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Up to 25% of pediatric cataract cases are inherited. There is sparse information in the literature regarding the cost of whole-exome sequencing (WES) for suspected hereditary pediatric cataracts. Molecular diagnosis of suspected hereditary pediatric cataracts is important for comprehensive genetic counseling. We performed a partial economic evaluation with a mixed costing analysis, using reimbursement data and microcosting approach with a bottom-up technique to estimate the cost of using WES for genetic diagnosis of suspected hereditary pediatric cataracts from the perspective of the Brazilian governmental health care system. One hundred and ten participants from twenty-nine families in Rio de Janeiro (RJ) were included. Costs of consumables, staff and equipment were calculated. Two scenarios were created: (1) The reference scenario included patients from RJ with suspected hereditary pediatric cataracts plus two family members. (2) The alternative scenario considered other genetic diseases, resulting in 5,280 exams per month. Sensitivity analysis was also performed. In the reference scenario, the total cost per exam was 700.09 United States dollars (USD), and in the alternative scenario, the total cost was 559.23 USD. The cost of WES alone was 527.85 USD in the reference scenario and 386.98 USD in the alternative scenario. Sensitivity analysis revealed that the largest costs were associated with consumables in both scenarios. Economic evaluations can help inform policy decisions, especially in middle-income countries such as Brazil. [ABSTRACT FROM AUTHOR]

Congenital cataracts are clouding of the crystalline lens inside the eye, which is present at birth and leads to a decrease in vision. It is one of the three leading causes of blindness in children, responsible for up to 27.6% of cases. The etiology of congenital cataracts varies. The main causes include heredity, chromosomal aberrations, metabolic diseases, and intrauterine infections. Early diagnosis and treatment of congenital cataracts are essential in the prevention of irreversible loss of vision. The red reflex test is an excellent tool in the screening of congenital cataracts and should be performed on each newborn. Congenital cataract therapy differs from adult cataract therapy, being based primarily on early surgical intervention. Long-term post-operative rehabilitation is also an important part of care.

Background: Patients with biallelic variants in the lanosterol synthase (LSS) gene has been reported to exhibit phenotypes as follows: non‐syndromic form of hypotrichosis, congenital cataracts, and alopecia with intellectual disability or growth retardation. However, genotype–phenotype correlations in the LSS gene are still not completely clear. Methods: In this study, we reported a Chinese girl who had congenital cataracts with hypotrichosis. The trio exome sequencing was performed to elucidate the genetic cause of the patient. Results: We identified compound heterozygous variants (c.296G>A, p.G99D and c.1025T>G, p.I342S) in the LSS gene. Both variants altered the amino acid coding at highly conserved amino acid residues and were predicted to be deleterious using prediction software. Conclusion: Our report expands the spectrum of variants in the LSS gene and will be helpful for genotype–phenotype correlations study. [ABSTRACT FROM AUTHOR]

The introduction of genomic testing into prenatal care has come at a rapid pace and has been met with significant clinical and ethical challenges, specifically when dealing with incidental findings. We present the case of a couple in their first pregnancy who were referred to our institution with isolated fetal cataracts on morphology scan. After an unremarkable infectious disease workup and microarray on an amniocentesis sample, the couple opted for fetal whole‐exome sequencing to investigate the cataracts further. This investigation did not find any cause for the cataracts but yielded an incidental finding of a de novo pathogenic variant in the SCN1A gene unrelated to the cataracts. Pathogenic variants in the SCN1A gene are strongly associated with severe myoclonic epilepsy of infancy, or Dravet syndrome. After extensive genetic counseling, the couple decided to terminate the pregnancy at 28 weeks' gestation based on this finding. This case highlights some of the important clinical and ethical considerations in prenatal genetic diagnosis, particularly in the group of patients in which there is no phenotypic evidence in‐utero of the incidental finding. The case demonstrates the value of frameworks and guidelines to guide management decisions for both clinicians and patients. [ABSTRACT FROM AUTHOR]

Abstract Introduction Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare genetic disease with diverse ocular malformations. This study aimed to investigate the disease-causing gene in members of a BPES pedigree presenting with the rare features of anisometropia, unilateral pathologic myopia (PM), and congenital cataracts. Methods The related BPES patients underwent a comprehensive ocular examination. Next, whole-exome sequencing (WES) was performed to screen for the disease-causing genetic variants. A step-wise variant filtering was performed to select candidate variants combined with the annotation of the variant's pathogenicity, which was assessed using several bioinformatic approaches. Co-segregation analysis and Sanger sequencing were then conducted to validate the candidate variant. Results The variant c.672_701dup in FOXL2 was identified to be the disease-causing variant in this rare BPES family. Combined with clinical manifestations, the two affected individuals were diagnosed with type II BPES. Conclusion This study uncovered the variant c.672_701dup in FOXL2 as a disease causal variant in a rare-presenting BPES family with anisometropia, unilateral pathogenic myopia, and/or congenital cataracts, thus expanding the phenotypic spectrum of FOXL2.

Introduction: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare genetic disease with diverse ocular malformations. This study aimed to investigate the disease-causing gene in members of a BPES pedigree presenting with the rare features of anisometropia, unilateral pathologic myopia (PM), and congenital cataracts. Methods: The related BPES patients underwent a comprehensive ocular examination. Next, whole-exome sequencing (WES) was performed to screen for the disease-causing genetic variants. A step-wise variant filtering was performed to select candidate variants combined with the annotation of the variant's pathogenicity, which was assessed using several bioinformatic approaches. Co-segregation analysis and Sanger sequencing were then conducted to validate the candidate variant. Results: The variant c.672_701dup in FOXL2 was identified to be the disease-causing variant in this rare BPES family. Combined with clinical manifestations, the two affected individuals were diagnosed with type II BPES. Conclusion: This study uncovered the variant c.672_701dup in FOXL2 as a disease causal variant in a rare-presenting BPES family with anisometropia, unilateral pathogenic myopia, and/or congenital cataracts, thus expanding the phenotypic spectrum of FOXL2. [ABSTRACT FROM AUTHOR]

Background: A cataract is an opacity of the crystalline lens that has the potential to cause vison loss or visual distortion. Etiologies of congenital cataracts include genetic mutation, hereditary, intrauterine infection during pregnancy, persistent fetal vasculature, association with metabolic disorders, and chromosomal syndromes. Congenital cataracts can present unilaterally or bilaterally and in a myriad of shapes, sizes, and colors. Depending on these characteristics, congenital cataracts may or may not affect vision. If they do, these cataracts warrant prompt surgical intervention to prevent deprivation amblyopia, which is reduced visual acuity due to a disruption to normal visual development. Optometrists play a crucial role in making the correct diagnosis and prompt referral. In addition, optometrists are responsible for managing these patients postoperatively for amblyopia treatment, correction of residual ametropia, and various post-operative complications. Case Report: A four-year-old male with Down syndrome presented with bilateral dense cataracts, sensory nystagmus, and decreased visual acuity. Due to the cataracts, refractive error and retinal health were unable to be assessed clinically. The patient was referred for consultation for surgical management with a guarded prognosis. The patient was also referred for a visual evoked potential to determine visual potential. Conclusion: If visually significant, one of the greatest concerns of congenital cataracts is deprivation amblyopia. Following prompt surgical intervention, optometrists must manage these patients closely, often over the course of their lives, to ensure optimal visual development and ocular health. Even if a patient presents outside the ideal treatment window, it is still important to recommend treatment, as there can be significant visual improvement recorded post-surgery. [ABSTRACT FROM AUTHOR]

Congenital cataracts are clouding of the crystalline lens inside the eye, which is present at birth and leads to a decrease in vision. It is one of the three leading causes of blindness in children, responsible for up to 27.6% of cases. The etiology of congenital cataracts varies. The main causes include heredity, chromosomal aberrations, metabolic diseases, and intrauterine infections. Early diagnosis and treatment of congenital cataracts are essential in the prevention of irreversible loss of vision. The red reflex test is an excellent tool in the screening of congenital cataracts and should be performed on each newborn. Congenital cataract therapy differs from adult cataract therapy, being based primarily on early surgical intervention. Long-term post-operative rehabilitation is also an important part of care. [ABSTRACT FROM AUTHOR]

IntroductionPathogenic variants of the junctional adhesion molecule 3 (JAM3/JAM-C; OMIM#606871) is the cause of the rare recessive disorder called hemorrhagic destruction of the brain, subependymal calcification, and cataracts (HDBSCC, OMIM#613730) disease. A similar phenotype is universal, including congenital cataracts and brain hemorrhages with high mortality rate in the first few weeks of life and with a poor neurologic outcome in survivors. We aim to describe and enlighten novel phenotype and genotype of a new patient and review the literature regarding all reported patients worldwide.Case reportWe report the case of a prenatal and postnatal phenotype of a new patient with a novel pathogenic loss-of-function variant in JAM3, who presented prenatally with cataracts and brain anomalies and postnatally with brain hemorrhages, failure to thrive (FTT), progressive microcephaly, recurrent posterior capsule opacities, and auditory neuropathy.DiscussionThis study enlightens novel possible functions of JAM3 in the normal development of the brain, the ocular lenses, the auditory system, and possibly the gastrointestinal tract. This study is the first to report of cataracts evident in as early as 23 weeks of gestation and a rare phenomenon of recurrent posterior capsule opacities despite performing recurrent posterior capsulectomy and anterior vitrectomy. We suggest that auditory neuropathy, which is reported here for the first time, is part of the phenotype of HDBSCC, probably due to an endothelial microvasculature disruption of the peripheral eighth nerve or possibly due to impaired nerve conduction from the synapse to the brainstem.ConclusionsPrenatal cataracts, brain anomalies, FTT, and auditory neuropathy are part of the phenotype of the HDBSCC disease. We suggest including JAM3 in the gene list known to cause congenital cataracts, brain hemorrhages, and hearing loss. Further studies should address the auditory neuropathy and FTT phenomena in knockout mice models. We further suggest performing comprehensive ophthalmic, audiologic, and gastroenterologic evaluations for living patients worldwide to further confirm these novel phenomena in this rare entity.

The Multidisciplinary Ophthalmic Genetics Clinic (MOGC) at the University of Michigan Kellogg Eye Center aims to provide medical and ophthalmic genetics care to patients with inherited ocular conditions. We have developed a clinical and referral workflow where each patient undergoes coordinated evaluation by our multidisciplinary team followed by discussions on diagnosis, prognosis, and genetic testing. Testing approaches are specific to each patient and can be targeted (single-gene, gene panel), broad (chromosomal microarray, whole-exome sequencing), or a combination. We hypothesize that this clinic model improves patient outcomes and quality of care. A retrospective chart review of patients in the MOGC from July 2020 to October 2022 revealed that the most common referral diagnoses were congenital cataracts, optic neuropathy, and microphthalmia, with 52% syndromic cases. Within this patient cohort, we saw a 76% uptake for genetic testing, among which 33% received a diagnostic test result. Our results support a tailored approach to genetic testing for specific conditions. Through case examples, we highlight the power and impact of our clinic. By integrating ophthalmic care with medical genetics and counseling, the MOGC has not only helped solve individual patient diagnostic challenges but has aided the greater population in novel genetic discoveries and research towards targeted therapeutics. [ABSTRACT FROM AUTHOR]

We describe a child from a consanguineous family born with a rare autosomal recessive disorder affecting junctional adhesion molecule 3 (JAM3) causing profound neurological and ophthalmological injury known as haemorrhagic brain destruction, subependymal calcifications, and congenital cataracts (HDBSCC; MIM# 613730). She was the product of an unremarkable pregnancy and was born near to term but was noted shortly after birth to have congenital cataracts, poor vision, increased muscle tone, seizures, and developmental delay. Her older sister had an identical syndrome and had previously been documented to have homozygous mutations in JAM3. Examination in our patient, although difficult because of bilateral central cataracts, revealed very poor vision, attenuated retinal vessels, optic atrophy, and a retinal haemorrhage in the right eye, implying that abnormal development of the retinas and/or optic nerves may at times play a significant role in the poor vision noted in children with HDBSCC. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the potential genetic defects in a five-generation Chinese family with autosomal dominant congenital cataract (ADCC). Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

In this study, we report on two different GJA8 variants related to congenital eye anomalies in two unrelated families, respectively. GJA8 (or Cx50) encoding a transmembrane protein to form lens connexons has been known as a common causative gene in congenital cataracts and its variants have recently been reported related to a wide phenotypic spectrum of eye defects. We identified two GJA8 variants, c.134G>T (p.Try45Leu, W45L) detected in a cataract family by Sanger sequencing and c.281G>A (p.Gly94Glu, G94E) found in a family with severe eye malformations including microphthalmia by whole-exome sequencing. These two variants were absent in healthy population and predicted deleterious by bioinformatic analysis. Furthermore, we compared the expression in cell lines between these mutants and the wildtype to explore their potential mechanism. Cell counting kit-8 assay showed that overexpression of either W45L or G94E decreased cell viability compared with wild-type Cx50 and the control. A lower protein level in W45L found by western blotting and fewer punctate fluorescent signals showed by fluorescence microscopy suggested that W45L may have less protein expression. A higher G94E protein level and abundant dotted distribution indicated that G94E may cause aberrant protein degradation and accumulation. Such results from in vitro assays confirmed the impact of these two variants and gave us a hint about their different pathogenic roles in different phenotypes. In conclusion, our study is the first to have the functional analysis of two GJA8 variants c.134G>T and c.281G>A in Chinese pedigrees and explore the impact of these variants, which can help in prenatal diagnosis and genetic counseling as well in basic studies on GJA8. [ABSTRACT FROM AUTHOR]

Early visual deprivation typically results in spatial impairments in other sensory modalities. It has been suggested that, since vision provides the most accurate spatial information, it is used for calibrating space in the other senses. Here we investigated whether sight restoration after prolonged early onset visual impairment can lead to the development of more accurate auditory space perception. We tested participants who were surgically treated for congenital dense bilateral cataracts several years after birth. In Experiment 1 we assessed participants' ability to understand spatial relationships among sounds, by asking them to spatially bisect three consecutive, laterally separated sounds. Participants performed better after surgery than participants tested before. However, they still performed worse than sighted controls. In Experiment 2, we demonstrated that single sound localization in the two-dimensional frontal plane improves quickly after surgery, approaching performance levels of sighted controls. Such recovery seems to be mediated by visual acuity, as participants gaining higher post-surgical visual acuity performed better in both experiments. These findings provide strong support for the hypothesis that vision calibrates auditory space perception. Importantly, this also demonstrates that this process can occur even when vision is restored after years of visual deprivation. [ABSTRACT FROM AUTHOR]

Being able to perform adept goal-directed actions requires predictive, feed-forward control, including a mapping between the visually estimated target locations and the motor commands reaching for them. When the mapping is perturbed, e.g., due to muscle fatigue or optical distortions, we are quickly able to recalibrate the sensorimotor system to update this mapping. Here, we investigated whether early visual and visuomotor experience is essential for developing sensorimotor recalibration. To this end, we assessed young individuals deprived of pattern vision due to dense congenital bilateral cataracts who were surgically treated for sight restoration only years after birth. We compared their recalibration performance to such distortion to that of age-matched sighted controls. Their sensorimotor recalibration performance was impaired right after surgery. This finding cannot be explained by their still lower visual acuity alone, since blurring vision in controls to a matching degree did not lead to comparable behavior. Nevertheless, the recalibration ability of cataract-treated participants gradually improved with time after surgery. Thus, the lack of early pattern vision affects visuomotor recalibration. However, this ability is not lost but slowly develops after sight restoration, highlighting the importance of sensorimotor experience gained late in life.

Purpose: To develop a model for predicting postoperative axial length (AL) in children undergoing cataract surgery younger than 2 years of age. Setting: The Eye Hospital of Wenzhou Medical University, Hangzhou, China Design: Retrospective study. Methods: Children were included only if AL data were available before surgery and at least 1 year after surgery. Eyes were divided into pseudophakic, aphakic, and unaffected eye groups. Variables that could influence axial growth were analyzed and a multivariable generalized estimating equation regression model was developed to predict postoperative AL. Results: 333 eyes from 190 patients were included. We observed a logarithmic linear correlation between age and AL in the unaffected eye group, AL = (2.7924 × log of age in months) + 17.607, R2 = 0.6596. Meanwhile, The GEE model of eyes with cataracts can be written as follows: Postoperative AL = 6.408 + 0.611 × (baseline AL) + 0.007 × (baseline age) − -0.006 (baseline age) × (age at follow-up) − -0.391 × coefficient of surgery. The ages were recorded in months, the ALs were recorded in millimeter. Conclusions: The assessment of AL is one of the most important parts of successful postoperative management in congenital cataract patients. This study established an AL estimate formula for children aged ≤ 2 years with congenital cataract who underwent cataract surgery. This model theoretically could be used to predict individual future AL for child undergoing cataract surgery. [ABSTRACT FROM AUTHOR]

Congenital cataracts are the most common cause of visual impairment worldwide. Inherited cataract is a clinically and genetically heterogeneous disease. Here we report disease-causing variants in a novel gene, CYP21A2, causing autosomal dominant posterior polar cataract. Variants in this gene are known to cause autosomal recessive congenital adrenal hyperplasia (CAH). Using whole-exome sequencing (WES), we have identified disease-causing sequence variants in two families of British and Irish origin, and in two isolated cases of Asian-Indian and British origin. Bioinformatics analysis confirmed these variants as rare with damaging pathogenicity scores. Segregation was tested within the families using direct Sanger sequencing. A nonsense variant NM_000500.9 c.955 C > T; p.Q319* was identified in CYP21A2 in two families with posterior polar cataract and in an isolated case with unspecified congenital cataract phenotype. This is the same variant previously linked to CAH and identified as Q318* in the literature. We have also identified a rare missense variant NM_000500.9 c.770 T > C; p.M257T in an isolated case with unspecified congenital cataract phenotype. This is the first report of separate sequence variants in CYP21A2 associated with congenital cataract. Our findings extend the genetic basis for congenital cataract and add to the phenotypic spectrum of CYP21A2 variants and particularly the CAH associated Q318* variant. CYP21A2 has a significant role in mineralo- and gluco-corticoid biosynthesis. These findings suggest that CYP21A2 may be important for extra-adrenal biosynthesis of aldosterone and cortisol in the eye lens. [ABSTRACT FROM AUTHOR]

Purpose: Crystallin 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. Design: Observational study. Participants: A Chinese family diagnosed with autosomal dominant (AD) CCs with or without microphthalmia. Methods: Because 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 Measures: We 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. Results: We 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. Conclusions: Our 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.

Heterozygous mutations in the OPA3 gene are associated with autosomal dominant optic atrophy-3 (OPA3), whereas biallelic mutations cause autosomal recessive 3-methylglutaconic aciduria type III. To date, all cases with pathogenic variants in the gene OPA3 have presented with optic atrophy. We report a large family with congenital cataracts, hearing loss and neuropathy, with a likely pathogenic novel missense variant in OPA3, c.30G>C; p.(Lys10Asn) that segregates with disease in the family pedigree. The family's clinical presentation has significant phenotypic overlap with previously reported cases of OPA3, except for a notable lack of optic atrophy. The analysis of all known disease-associated variants in OPA3 revealed an enrichment in missense variants in patients with OPA3 phenotype compared with loss-of-function variants, which are more likely to be observed in individuals with 3-methylglutaconic aciduria type III, supporting different mechanisms of disease. This case broadens the clinical and genetic spectrum associated with OPA3 mutations and highlights that optic atrophy is not an obligate feature of OPA3-related disorders., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Patients treated for bilateral congenital cataracts provide a unique model to test the role of early visual input in shaping the development of the human cortex. Previous studies showed that brief early visual deprivation triggers long-lasting changes in the human visual cortex. However, it remains unknown if such changes interact with the development of other parts of the cortex. With high-resolution structural and resting-state fMRI images, we found changes in cortical thickness within, but not limited to, the visual cortex in adult patients, who experienced transient visual deprivation early in life as a result of congenital cataracts. Importantly, the covariation of cortical thickness across regions was also altered in the patients. The areas with altered cortical thickness in patients also showed differences in functional connectivity between patients and normally sighted controls. Together, the current findings suggest an impact of early visual deprivation on the interactive development of the human cortex.

Purpose: To broaden the mutation and phenotype spectrum of the GJA8 and CHMP4B genes and to reveal genotype-phenotype correlations in a cohort of Chinese patients with congenital cataracts (CCs).Methods: Six Chinese Han families with CCs inherited in an autosomal dominant (AD) pattern were recruited for this study. All patients underwent full ocular examinations. Genomic DNA was extracted from the leukocytes of peripheral blood collected from all available patients and their unaffected family members. Whole-exome sequencing (WES) was performed on all probands and at least one of their parents. Candidate variants were further confirmed by Sanger sequencing. Bioinformatic analysis with several computational predictive programs was performed to assess the impacts of the candidate variants on the structure and function of the proteins.Results: Four heterozygous candidate variants in three different genes (CRYBB2, GJA8, and CHMP4B) were identified in affected individuals from the six families, including two novel missense variants (GJA8: c.64G > C/p. G22R, and CHMP4B: c.587C > G/p. S196C), one missense mutation (CRYBB2: c.562C > T/p. R188C), and one small deletion (GJA8: c.426_440delGCTGGAGGGGACCCT/p.143_147delLEGTL). The three missense mutations were predicted as deleterious in all four computational prediction programs. In the homologous model, the GJA8: p.143_147delLEGTL mutation showed a sequence deletion of five amino acids at the cytoplasmic loop of the Cx50 protein, close to the third transmembrane domain. Patients carrying mutations in the same gene showed similar cataract phenotypes at a young age, including total cataracts, Y-sutural with fetal nuclear cataracts, and subcapsular cataracts.Conclusion: This study further expands the mutation spectrum and genotype-phenotype correlation of CRYBB2, GJA8, and CHMP4B underlying CCs. This study sheds light on the importance of comparing congenital cataract phenotypes in patients at the same age stage. It offers clues for the pathogenesis of CCs and allows for an early prenatal diagnosis for families carrying these genetic variants.

Abstract Background Congenital nystagmus (CN) and congenital cataracts are distinct eye diseases and are usually isolated. Cases with CN and congenital cataracts caused by different genes in one family have been rarely reported. Case presentation A 27-year-old man presented with CN and congenital cataracts and he underwent cataract extraction 2 weeks after birth. Three years later, he had posterior chamber intraocular lens implantation. The proband’s mother was only afflicted by bilateral lens opacities. Lensectomy was performed in both eyes at age 15. The proband’s daughter had bilateral central cataracts and no nystagmus. She had undergone cataract extraction when she was two months old. In this family, 8 affected individuals were affected by bilateral cataracts, and three of them presented with CN. The genetic analysis was performed using a specific Hereditary Ophthalmological Disease Gene Panel on proband and his parents (one of which was a patient). PCR and Sanger sequencing verified the presence of these variants in all members of the family. The novel mutation, c.498-3C > T, in FRMD7 explains why X-Linked recessive inheritance of CN was found in a subset of patients. A heterozygous mutation of the GJA8 gene (c.139G > C), was identified in all patients and thus explains the autosomal dominant pattern of inheritance of congenital cataracts within the family. Conclusions This is the first time that FRMD7 and GJA8 gene mutations have been linked to the pathogenesis of a family with both CN and congenital cataracts. The phenomenon of two different genetic patterns coexisting in one family is rare.

ObjectivesNumerous task-based functional magnetic resonance imaging studies indicate the presence of compensatory functional improvement in patients with congenital cataracts. However, there is neuroimaging evidence that shows decreased sensory perception or cognition information processing related to visual dysfunction, which favors a general loss hypothesis. This study explored the functional connectivity between visual and other networks in children with congenital cataracts using resting state electroencephalography.MethodsTwenty-one children with congenital cataracts (age: 8.02 ± 2.03 years) and thirty-five sex- and age-matched normal sighted controls were enrolled to investigate functional connectivity between the visual cortex and the default mode network, the salience network, and the cerebellum network during resting state electroencephalography (eyes closed) recordings.ResultThe congenital cataract group was less active, than the control group, in the occipital, temporal, frontal and limbic lobes in the theta, alpha, beta1 and beta2 frequency bands. Additionally, there was reduced alpha-band connectivity between the visual and somatosensory cortices and between regions of the frontal and parietal cortices associated with cognitive and attentive control.ConclusionThe results indicate abnormalities in sensory, cognition, motion and execution functional connectivity across the developing brains of children with congenital cataracts when compared with normal controls. Reduced frontal alpha activity and alpha-band connectivity between the visual cortex and salience network might reflect attenuated inhibitory information flow, leading to higher attentional states, which could contribute to adaptation of environmental change in this group of patients.

Objectives: Numerous task-based functional magnetic resonance imaging studies indicate the presence of compensatory functional improvement in patients with congenital cataracts. However, there is neuroimaging evidence that shows decreased sensory perception or cognition information processing related to visual dysfunction, which favors a general loss hypothesis. This study explored the functional connectivity between visual and other networks in children with congenital cataracts using resting state electroencephalography. Methods: Twenty-one children with congenital cataracts (age: 8.02 ± 2.03 years) and thirty-five sex- and age-matched normal sighted controls were enrolled to investigate functional connectivity between the visual cortex and the default mode network, the salience network, and the cerebellum network during resting state electroencephalography (eyes closed) recordings. Result: The congenital cataract group was less active, than the control group, in the occipital, temporal, frontal and limbic lobes in the theta, alpha, beta1 and beta2 frequency bands. Additionally, there was reduced alpha-band connectivity between the visual and somatosensory cortices and between regions of the frontal and parietal cortices associated with cognitive and attentive control. Conclusion: The results indicate abnormalities in sensory, cognition, motion and execution functional connectivity across the developing brains of children with congenital cataracts when compared with normal controls. Reduced frontal alpha activity and alpha-band connectivity between the visual cortex and salience network might reflect attenuated inhibitory information flow, leading to higher attentional states, which could contribute to adaptation of environmental change in this group of patients. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital cataract is the leading cause of blindness in children worldwide. Approximately half of all congenital cataracts have a genetic basis. Protein aggregation is the single most important factor in cataract formation. Methods A four-generation Chinese family diagnosed with autosomal dominant congenital cataracts and microphthalmia was recruited at the Shengjing Hospital of China Medical University. Genomic DNA was extracted from the peripheral blood of the participants. All coding exons and flanking regions of seven candidate genes (CRYAA, CRYBA4, CRYBB2, CRYGC, GJA8, MAF, and PITX3) were amplified and sequenced. Restriction fragment length polymorphism (RFLP) assays were performed to confirm the candidate causative variant, c.35G > T in the CRYAA gene. We constructed pcDNA3.1(+)-CRYAA expression plasmids containing either the wild-type or the R12L mutant alleles and respectively transfected them into HEK293T cells and into HeLa cells. Western blotting was performed to determine protein expression levels and protein solubility. Immunofluorescence was performed to determine protein sub-cellular localization. Results A heterozygous variant c.35G > T was identified in exon 1 of CRYAA, which resulted in a substitution of arginine to leucine at codon 12 (p.R12L). The nucleotide substitution c.35G > T was co-segregated with the disease phenotype in the family. The mutant R12L-CRYAA in HEK293T cells showed a significant increase in the expression level of the CRYAA protein compared with the wild-type cells. Moreover, a large amount of the mutant protein aggregated in the precipitate where the wild-type protein was not detected. Immunofluorescence studies showed that the overexpressed mutant CRYAA in HeLa cells formed large cytoplasmic aggregates and aggresomes. Conclusions In summary, we described a case of human congenital cataract and microphthalmia caused by a novel mutation in the CRYAA gene, which substituted an arginine at position 12 in the N-terminal region of αA-crystallin. The molecular mechanisms that underlie the pathogenesis of human congenital cataract may be characterized by the prominent effects of the p.R12L mutation on αA-crystallin aggregation and solubility. Our study also expands the spectrum of known CRYAA mutations.

Abstract Background Congenital cataract, a kind of cataract presenting at birth or during early childhood, is a leading cause of childhood blindness. To date, more than 30 genes on different chromosomes are known to cause this disorder. This study aimed to identify the HSF4 mutations in a cohort from Chinese families affected with congenital cataracts. Methods Forty-two unrelated non-syndromic congenital cataract families and 112 ethnically matched controls from southeast China were recruited from the southeast of China. We employed Sanger sequencing method to discover the variants. To confirm the novel mutations, STR haplotypes were constructed to check the co-segregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools including SIFT, Polyphen2, and Human Splicing Finder. The pathogenicity of all the mutations was evaluated by the guidelines of American College of Medical Genetics and InterVar software. Results No previously reported HSF4 mutations were found in all the congenital cataract families. Five novel HSF4 mutations including c.187 T > C (p.Phe63Leu), c.218G > T (p.Arg73Leu), c.233A > G (p.Tyr78Cys), IVS5 c.233-1G > A and c.314G > C (p.Ser105Thr) were identified in five unrelated families with congenital cataracts, respectively. These mutations co-segregated with all affected individuals in each family were not observed in the unaffected family members or in 112 unrelated controls. All five mutations were categorized to be the disease “pathogenic” according to ACMG guidelines and using InterVar software. Mutations in the HSF4 were responsible for 11.90% Chinese families with congenital cataracts in our cohort. Conclusions In the study, we identified five novel HSF4 mutations in Chinese families with congenital cataracts. Our results expand the spectrum of HSF4 mutations causing congenital cataracts, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine.

Nucleoporins (NUPs) are an essential component of the nuclear-pore complex, which regulates nucleocytoplasmic transport of macromolecules. Pathogenic variants in NUP genes have been linked to several inherited human diseases, including a number with progressive neurological degeneration. We present six affected individuals with bi-allelic truncating variants in NUP188 and strikingly similar phenotypes and clinical courses, representing a recognizable genetic syndrome; the individuals are from four unrelated families. Key clinical features include congenital cataracts, hypotonia, prenatal-onset ventriculomegaly, white-matter abnormalities, hypoplastic corpus callosum, congenital heart defects, and central hypoventilation. Characteristic dysmorphic features include small palpebral fissures, a wide nasal bridge and nose, micrognathia, and digital anomalies. All affected individuals died as a result of respiratory failure, and five of them died within the first year of life. Nuclear import of proteins was decreased in affected individuals' fibroblasts, supporting a possible disease mechanism. CRISPR-mediated knockout of NUP188 in Drosophila revealed motor deficits and seizure susceptibility, partially recapitulating the neurological phenotype seen in affected individuals. Removal of NUP188 also resulted in aberrant dendrite tiling, suggesting a potential role of NUP188 in dendritic development. Two of the NUP188 pathogenic variants are enriched in the Ashkenazi Jewish population in gnomAD, a finding we confirmed with a separate targeted population screen of an international sampling of 3,225 healthy Ashkenazi Jewish individuals. Taken together, our results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype. [ABSTRACT FROM AUTHOR]

Background: Congenital cataract is the most common cause of blindness in the world. Congenital cataracts are clinically and genetically heterogeneous and are mostly inherited in an autosomal dominant fashion. We identified the genetic cause of isolated autosomal dominant cataract in a four-generation British family and a Czech family. Methods: Whole exome sequencing (WES) was performed on one affected member in the British family and two affected members in the Czech family. Results: A novel missense variant c.388C > T; p.(R130C) was identified in the Lens integral membrane protein (LIM2) and found to co-segregate with disease in both families. Conclusions: Here we report the first autosomal dominant congenital cataract variant p.(R130C) in LIM2, causing a non-syndromic pulverulent and nuclear phenotype in European families. [ABSTRACT FROM AUTHOR]