Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations.
Ontology highlight
ABSTRACT:
SUBMITTER: Tumer Z
PROVIDER: S-EPMC2987033 | biostudies-literature | 2009 Dec
REPOSITORIES: biostudies-literature
Publications
Axenfeld-Rieger syndrome and spectrum of PITX2 and FOXC1 mutations.
Tümer Zeynep Z Bach-Holm Daniella D
European journal of human genetics : EJHG 20090610 12
Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder, which encompasses a range of congential malformations affecting the anterior segment of the eye. ARS shows genetic heterogeneity and mutations of the two genes, PITX2 and FOXC1, are known to be associated with the pathogenesis. There are several excellent reviews dealing with the complexity of the phenotype and genotype of ARS. In this study, we will attempt to give a brief review of the clinical features and the relevant diag ...[more]
Similar Datasets
Project description:Axenfeld-Rieger syndrome is a genetic condition characterized by ocular and systemic features and is most commonly caused by variants in the FOXC1 or PITX2 genes. Facial dysmorphism is part of the syndrome but the differences between both genes have never been systematically assessed. Here, 11 facial traits commonly reported in Axenfeld-Rieger syndrome were assessed by five clinical geneticists blinded to the molecular diagnosis. Individuals were drawn from the Australian and New Zealand Registry of Advanced Glaucoma in Australia or recruited through the Genetic and Ophthalmology Unit of l'Azienda Socio-Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda in Italy. Thirty-four individuals from 18 families were included. FOXC1 variants were present in 64.7% of individuals and PITX2 variants in 35.3% of individuals. A thin upper lip (55.9%) and a prominent forehead (41.2%) were common facial features shared between both genes. Hypertelorism/telecanthus (81.8% vs 25.0%, p = 0.002) and low-set ears (31.8% vs 0.0%, p = 0.036) were significantly more prevalent in individuals with FOXC1 variants compared with PITX2 variants. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.
| S-EPMC7839469 | biostudies-literature
Project description:Purpose:The aims of this study were to examine novel mutations in PITX2 and FOXC1 in Chinese patients with anterior segment dysgenesis (ASD) and to compare the clinical presentations of these mutations with previously reported associated phenotypes. Methods:Twenty-six unrelated patients with different forms of ASD were enrolled from our paediatric and genetic eye clinic. The ocular manifestations of both eyes of each patient were recorded. Genomic DNA was prepared from venous leukocytes. All coding exons of PITX2 and FOXC1 were amplified by polymerase chain reaction (PCR) from genomic DNA and subjected to direct DNA sequencing. Analysis of mutations in control subjects was performed by heteroduplex single-strand conformation polymorphism (SSCP) analysis. Results:Sequence analysis of the PITX2 gene revealed four mutations, including c.475_476delCT (P.L159VfsX39), c.64C?>?T (P.Q22X), c.296delG (P.R99PfsX56), and c.206G?>?A (P.R69H). The first three mutations were found to be novel. The c.475_476delCT (P.L159VfsX39) mutation, located at the 3' end of the PITX2-coding region, was identified in a Chinese Axenfeld-Rieger syndrome (ARS) patient who presented with an unusual severe phenotype of bilateral aniridia. The clinical characteristics, including the severity and manifestations of the patient's phenotype, were compared with reported PITX2-associated aniridia phenotypes of ARS in the literature. Conclusions:These results expand the mutation spectrum of the PITX2 gene in patients with ARS. The PITX2 gene may be responsible for a significant portion of ARS with additional systemic defects in the Chinese population. This is the first reported case of a mutation at the 3' end of the PITX2-coding region extending the phenotypic consequences to bilateral aniridia. The traits of ARS could display tremendous variability in severity and manifestations due to the dominant-negative effect of PITX2. Our results further emphasize the importance of careful clinical and genetic analysis in determining mutation-disease associations and may lead to a better understanding of the role of PITX2 in ocular development.
| S-EPMC6636469 | biostudies-literature
Project description:PURPOSE:Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant disorder that affects the anterior segment of the eye. The aim of this study was to examine the PITX2 gene to identify possible novel mutations in Pakistani and Mexican families affected by the ARS phenotype. METHODS:Three unrelated probands with a diagnosis of ARS were recruited for this study. Genomic DNA was isolated from the peripheral blood of the probands and their family members. Polymerase chain reaction and Sanger sequencing were used for the analysis of coding exons and the flanking intronic regions of the PITX2 gene. Bioinformatics tools and database (VarSome, Provean, and MutationTaster, SIFT, PolyPhen-2, and HOPE) were evaluated to explore missense variants. RESULTS:We identified novel heterozygous variations in the PITX2 gene that segregated with the ARS phenotype within the families. The variant NM_153426.2(PITX2):c.226G > T or p.(Ala76Ser) and the mutation NM_153426.2(PITX2):c.455G > A or p.(Cys152Tyr) were identified in two Pakistani pedigrees, and the mutation NM_153426.2(PITX2):c.242_265del or p.(Lys81_Gln88del), segregated in a Mexican family. CONCLUSION:Our study extends the spectrum of PITX2 mutations in individuals with ARS, enabling an improved diagnosis of this rare but serious syndrome.
| S-EPMC7336731 | biostudies-literature
Project description:Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-021-01130-7.
| S-EPMC8609746 | biostudies-literature
Project description:Axenfeld-Rieger syndrome (ARS) (OMIM Nr.: 180500) is a rare autosomal dominant disorder (1 : 200000) with genetic and morphologic variability. Glaucoma is associated in 50% of the patients. Craniofacial and dental anomalies are frequently reported with ARS. The present study was designed as a multidisciplinary analysis of orthodontic, ophthalmologic, and genotypical features. A three-generation pedigree was ascertained through a family with ARS. Clinically, radiographic and genetic analyses were performed. Despite an identical genotype in all patients, the phenotype varies in expressivity of craniofacial and dental morphology. Screening for PITX2 and FOXC1 mutations by direct DNA-sequencing revealed a P64L missense mutation in PITX2 in all family members, supporting earlier reports that PITX2 is an essential factor in morphogenesis of teeth and craniofacial skeleton. Despite the fact that the family members had identical mutations, morphologic differences were evident. The concomitant occurrence of rare dental and craniofacial anomalies may be early diagnostic indications of ARS. Early detection of ARS and elevated intraocular pressure (IOP) helps to prevent visual field loss.
| S-EPMC2842968 | biostudies-literature
Project description:PURPOSE: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant disorder characterized by extraocular anomalies and developmental defects of the anterior segment. PITX2 (paired-like homeodomain transcription factor 2) is considered the major causative gene. In this study, we characterized the molecular defect in PITX2 in a Chinese family with ARS. METHODS: Two generations of the family with ARS were enrolled in the present study. In addition to ophthalmologic examinations, polymerase chain reaction (PCR) amplification and nucleotide sequencing of all coding exons of PITX2 were performed. Exon 5 (region 1) was also sequenced in 100 healthy controls unrelated to the family for comparison. RESULTS: A novel PITX2 mutation, c.840G>T, was identified in all affected members of the family with ARS that causes an amino acid substitution from tryptophan to cysteine at codon 86. CONCLUSIONS: We found a novel p.W86C mutation in PITX2 in a Chinese family with ARS. The tryptophan residue at position 86 is strictly conserved in PITX2a proteins from several species and in homeodomain proteins. We suggest that this mutation in PITX2 is the cause of typical ARS in patients. Our results may be useful for better understanding of the spectrum of PITX2 mutations and the role of PITX2 in the development and progression of ARS.
| S-EPMC2592999 | biostudies-literature
Project description:Precise spatiotemporal expression of the Nodal-Lefty-Pitx2 cascade in the lateral plate mesoderm establishes the left-right axis, which provides vital cues for correct organ formation and function. Mutations of one cascade constituent PITX2 and, separately, the Forkhead transcription factor FOXC1 independently cause a multi-system disorder known as Axenfeld-Rieger syndrome (ARS). Since cardiac involvement is an established ARS phenotype and because disrupted left-right patterning can cause congenital heart defects, we investigated in zebrafish whether foxc1 contributes to organ laterality or situs. We demonstrate that CRISPR/Cas9-generated foxc1a and foxc1b mutants exhibit abnormal cardiac looping and that the prevalence of cardiac situs defects is increased in foxc1a-/-; foxc1b-/- homozygotes. Similarly, double homozygotes exhibit isomerism of the liver and pancreas, which are key features of abnormal gut situs. Placement of the asymmetric visceral organs relative to the midline was also perturbed by mRNA overexpression of foxc1a and foxc1b. In addition, an analysis of the left-right patterning components, identified in the lateral plate mesoderm of foxc1 mutants, reduced or abolished the expression of the NODAL antagonist lefty2. Together, these data reveal a novel contribution from foxc1 to left-right patterning, demonstrating that this role is sensitive to foxc1 gene dosage, and provide a plausible mechanism for the incidence of congenital heart defects in Axenfeld-Rieger syndrome patients.
| S-EPMC7912076 | biostudies-literature
Project description:BackgroundAnterior segment dysgenesis (ASD) disorders are a group of clinically and genetically heterogeneous phenotypes in which frequently cornea, iris, and lens are affected. This study aimed to identify novel mutations in PAX6, PITX2 and FOXC1 in families with anterior segment dysgenesis disorders.MethodsWe studied 14 Pakistani and one Mexican family with Axenfeld Rieger syndrome (ARS; n = 10) or aniridia (n = 5). All affected and unaffected family members underwent full ophthalmologic and general examinations. Total genomic DNA was isolated from peripheral blood. PCR and Sanger sequencing were performed for the exons and intron-exon boundaries of the FOXC1, PAX6, and PITX2 genes.ResultsMutations were identified in five of the 15 probands; four variants were novel and one variant was described previously. A novel de novo variant (c.225C>A; p.Tyr75*) was identified in the PAX6 gene in two unrelated probands with aniridia. In addition, a known variant (c.649C>T; p.Arg217*) in PAX6 segregated in a family with aniridia. In the FOXC1 gene, a novel heterozygous variant (c.454T>C; p.Trp152Arg) segregated with the disease in a Mexican family with ARS. A novel homozygous variant (c.92_100del; p.Ala31_Ala33del) in the FOXC1 gene segregated in a Pakistani family with ARS and congenital glaucoma.ConclusionsOur study expands the mutation spectrum of the PAX6 and FOXC1 genes in individuals with anterior segment dysgenesis disorders. In addition, our study suggests that FOXC1 mutations, besides typical autosomal dominant ARS, can also cause ARS with congenital glaucoma through an autosomal recessive inheritance pattern. Our results thus expand the disease spectrum of FOXC1, and may lead to a better understanding of the role of FOXC1 in development.
| S-EPMC4963127 | biostudies-literature
Project description:Axenfeld-Rieger syndrome (ARS) is characterized by anomalies of the anterior segment of the eye and systemic abnormalities. Mutations in the FOXC1 and PITX2 genes are underlying causes of ARS, but there has been few reports on genetically confirmed ARS in Korea. We identified a novel PITX2 mutation (c.300_301delinsT) in 2 Korean patients from a family with ARS. We expand the spectrum of PITX2 mutations and, to the best of our knowledge, this is the first confirmed family of PITX2-related ARS in Korea.
| S-EPMC3756242 | biostudies-literature
Project description:Axenfeld-Rieger syndrome is a rare autosomal dominant condition. Anomalies include anterior segment dysgenesis of the eye, dental anomalies, maxillary hypoplasia, periumbilical anomalies, and congenital heart defects. We report a patient with Peters anomaly, dysmorphic features, congenital heart defect, umbilical hernia, short stature, and developmental delay. Diagnostic sequencing of 23 genes known to be causally related to the condition was performed on the patient, parents, and maternal grandparents. A variant of uncertain significance in PITX2 was identified. The mother had the same mutation and the father did not. The mother had decreased vision, congenitally missing teeth, and required jaw surgery as a child. Her asymptomatic parents elected to be tested and were negative for the mutation. The mutation, NM_153427.2:c.272G>A (p.Arg91Gln), is predicted to be damaging by PolyPhen-2 (score of 0.997), identified as a missense mutation with an allele frequency of 1.648e-05 by the Exome Aggregation Consortium, and has been reported in ClinVar once, by the laboratory that analyzed our patient's sample. Due to the in silico predictions and the results of family studies, it is suggested that this variant can be classified as pathogenic according to the American College of Medical Genetics and Genomics 2015 rule Pathogenic(iii)(b), specifically rules PS2, PM2, PM5, PP1, and PP3.
| S-EPMC5465683 | biostudies-literature