Detection of a novel PAX6 variant in a Chinese family with multiple ocular abnormalities

Ouyang, Junyi; Cai, Ziyan; Guo, Yinjie; Nie, Fan; Cao, Mengdan; Duan, Xuanchu

doi:10.1186/s12886-022-02256-7

Cited by 4 publications

(5 citation statements)

References 15 publications

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“…RB1 was the only causative gene for retinoblastoma, 36 70% ( n = 7) of variants were LOF mutations, 20% ( n = 2) were missense mutations, and 10% ( n = 1) were in-frame mutations. Aniridia was known to be predominantly caused by variants in PAX6 , 37 all variant types being LOF mutations ( n = 6). The overall diagnostic yield was 60% (6/10), of which the diagnostic yield of DNM accounted for 66.67% (4/6).…”

Section: Resultsmentioning

confidence: 99%

De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases

Yang

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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Purpose The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs). Methods To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing. Results All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia ( n = 40%), Marfan syndrome/ectopia lentis ( n = 38.78%), and retinoblastoma ( n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal ( P = 0.154) and maternal ( P = 0.959) age at reproduction. Conclusions Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.

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Section: Resultsmentioning

confidence: 99%

De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases

Yang

et al. 2023

Invest. Ophthalmol. Vis. Sci.

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“…Overall, particular variants may lead to distinct phenotypes. Loss of function variants-including frameshift, nonsense, and splicing site mutations-of PAX6 are the most common cause of classic aniridia, which is more likely to be associated with severely affected individuals [1,[4][5][8][9]28] . Milder iris abnormalities are typically attributed to missense mutations [3,17,[28][29] .…”

Section: Pax6 Mutation In Atypical Aniridiamentioning

confidence: 99%

“…C ongenital aniridia is a rare genetic eye disorder that affects up to 1 in 64 000 individuals worldwide and demonstrates no predilection for race or sex. Approximately two-thirds of diagnosed patients are autosomal dominantly inherited and the remaining one-third of cases arise sporadically [1][2] . Classical aniridia is characterized by partial or complete bilateral absence of the iris, however other manifestations may also occur, including developmental defects of the cornea, lens, retina, anterior chamber angle, and optic nerve in both eyes.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, aniridia can manifest as an isolated ocular abnormality or be a part of a systemic disorder such as Wilms tumour-aniridia syndrome, which consists of Wilms' tumor, aniridia, genitourinary abnormalities, and intellectual disability; Wilms tumour-aniridia syndrome occurs with or without obesity [5][6] . The majority of clinical aniridia cases result from mutations in the paired box gene-6 (PAX6, OMIM: 607108) and its associated regulatory regions [1,[3][4][5][7][8][9][10] . The PAX6 gene, located on chromosome 11p13, is a member of the highly conserved paired box gene family.…”

Section: Introductionmentioning

confidence: 99%

“…It encodes a transcriptional regulator including two DNA binding domains-the paired domain (PD) and the homeodomain (HD) [2,8,[10][11] -and is critical for eye, brain, spinal cord, and pancreas development [11][12][13] . So far, more than 500 variants of PAX6 related to aniridia have been identified [1] . The majority of these variants involve frameshift, nonsense, or splice site mutations that lead to loss of function nucleotide substitutions or the production of truncated proteins [14][15] .…”

Section: Introductionmentioning

confidence: 99%

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A rare missense PAX6 mutation causes atypical aniridia in a three-generation Chinese family

Lin,

Li,

Pan

et al. 2024

Int J Ophthalmol

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AIM: To investigate the molecular diagnosis of a three-generation Chinese family affected with aniridia, and further to identify clinically a PAX6 missense mutation in members with atypical aniridia. METHODS: Eleven family members with and without atypical aniridia were recruited. All family members underwent comprehensive ophthalmic examinations. A combination of whole exome sequencing (WES) and direct Sanger sequencing were performed to uncover the causative mutation. RESULTS: Among the 11 family members, 8 were clinically diagnosed with congenital aniridia (atypical aniridia phenotype). A rare heterozygous mutation c.622C>T (p.Arg208Trp) in exon 8 of PAX6 was identified in all affected family members but not in the unaffected members or in healthy control subjects. CONCLUSION: A rare missense mutation in the PAX6 gene is found in members of a three-generation Chinese family with congenital atypical aniridia. This result contributes to an increase in the phenotypic spectrum caused by PAX6 missense heterozygous variants and provides useful information for the clinical diagnosis of atypical aniridia, which may also contribute to genetic counselling and family planning.

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Genetic changes and testing associated with childhood glaucoma: A systematic review

Kumar,

Han,

Oatts

2024

PLoS ONE

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Many forms of childhood glaucoma have been associated with underlying genetic changes, and variants in many genes have been described. Currently, testing is variable as there are no widely accepted guidelines for testing. This systematic review aimed to summarize the literature describing genetic changes and testing practices in childhood glaucoma. This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) 2020 guidelines and registered with Prospero (ID CRD42023400467). A comprehensive review of Pubmed, Embase, and Cochrane databases was performed from inception through March 2, 2023 using the search terms: (glaucoma) AND (pediatric OR childhood OR congenital OR child OR infant OR infantile) AND (gene OR genetic OR genotype OR locus OR genomic OR mutation OR variant OR test OR screen OR panel). Information was extracted regarding genetic variants including genotype-phenotype correlation. Risk of bias was assessed using the Newcastle-Ottawa Scale. Of 1,916 records screened, 196 studies met inclusion criteria and 53 genes were discussed. Among study populations, mean age±SD at glaucoma diagnosis was 8.94±9.54 years and 50.4% were male. The most common gene discussed was CYP1B1, evaluated in 109 (55.6%) studies. CYP1B1 variants were associated with region and population-specific prevalence ranging from 5% to 86% among those with primary congenital glaucoma. MYOC variants were discussed in 31 (15.8%) studies with prevalence up to 36% among patients with juvenile open angle glaucoma. FOXC1 variants were discussed in 25 (12.8%) studies, which demonstrated phenotypic severity dependent on degree of gene expression and type of mutation. Overall risk of bias was low; the most common domains of bias were selection and comparability. Numerous genes and genetic changes have been associated with childhood glaucoma. Understanding the most common genes as well as potential genotype-phenotype correlation has the potential to improve diagnostic and prognostic outcomes for children with glaucoma.

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Detection of a novel PAX6 variant in a Chinese family with multiple ocular abnormalities

Cited by 4 publications

References 15 publications

De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases

De Novo Mutations Contributes Approximately 7% of Pathogenicity in Inherited Eye Diseases

A rare missense PAX6 mutation causes atypical aniridia in a three-generation Chinese family

Genetic changes and testing associated with childhood glaucoma: A systematic review

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