Analysis of genotype–phenotype correlations in PAX6-associated aniridia

BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher’s exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini–Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3′-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.

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

BMC Ophthalmology ◽

10.1186/s12886-022-02256-7 ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Genetic Variants ◽

Chinese Family ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Whole Exome ◽

Novel Variant ◽

Health Related ◽

Congenital Aniridia ◽

Foveal Hypoplasia

Abstract Background Aniridia is a congenital, panocular disease that can affect the cornea, anterior chamber angle, iris, lens, retina and optic nerve. PAX6 loss-of-function variants are the most common cause of aniridia, and variants throughout the gene have been linked to a range of ophthalmic abnormalities. Furthermore, particular variants at a given site in PAX6 lead to distinct phenotypes. This study aimed to characterize genetic variants associated with congenital aniridia in a Chinese family. Methods The proband and family underwent ophthalmologic examinations. DNA was sampled from the peripheral blood of all 6 individuals, and whole-exome sequencing was performed. Sanger sequencing was used to verify the variant in this family members. Results A novel variant (c.114_119delinsAATTTCC: p.Pro39llefsTer17) in the PAX6 gene was identified in subjects II-1, III-1 and III-2, who exhibited complete aniridia and cataracts. The proband and the proband’s brother also had glaucoma, high myopia, and foveal hypoplasia. Conclusions We identified that a novel PAX6 frameshift heterozygous deletion variant is the predominant cause of aniridia in this Chinese family. Trial registration We did not perform any health-related interventions for the participants.

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A Novel Multi-Exon Deletion of PACS1 in a Three-Generation Pedigree: Supplements to PACS1 Neurodevelopmental Disorder Spectrum

Frontiers in Genetics ◽

10.3389/fgene.2021.690216 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuan Liu ◽

Hongke Ding ◽

Tizhen Yan ◽

Ling Liu ◽

Lihua Yu ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Dominant Negative ◽

Facial Features ◽

Missense Mutations ◽

Loss Of Function ◽

Pathogenic Variants ◽

Cognitive Delay ◽

Whole Exome ◽

Before And After ◽

Exon Deletion

PACS1 neurodevelopmental disorder (PACS1-NDD) is a category of rare disorder characterized by intellectual disability, speech delay, dysmorphic facial features, and developmental delay. Other various physical abnormalities of PACS1-NDD might involve all organs and systems. Notably, there were only two unique missense mutations [c.607C > T (p.Arg203Trp) and c.608G > A (p.Arg203Gln)] in PACS1 that had been identified as pathogenic variants for PACS1-NDD or Schuurs-Hoeijmakers syndrome (SHMS). Previous reports suggested that these common missense variants were likely to act through dominant-negative or gain-of-function effects manner. It is still uncertain whether the intragenic deletion or duplication in PACS1 will be disease-causing. By using whole-exome sequencing, we first identified a novel heterozygous multi-exon deletion covering exons 12–24 in PACS1 (NM_018026) in four individuals (two brothers and their father and grandfather) in a three-generation family. The younger brother was referred to our center prenatally and was evaluated before and after the birth. Unlike SHMS, no typical dysmorphic facial features, intellectual problems, and structural brain anomalies were observed among these four individuals. The brothers showed a mild hypermyotonia of their extremities at the age of 3 months old and recovered over time. Mild speech and cognitive delay were also noticed in the two brothers at the age of 13 and 27 months old, respectively. However, their father and grandfather showed normal language and cognitive competence. This study might supplement the spectrum of PACS1-NDD and demonstrates that the loss of function variation in PACS1 displays no contributions to the typical SHMS which is caused by the recurrent c.607C > T (p.Arg203Trp) variant.

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Exome sequencing identifies novel AD-associated genes.

10.1101/2020.07.22.20159251 ◽

2020 ◽

Cited By ~ 1

Author(s):

Henne Holstege ◽

Marc Hulsman ◽

Camille Charbonnier ◽

Benjamin Grenier-Boley ◽

Olivier Quenez ◽

...

Keyword(s):

Exome Sequencing ◽

Genetic Variants ◽

Rare Variants ◽

Mendelian Inheritance ◽

Loss Of Function ◽

App Processing ◽

Complex Disorders ◽

Pathogenic Variants ◽

Increased Risk ◽

The Impact

Background: With the development of next-generation sequencing technologies, it is possible to identify rare genetic variants that influence the risk of complex disorders. To date, whole exome sequencing (WES) strategies have shown that specific clusters of damaging rare variants in the TREM2, SORL1 and ABCA7 genes are associated with an increased risk of developing Alzheimers Disease (AD), reaching odds ratios comparable with the APOE-ε4 allele, the main common AD genetic risk factor. Here, we set out to identify additional AD-associated genes by an exome-wide investigation of the burden of rare damaging variants in the genomes of AD cases and cognitively healthy controls. Method: We integrated the data from 25,982 samples from the European ADES consortium and the American ADSP consortium. We developed new techniques to homogenise and analyse these data. Carriers of pathogenic variants in genes associated with Mendelian inheritance of dementia were excluded. After quality control, we used 12,652 AD cases and 8,693 controls for analysis. Genes were analysed using a burden analysis, including both non-synonymous and loss-of-function rare variants, the impact of which was prioritised using REVEL. Result: We confirmed that carrying rare protein-damaging genetic variants in TREM2, SORL1 or ABCA7 is associated with increased AD-risk. Moreover, we found that carrying rare damaging variants in the microglial ATP8B4 gene was significantly associated with AD, and we found suggestive evidence that rare variants in ADAM10, ABCA1, ORC6, B3GNT4 and SRC genes associated with increased AD risk. High-impact variants in these genes were mostly extremely rare and enriched in AD patients with earlier ages at onset. Additionally, we identified two suggestive protective associations in CBX3 and PRSS3. We are currently replicating these associations in independent datasets. Conclusion: With our newly developed homogenisation methods, we identified novel genetic determinants of AD which provide further evidence for a pivotal role of APP processing, lipid metabolism, and microglia and neuro-inflammatory processes in AD pathophysiology.

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

10.21203/rs.3.rs-32697/v4 ◽

2021 ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Novel Mutation ◽

Chinese Family ◽

Genetic Mutations ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Generation Sequencing ◽

Pax6 Mutation

Abstract Background: Aniridia is a congenital,panocular disease affecting the cornea,anterior chamber angle,iris,lens,retina and optic nerve.PAX6 loss-of-function mutations were the most common cause of aniridia.Mutations throughout the PAX6 gene have been linked to a range of ophthalmic abnormalities,with distinct mutations at a given site within this gene leading to distinct phenotypic findings.This study aimed to characterize genetic mutations associated with congenital aniridia in a Chinese family. Methods: The proband and the proband’s brother of this family underwent comprehensive ophthalmologic examinations as well as exome sequencing,with Next Generation Sequencing being used to confirm these results. Results: A novel mutation(c.114_119delinsAATTTCC:p.Pro39fs)in the PAX6 gene was identified in subjects III-2 and III-3 in these family,and both of these subjects exhibited completeaniridia,cataracts,glaucoma,high myopia,and foveal hypoplasia. Conclusions We identified a novel PAX6 frameshift heterozygous deletion mutation in a Chinese family and determined that this mutation was a probable cause of various eye abnormalities in carriers.

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

10.21203/rs.3.rs-32697/v3 ◽

2020 ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Novel Mutation ◽

Chinese Family ◽

Pax6 Gene ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Generation Sequencing ◽

Pax6 Mutation

Abstract Background: Aniridia is a congenital, panocular disease affecting the cornea, anterior chamber angle, iris, lens, retina and optic nerve. PAX6 loss-of-function mutations were the most common cause of aniridia .Mutations throughout the PAX6 gene have been linked to a range of ophthalmic abnormalities, with distinct mutations at a given site within this gene leading to distinct phenotypic findings.This s tudy aimed to characterize genetic mutations associated with congenital aniridia in a Chinese family. Methods: The proband and the proband’s brother of this family underwent comprehensive ophthalmologic examinations as well as exome sequencing, with Next Generation Sequencing being used to confirm these results. Results: A novel mutation (c.114_119delinsAATTTCC:p.Pro39fs) in the PAX6 gene was identified in subjects III-2 and III-3 in these family, and both of these subjects exhibited complete aniridia, cataracts, glaucoma, high myopia, and foveal hypoplasia. Conclusions: We identified a novel PAX6 frameshift heterozygous deletion mutation in a Chinese family and determined that this mutation was a probable cause of various eye abnormalities in carriers.

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Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns

10.1101/018648 ◽

2015 ◽

Author(s):

Tychele Turner ◽

Christopher Douville ◽

Dewey Kim ◽

Peter D Stenson ◽

David N Cooper ◽

...

Keyword(s):

Missense Mutation ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Distribution Patterns ◽

Missense Mutations ◽

Loss Of Function ◽

Gain Of Function ◽

Disease Etiology ◽

Missense Variants ◽

Significant Difference

The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF<0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss of function. Loss- of-function mutations tend to be distributed uniformly along protein sequence, while gain-of- function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position (CLUMP). These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P=5.7x10-4, permutation P=8.4x10-4). Rare missense mutation in proteins linked to either AD or AR diseases were more clustered than controls (1000G) (Wilcoxon P=2.8x10-15 for AD and P=4.5x10-4 for AR, permutation P=3.1x10-12 for AD and P=0.03 for AR). Differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies.

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Biallelic Loss-of-Function Variants in AIMP1 Cause a Rare Neurodegenerative Disease

Journal of Child Neurology ◽

10.1177/0883073818811223 ◽

2018 ◽

Vol 34 (2) ◽

pp. 74-80 ◽

Cited By ~ 3

Author(s):

Andrea Accogli ◽

Kether Guerrero ◽

Maria Daniela D’Agostino ◽

Luan Tran ◽

Cécile Cieuta-Walti ◽

...

Keyword(s):

Neuronal Development ◽

Neurodegenerative Disorder ◽

Cerebral Atrophy ◽

Trna Synthetase ◽

Homozygous Mutation ◽

Missense Mutations ◽

Loss Of Function ◽

Pathogenic Variants ◽

The Central Nervous System ◽

And Function

AIMP1/p43, is a noncatalytic component of the mammalian multi-tRNA synthetase complex that catalyzes the ligation of amino acids to their cognate tRNAs. AIMP1 is largely expressed in the central nervous system, where it is part of the regulatory machine of the neurofilament assembly, playing a crucial role in neuronal development and function. To date, nonsense mutations in AIMP1 have been associated with a primary neurodegenerative disorder consisting of cerebral atrophy, hypomyelination, microcephaly and epilepsy, whereas missense mutations have recently been linked to intellectual disability without neurodegeneration. Here, we report the first French-Canadian patient with a novel frameshift AIMP1 homozygous mutation (c.191_192delAA, p.Gln64Argfs*25), resulting in a severe neurodegenerative phenotype. We review and discuss the phenotypic spectrum associated with AIMP1 pathogenic variants.

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Identification of Peptidyl-Prolyl Cis-Trans Isomerase-Like 4 as a Disease Causing Gene in Intracranial Aneurysms and its Role in Vertebrate CNS Specific Angiogenesis

Neurosurgery ◽

10.1093/neuros/nyz310_303 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Tanyeri Barak ◽

Adife Gulhan Ercan Sencicek ◽

Danielle F Miyagishima ◽

Octavian Henegariu ◽

Ketu Mishra Gorur ◽

...

Keyword(s):

Mrna Stability ◽

Rna Binding ◽

The United States ◽

Rna Modification ◽

Control Group ◽

Fisher Exact Test ◽

Missense Mutations ◽

Loss Of Function ◽

Exact Test

Abstract INTRODUCTION Intracranial aneurysm (IA) is a significant health burden affecting nearly 6 million people in the United States with an estimated prevalence of 3.2% worldwide. Using whole exome sequencing (WES) of 728 European IA cases, we identified damaging mutations in and RNA binding protein peptidyl-prolyl cis-trans isomerase-like 4 (PPIL4) in both familial and sporadic IA cases. METHODS We performed WES in 728 European IA cases followed by a mutational burden analysis between IA cases and a European (Finnish + Non-Finnish) control group of 1443 unaffected individuals, and European subjects (non-Finnish + Finnish) in the ExAC and gnomAD databases. Fisher exact test was used to determine the significance of the enrichment of rare (ExAC MAF <0.0001) and deleterious variants consisting of loss of function and deleterious missense mutations (MetSVM-D). Mutant ppil4 lines were generated using Crispr-CAS9 in zebrafish and X.tropicalis. RNA-seq and Slam-Seq were performed to identify transcriptome-wide changes in RNA half-life mediated by PPIL4. RESULTS Burden analysis revealed a significant enrichment of rare and deleterious PPIL4 variants in European IA cases when compared to 1443 controls (OR = INF., Fisher P = 3.17 × 10–4), ExAC (OR = 12.26, Fisher P = 5 × 10–4) or gnomAD (OR = 13.14, Fisher P = 3.4 × 10–4). PPIL4 mutants both in zebrafish and X.tropicalis models displayed cerebral hemorrhage and cerebrovascular simplification. Slam-seq analysis revealed that PPIL4 promotes mRNA stability of the genes implicated in VEGF signaling (FDR = 3.75E-07) and Focal adhesion pathways (FDR = 2.04E-06). CONCLUSION In this study, we identified PPIL4 as a candidate gene in IA pathogenesis and demonstrated morphological and hemodynamic impairment in vivo upon abrogating PPIL4 in 2 vertebrate models. Furthermore, we demonstrated that PPIL4 plays a major role in CNS angiogenesis and IA pathogenesis through promoting mRNA stability of key angiogenesis related genes, emphasizing the role of post-transcriptional RNA modification in cerebrovascular development and pathologies.

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Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Neurology Genetics ◽

10.1212/nxg.0000000000000316 ◽

2019 ◽

Vol 5 (2) ◽

pp. e565 ◽

Cited By ~ 2

Author(s):

Chong Sun ◽

Jie Song ◽

Yanjun Jiang ◽

Chongbo Zhao ◽

Jiahong Lu ◽

...

Keyword(s):

Missense Mutation ◽

Protein Function ◽

Trna Synthetase ◽

Insertion Mutation ◽

Compound Heterozygous ◽

Missense Mutations ◽

Loss Of Function ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

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

10.21203/rs.3.rs-32697/v1 ◽

2020 ◽

Author(s):

Junyi Ouyang ◽

Ziyan Cai ◽

Yinjie Guo ◽

Fen Nie ◽

Mengdan Cao ◽

...

Keyword(s):

Novel Mutation ◽

Chinese Family ◽

Genetic Mutations ◽

Anterior Chamber Angle ◽

Loss Of Function ◽

Heterozygous Deletion ◽

Congenital Aniridia ◽

Foveal Hypoplasia ◽

Generation Sequencing ◽

Pax6 Mutation

Abstract Background Aniridia is a congenital,panocular disease affecting the cornea,anterior chamber angle,iris,lens,retina and optic nerve.PAX6 loss-of-function mutations were the most common cause of aniridia.Mutations throughout the PAX6 gene have been linked to a range of ophthalmic abnormalities,with distinct mutations at a given site within this gene leading to distinct phenotypic findings.This study aimed to characterize genetic mutations associated with congenital aniridia in a Chinese family.MethodsThe proband and the proband’s brother of this family underwent comprehensive ophthalmologic examinations as well as exome sequencing,with Next Generation Sequencing being used to confirm these results.Results A novel mutation(c.114_119delinsAATTTCC:p.Pro39fs)in the PAX6 gene was identified in subjects III-2 and III-3 in these family,and both of these subjects exhibited completeaniridia,cataracts,glaucoma,high myopia,and foveal hypoplasia.Conclusions We identified a novel PAX6 frameshift heterozygous deletion mutation in a Chinese family and determined that this mutation was a probable cause of various eye abnormalities in carriers.

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