how the mutations impact the structure and function of the protein. The sequencing results reveal four potential disease-causing mutations: c.436G > A (p.V146M) of CRYBB2 Family 1, c.26G > T (p.R9I) of GJA3 in family 2, c.227G > A (p.R76H) of GJA8 in family 3, c.-168G > T of FTL in family 4. Among them, the causative mutation in Family GJA3 is novel, and Family FTL is a rare cataract syndrome. These familial mutations showed complete co-segregation with the affected individuals, with no presence in unaffected family members or the 100 controls. Several bioinformatic prediction tools also support the likely pathogenicity of these mutations. Our findings expand the mutational and phenotypic spectrum of genes associated with congenital cataracts and provide clues to the pathogenesis of congenital cataracts. These data also demonstrate the importance of NGS technology for the molecular diagnosis of congenital cataract patients.

A novel base substitution mutation of the CRYBA2 gene is associated with autosomal dominant congenital cataract

Congenital cataract is one of the leading causes of vision loss in children, and a large proportion of cases are related to genetics. In a Chinese family, we reported a new missense mutation in CRYBA2 (c.223T>C: p.Tyr75His), which can cause autosomal dominant congenital bilateral cataract. We collected blood samples from family members (mother and two sons) and extracted DNA. Through whole-exome sequencing, we discovered a novel unreported mutation. According to relevant ACMG guidelines, this mutation was determined to be a variant of unknown clinical significance. This article further expands the site information on the CRYBA2 mutations.

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

To identify genetic defects in a Chinese family with congenital posterior polar cataracts and assess the pathogenicity. 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. 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. 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.

To identify disease-causative mutations in families with congenital cataract. Two Chinese families with autosomal-dominant 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. 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. 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.

Novel and known variants in GJA3 and LIM2 in congenital cataract families from North India

BackgroundTo identify the underlying genetic defects in autosomal dominant (ADCC) and autosomal recessive (ARCC) congenital cataract families from North India.MethodsDetailed family histories were collected, pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening was performed using Sanger sequencing in the known candidate genes for crystallins, connexins, and membrane proteins. The pathogenicity of identified variants was assessed bioinformatically.ResultsIn two ADCC families (CC-281 and CC-3015) with posterior lenticonus cataract, a novel change c.263C > T (p.P88L) in GJA3 in CC-281 family and a previously reported substitution c.388C > T (p.R130C) in LIM2 in CC-3015 family was observed. In an ARCC family (CC-3005) having central pulverulent cataract, a novel frameshift deletion (c.764delT;p.L255R46fs) in GJA3 was detected. The observed variants segregated completely with phenotypes in the affected members and were neither present in unaffected family members nor in the ethnically matched 150 controls (tested for two novel variants), hence excluding these as polymorphisms.ConclusionsPresent study identified two novel mutations i.e., c.263C > T;p.P88L and c.764delT;p.L255R46fs in GJA3 in an ADCC and an ARCC family having posterior lenticonus and central pulverulent cataract, respectively. In another ADCC family with posterior lenticonus cataract, a previously reported mutation c.388C > T;p.R130C in LIM2 was observed. R130 may be a mutation hotspot as previously ADCC families from different ethnicities (UK/Czechia, China, Spain, Japan) also harbored the same substitution, however, with different phenotypes i.e., nuclear pulverulent, membranous, nuclear, lamellar, and sutural/lamellar. Findings in present study thus expand the mutation spectrum and phenotypic heterogeneity linked with GJA3 and LIM2.

A novel single-base deletional mutation of MIP impairs protein distribution and cell-to-cell adhesion in autosomal dominant cataracts in a Chinese family.

Congenital cataracts are the leading cause of irreversible visual disability in children, and genetic factors play an important role in their development. In this study, targeted exome sequencing revealed a novel single-base deletional mutation of MIP (c.301delG; p.Ala101Profs*16) segregated with congenital punctate cataract in a Chinese family. The hydrophobic properties, and secondary and tertiary structures for truncated MIP were predicted to affect the function of protein by bioinformatics analysis. When MIP-WT and MIP-Ala101fs expression constructs were singly transfected into HeLa cells, it was found that the mRNA level showed no significant difference, while the protein level of the mutant was remarkably reduced compared to that of the wild-type MIP. Immunofluorescence images showed that the MIP-WT was principally localized to the plasma membrane, whereas the MIP-Ala101fs protein was aberrantly trapped in the cytoplasm. Furthermore, the cell-to-cell adhesion capability and the cell-to-cell communication property were both significantly reduced for MIP-Ala101fs compared to the MIP-WT (all *p < 0.05). This is the first report of the c.301delG mutation in the MIP gene associated with autosomal dominant congenital cataracts. We propose that the cataract is caused by the decreased protein expression and reduced cell-to-cell adhesion by the mutant MIP. The impaired trafficking or instability of the mutant protein, as well as compromised intercellular communication is probably a concurrent result of the mutation. The results expand the genetic and phenotypic spectra of MIP and help to better understand the molecular basis of congenital cataracts.

Mutations in alpha-B-crystallin cause autosomal dominant axonal Charcot-Marie-Tooth disease with congenital cataracts.

Mutations in the alpha-B-crystallin (CRYAB) gene have initially been associated with myofibrillar myopathy, dilated cardiomyopathy and cataracts. For the first time, peripheral neuropathy is reported here as a novel phenotype associated with CRYAB. Whole-exome sequencing was performed in two unrelated families with genetically unsolved axonal Charcot-Marie-Tooth disease (CMT2), assessing clinical, neurophysiological and radiological features. The pathogenic CRYAB variant c.358A>G;p.Arg120Gly was segregated in all affected patients from two unrelated families. The disease presented as late onset CMT2 (onset over 40 years) with distal sensory and motor impairment and congenital cataracts. Muscle involvement was probably associated in cases showing mild axial and diaphragmatic weakness. In all cases, nerve conduction studies demonstrated the presence of an axonal sensorimotor neuropathy along with chronic neurogenic changes on needle examination. In cases with late onset autosomal dominant CMT2 and congenital cataracts, it is recommended that CRYAB is considered for genetic testing. The identification of CRYAB mutations causing CMT2 further supports a continuous spectrum of expressivity, from myopathic to neuropathic and mixed forms, of a growing number of genes involved in protein degradation and chaperone-assisted autophagy.

GJA3 Genetic Variation and Autosomal Dominant Congenital Cataracts and Glaucoma Following Cataract Surgery

The p.Asp67Tyr genetic variant in the GJA3 gene is responsible for congenital cataracts in a family with a high incidence of glaucoma following cataract surgery. To describe the clinical features of a family with a strong association between congenital cataracts and glaucoma following cataract surgery secondary to a genetic variant in the GJA3 gene (NM_021954.4:c.199G>T, p.Asp67Tyr). This was a retrospective, observational, case series, genetic association study from the University of Iowa spanning 61 years. Examined were the ophthalmic records from 1961 through 2022 of the family members of a 4-generation pedigree with autosomal dominant congenital cataracts. Frequency of glaucoma following cataract surgery and postoperative complications among family members with congenital cataract due to the p.Asp67Tyr GJA3 genetic variant. Medical records were available from 11 of 12 family members (7 male [63.6%]) with congenital cataract with a mean (SD) follow-up of 30 (21.7) years (range, 0.2-61 years). Eight of 9 patients with congenital cataracts developed glaucoma, and 8 of 8 patients who had cataract surgery at age 2 years or younger developed glaucoma following cataract surgery. The only family member with congenital cataracts who did not develop glaucoma had delayed cataract surgery until 12 and 21 years of age. Five of 11 family members (45.5%) had retinal detachments after cataract extraction and vitrectomy. No patients developed retinal detachments after prophylactic 360-degree endolaser. The GJA3 genetic variant, p.Asp67Tyr, was identified in a 4-generation congenital cataract pedigree from Iowa. This report suggests that patients with congenital cataract due to some GJA3 genetic variants may be at especially high risk for glaucoma following cataract surgery. Retinal detachments after cataract extraction in the first 2 years of life were also common in this family, and prophylactic retinal endolaser may be indicated at the time of surgery.

Mutation screening in autosomal dominant congenital cataract families from North India.

Congenital cataract an opacity of the eye lens is present at birth and results in visual impairment during early childhood. If left untreated, it can lead to permanent blindness. Its prevalence is ten times higher in developing countries like India. Thus, we aimed to investigate the underlying genetic defects in three autosomal dominant congenital cataract (ADCC) families from North India. Detailed family histories were collected, pedigrees drawn followed by slit-lamp examination and lens photography. Mutation screening was performed in the candidate genes for crystallins, connexins, and membrane proteins by Sanger sequencing. Pathogenicity of novel variant was assessed bioinformatically. In an ADCC (CC-3006) family with bilateral membranous cataract and microcornea, a novel change (c.1114C>T;p.P372S) in GJA3 has been detected. In other two ADCC families affected with subcapsular (CC-286) and shrunken membranous hypermature cataract (CC-3014), a nonsense mutation (c.463C>T;p.Q155X) in CRYβB2 and a frameshift deletion (c.590_591delAG;p.E197VfsX22) in CRYβA1/A3 respectively, are observed. These variants segregated completely with the phenotypes in respective families and were absent in their unaffected family members and unrelated controls (testedfor novel variant in GJA3). Earlier p.Q155X (CRYβB2) and p.E197VfsX22 (CRYβA1/A3) are reported with entirely different phenotypes. Thus, findings in present study expand the mutation spectrum and phenotypic heterogeneity linked with GJA3, CRYβB2, and CRYβA1/A3 for congenital cataracts. Identifying underlying genetic defects is essential for disease management and appropriate genetic counseling.

A Novel CRYBB2 Silent Variant in Autosomal Dominant Congenital Cataracts (ADCC) in Pakistani families.

Congenital Cataract is a type of ophthalmic genetic disorder that appears at birth or in early childhood. Among 30 genes, CRYBB2 is one of the most common and a water-soluble protein of lens's that code for the βB2-crystallin. This study aimed to investigate the novel silent mutation in CRYBB2 of exon six in the Pakistani families of Autosomal Dominant Congenital Cataracts (ADCC). It is a family-based study that presents three to five-generations of two Pakistani families. Data and blood samples from the families were collected from January to August 2019 from LRBT (Layton Rahmatullah Benevolent Trust) Hospital, Mansehra, Pakistan. We only included patients >15 years old. Before enrollment in the current study, each patient obtained a thorough optical examination. Samples were moved to the molecular lab using the collection and storage method. The phenol-chloroform technique was used to extract the DNA. The technique of Sanger sequencing was used to find any potential mutation in some of the selected families. Statistical and bioinformatics analysis were carried out. By using bioinformatics tools, the novel silent mutation was identified. Heterozygous silent mutation of CRYBB2 of exon 6 (c. 495G>A) was detected by the alignment of sequences. Computational prediction program did not predict the silent mutation. This study investigated a novel important sequence variant in the beta-crystalline protein that causes autosomal dominant congenital cataract (ADCC) in Pakistani families. Thus, our study enlarges the CRYBB2 mutation spectrum and associated phenotypes to help clinical diagnosis of human genetic diseases.

Multimorbidity due to novel pathogenic variants in the WFS1/RP1/NOD2 genes: autosomal dominant congenital lamellar cataract, retinitis pigmentosa and Crohn’s disease in a British family

BackgroundA five generation family has been analysed by whole exome sequencing (WES) for genetic associations with the multimorbidities of congenital cataract (CC), retinitis pigmentosa (RP) and Crohn’s disease (CD).MethodsWES was...

Identification of a Missense Mutation in GJA8 Gene in an Iranian Family with Autosomal Dominant Congenital Cataract.

To identify the causative mutations of autosomal dominant (AD) congenital cataracts in a large Iranian family. The complete and accurate family history and clinical information of participants were collected. A total of 51 family members, including 22 affected and 29 unaffected individuals, were recruited in this study. We performed whole exome sequencing to reveal pathogenic mutation. We used amplification refractory mutation system polymerase chain reaction and Sanger sequencing techniques to confirm segregation in patients and also to rule it out in the healthy participants. A known missense mutation, c.827C>T (S276F), in GJA8 was identified. This mutation was confirmed in all patients. Neither all healthy family members nor 100 healthy individuals who served as controls from general population had this mutation. The missense mutation c. 827C>T in the GJA8 gene is associated with AD congenital lamellar cataract with complete penetrance in a six-generation Iranian family.

Molecular Genetic Analysis of Ukrainian Families with Congenital Cataracts.

This study was designed to identify the pathogenic variants in five Ukrainian families with autosomal dominant congenital cataracts. Cataracts can be defined broadly as any opacity of the crystalline lens. Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes, including the lens crystallins, are associated with congenital cataracts and other eye diseases. Whole-exome sequencing identified heterozygous disease-causing variants in five Ukrainian families with autosomal dominant congenital cataracts and cosegregation with cataracts was confirmed using Sanger sequencing. Family 97001 showed a missense variant (c.341T>A: p.L114Q) in HSF4; family 97003 showed a missense variant (c.53A>T: p.N18I) in CRYGA; family 97004 showed a missense variant (c. 82G>A: p.V28M) in GJA3; family 97006 showed a missense variant (c.83C>T: p. P28L) in CRYGC; and family 97008 showed a single-base insertion resulting in a frameshift (c.443_444insA: p. Met148IfsTer51) in PAX6. All five families are associated with congenital cataracts. Overall, we report four novel mutations in HSF4, CRYGA, CRYGC and PAX6, and one previously reported mutation in GJA3 that cause autosomal dominant congenital cataracts.

Molecular diagnosis of autosomal dominant congenital cataract in two families from North India reveals a novel and a known variant in GJA8 and GJA3.

The study aims to detect the underlying genetic defect in two autosomal dominant congenital cataract (ADCC) families. A detailed family history was collected, pedigrees were drawn, and slit-lamp examination and lens photography were performed. Mutation screening was carried out in the genes for crystallins and connexins by PCR and Sanger sequencing. Ethnically matched controls were tested for the identified variants. Different bioinformatics tools were used to assess the pathogenicity of the observed variants. In an ADCC family with total cataract, a novel change (c.166A > G) (p.Thr56Ala) in GJA8 was identified. In another ADCC family with nuclear cataract, c.134G > C (p.Trp45Ser) in GJA3 has been detected. These variants co-segregated completely in patients in their respective families and were neither observed in unaffected family members nor in ethnically matched 100 controls, excluding them as polymorphisms. The present study identifies a novel variant c.166A > G (p.Thr56Ala) in GJA8 in an ADCC family having total cataract and a previously known mutation c.134G > C (p.Trp45Ser) in GJA3 in another ADCC family. Thr56 in GJA8 seems to be a mutation hotspot, as previously an ADCC Mauritanian family harbored a different substitution (p.Thr56Pro) at the same codon, although for a different phenotype (nuclear cataract). Similarly, Trp45 in GJA3 appears as a mutation hotspot, as p.Trp45Ser has previously been reported for nuclear cataract in a Chinese ADCC family. p.Thr56 (GJA8) and p.Trp45 (GJA3) are in the extracellular loop 1 (EL1) in their respective connexin proteins, which, along with EL2, are essential for gap junction formation, hemichannel docking, and regulating the voltage gating of the channels. Hence, residues in these regions seem crucial for maintaining eye lens transparency.

Loss of fiber cell communication may contribute to the development of cataracts of many different etiologies.

The lens is an avascular organ that is supported by an internal circulation of water and solutes. This circulation is driven by ion pumps, channels and transporters in epithelial cells and by ion channels in fiber cells and is maintained by fiber-fiber and fiber-epithelial cell communication. Gap junctional intercellular channels formed of connexin46 and connexin50 are critical components of this circulation as demonstrated by studies of connexin null mice and connexin mutant mice. Moreover, connexin mutants are one of the most common causes of autosomal dominant congenital cataracts. However, alterations of the lens circulation and coupling between lens fiber cells are much more prevalent, beyond the connexin mutant lenses. Intercellular coupling and levels of connexins are decreased with aging. Gap junction-mediated intercellular communication decreases in mice expressing mutant forms of several different lens proteins and in some mouse models of lens protein damage. These observations suggest that disruption of ionic homeostasis due to reduction of the lens circulation is a common component of the development of many different types of cataracts. The decrease in the lens circulation often reflects low levels of lens fiber cell connexins and/or functional gap junction channels.

A novel missense variant c.71G > T (p.Gly24Val) of the CRYBA4 gene contributes to autosomal-dominant congenital cataract in a Chinese family.

To investigate the potential genetic defects in a five-generation Chinese family with autosomal dominant congenital cataract (ADCC). Whole exome sequencing was performed to search the variants in the candidate genes associated with congenital cataract. Sanger sequencing was used to validate the variants and examine their co-segregation in the patients and their relatives. The potential effect of the variants was analyzed using several bioinformatic methods and further examined through Western blotting and co-immunoprecipitation. A missense variant c. 71 G > T (p. Gly24Val) in the CRYBA4 gene, a known ADCC candidate gene, was identified to be heterozygously present in the patients and co-segregate with cataract in the family. The mutation was absent in all of the searched databases, including our in-house exome sequences of 10,000 Chinese. The alignments of the amino acid sequences of CRYBA4 in a variety of species revealed that the amino acid residue Gly24 was evolutionarily highly conserved, and the in silico analysis predicted that the missense mutation of Gly24Val was damaging for the protein structure and function of CRYBA4. Then, the in vitro expression analysis further revealed that the Gly24Val mutation in CRYBA4 inhibited its binding with CRYBB1. The impaired interaction of β-crystallin proteins may affect their water-solubility and contribute to the formation of precipitates in lens fiber cells. We identified a novel missense variant in the CRYBA4 gene as a pathogenic mutation of ADCC in a Chinese family. Our finding expanded the CRYBA4 variation spectrum associated with congenital cataracts.

A novel mutation GJA8 NM_005267.5: c.124G\u2009>\u2009A, p.(E42K) causing congenital nuclear cataract

BackgroundTo identify the genetic mutation of a four-generation autosomal dominant congenital cataract family in China.MethodsTargeted region sequencing containing 778 genes associated with ocular diseases was performed to screen for the potential mutation, and Sanger sequencing was used to confirm the mutation. The homology model was constructed to identify the protein structural change, several online software were used to predict the mutation impact. CLUSTALW was used to perform multiple sequence alignment from different species.ResultsA novel heterozygous mutation, GJA8 NM_005267.5: c.124G > A, p.(E42K) was found, which cosegregated with congenital cataract phenotype in this family. Bioinformatics analysis of the mutation showed that the surface potential diagram of proteins changed. Several online programs predicted the mutation was ‘Pathogenic’, ‘Damaging’, ‘Disease causing’ or ‘Deleterious’.ConclusionsA novel mutation NM_005267.5(GJA8):c.124G > A was identified in our study. Our finding can broaden the mutation spectrum of GJA8, enrich the phenotype-genotype correlation of congenital cataract and help to better understand the genetic background of congenital cataract.

A Novel Mutation in CRYGC Mutation Associated with Autosomal Dominant Congenital Cataracts and Microcornea.

PurposeCrystallin protein mutations are associated with congenital cataract (CC), and several disease-causing mutations in the CRYGC gene have been identified. We present the location of a new mutation in CRYGC in members of a Chinese family who presented with CCs with or without microcornea.DesignObservational study.ParticipantsA Chinese family diagnosed with autosomal dominant (AD) CCs with or without microphthalmia.MethodsBecause this was an observational study, it was not registered as a clinical trial. The proband and her 2 children were diagnosed with AD CCs and microcornea and were recruited for the study. Participants underwent complete ophthalmological examinations, and blood samples were used for genomic extraction.Main Outcome MeasuresWe detected 1 disease-associated variant using Exomiser analysis by matching the proband’s phenotype and the inheritance pattern. The variant was determined to be pathogenic according to American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsWe detected 1 disease-associated variant using Exomiser analysis by matching the proband’s phenotype and the inheritance pattern. The variant was determined to be pathogenic according to the American College of Medical Genetics and Genomics guidelines. Next-generation sequencing was verified using Sanger sequencing, and we confirmed that the proband and her children carried the same mutation. We identified the heterozygous variant c.389_390insGCTG (p.C130fs), which includes a frameshift mutation. The residues in p.C130fs are all highly conserved across species. This disease-causing frameshift mutation in the CRYGC gene is not currently present in the ClinVar database.ConclusionsOur findings expand the repertoire of known mutations in the CRYGC gene that cause CCs and provide new insights into the etiology and molecular diagnosis of CCs; however, the molecular mechanism of this mutation warrants further investigation.

Variants in PAX6, PITX3 and HSF4 causing autosomal dominant congenital cataracts

BackgroundLens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes are associated with congenital cataracts and other eye anomalies.MethodsUsing whole exome sequencing, we identified disease-causing variants in two large British families and one isolated case with autosomal dominant congenital cataract. Bioinformatics analysis confirmed these disease-causing mutations as rare or novel variants, with a moderate to damaging pathogenicity score, with testing for segregation within the families using direct Sanger sequencing.ResultsFamily A had a missense variant (c.184 G>A; p.V62M) in PAX6 and affected individuals presented with nuclear cataract. Family B had a frameshift variant (c.470–477dup; p.A160R*) in PITX3 that was also associated with nuclear cataract. A recurrent missense variant in HSF4 (c.341 T>C; p.L114P) was associated with congenital cataract in a single isolated case.ConclusionsWe have therefore identified novel variants in PAX6 and PITX3 that cause autosomal dominant congenital cataract.

A mutated CRYGD associated with congenital coralliform cataracts in two Chinese pedigrees.

To investigate the causal gene mutation and clinical characteristics for two Chinese families with autosomal dominant congenital coralliform cataract. Two Chinese pedigrees with congenital cataract were investigated. Routine ophthalmic examinations were performed on all patients and non-affected family members. Peripheral blood samples were collected, and the genomic DNAs were extracted. The coding regions of proband's DNAs were analyzed with cataract gene panel. The identified mutation was amplified by polymerase chain reaction, and automated sequencing was performed in other members of two families to verify whether the mutated gene was co-segregated with the disease. Congenital coralliform cataract was inherited in an autosomal dominant mode in both pedigrees. For each family, more than half of the family members were affected. All patients presented with severe visual impairment after birth as a result of bilateral symmetric coralliform lens opacification. An exact the same defect in the same gene, a heterozygous mutation of c.70C>A (p. P24T) in exon 2 of γD-crystallin gene, was detected in both probands from each family. Sanger sequencing analysis demonstrated that the mutated CRYGD was co-segregated in these two families. A c.70C>A (p. P24T) variant in CRYGD gene was reconfirmed to be the causal gene in two Chinese pedigrees. It is known that mutated CRYGD caused most of the congenital coralliform cataracts, suggesting that the CRYGD gene is associated with coralliform congenital cataract.