Whole exome sequencing reveals a novel de novo FOXC1 mutation in a patient with unrecognized Axenfeld–Rieger syndrome and glaucoma

Pasutto, Francesca; Mauri, Lucia; Popp, Bernt; Sticht, Heinrich; Ekici, Arif B.; Piozzi, Elena; Bonfante, Aldo; Penco, Silvana; Schlötzer‐Schrehardt, Ursula; Reis, André

doi:10.1016/j.gene.2015.05.015

Cited by 12 publications

(13 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Two of the four FOXC1 carriers had hearing loss and the other two PITX2 carriers had dental and/or umbilical anomalies, none of which had been recorded before the molecular diagnosis. Individuals with variants in FOXC1 or PITX2 but without ocular features of ARS have been reported before, 15, 27, 28 and in some individuals ARM can be so mild that it results in a clinical diagnosis of PCG or POAG. The variable expressivity associated with FOXC1 and PITX2 variants can make clinical diagnosis of ARS challenging, especially in the absence of ARM.…”

Section: Discussionmentioning

confidence: 89%

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

et al. 2017

View full text Add to dashboard Cite

Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.

show abstract

Section: Discussionmentioning

confidence: 89%

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Two clinically distinct ASD disorders have been recognized as separate entities based on unique combinations of diagnostic criteria: Axenfeld-Rieger anomaly (iris hypoplasia, posterior embryotoxon, iris hypoplasia, corectopia/polycoria, and/or irido-corneal adhesions) and Peters anomaly (corneal opacity, defects in the posterior layers of the cornea, and lenticulo-corneal and/or irido-corneal adhesions). Causative mutations are identified in ∼40% of individuals with Axenfeld-Rieger anomaly, mainly in two genes, PITX2 and FOXC1 (Pasutto et al 2015). Despite the fact that thirteen genes have been associated with Peters anomaly, the genetic basis of this ocular anomaly remains unknown in the majority of cases (Weh et al 2014).…”

mentioning

confidence: 99%

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

et al. 2016

View full text Add to dashboard Cite

Ocular developmental anomalies (ODA) such as anophthalmia/microphthalmia (AM) or anterior segment dysgenesis (ASD) have an estimated combined prevalence of 3.7 in 10,000 births. Mutations in SOX2 are the most frequent contributors to severe ODA, yet account for a minority of the genetic drivers. To identify novel ODA loci, we conducted targeted highthroughput sequencing of 407 candidate genes in an initial cohort of 22 sporadic ODA patients. Patched 1 (PTCH1), an inhibitor of sonic hedgehog (SHH) signaling, harbored an enrichment of rare heterozygous variants in comparison to either controls, or to the other candidate genes (four missense and one frameshift); targeted resequencing of PTCH1 in a second cohort of 48 ODA patients identified two additional rare nonsynonymous changes. Using multiple transient models and a CRISPR/Cas9-generated mutant, we show physiologically relevant phenotypes altering SHH signaling and eye development upon abrogation of ptch1 in zebrafish for which in vivo complementation assays using these models showed that all six patient missense mutations affect SHH signaling. Finally, through transcriptomic and ChIP analyses, we show that SOX2 binds to an intronic domain of the PTCH1 locus to regulate PTCH1 expression, findings that were validated both in vitro and in vivo. Together, these results demonstrate that PTCH1 mutations contribute to as much as 10% of ODA, identify the SHH signaling pathway as a novel effector of SOX2 activity during human ocular development, and indicate that ODA is likely the result of overactive SHH signaling in humans harboring mutations in either PTCH1 or SOX2.

show abstract

“…O diagnóstico e tratamento precoce poderiam ter prevenido a perda severa na acuidade visual. 10 Quanto à conduta, quadros como esse são restritos a abordagens tópicas e cirurgias fistulizantes (como implantação de shunt para glaucoma e trabeculectomia clássica). 9,11 Observa-se na literatura que a indicação da TREC foi feita corretamente.…”

Section: Discussionunclassified

“…1,2,3,5,6 Dessa forma, faz-se necessário o reconhecimento precoce da SAR a fim de proporcionar um manejo clínico e cirúrgico adequados, com intuito de preservar a função visual dos pacientes e evitar uma evolução desfavorável como no caso relatado. 7,9,10,11…”

Section: Conclusãounclassified

Síndrome de Axenfeld-Rieger: a importância do diagnóstico precoce e da avaliação oftalmológica

Beneti¹,

Barbosa²,

Faria³

et al. 2018

Revista Médica De Minas Gerais

View full text Add to dashboard Cite

A síndrome de Axenfeld-Rieger (SAR) é uma doença de origem hereditária com padrão autossômico dominante, com incidência de 1 em 200000 pacientes, caracterizada por distúrbios heterogêneos oculares e sistêmicos. As alterações oculares são geralmente bilaterais e afetam principalmente a íris, a córnea, a linha de Schwalbe e ângulo da câmara. Dentre as manifestações não oculares estão as malformações cardíacas e renais, pele periumbilical redundante, malformações auriculares e alterações hipofisárias. O objetivo do presente trabalho é relatar um caso de SAR de diagnóstico tardio associada a glaucoma, com evolução para dano visual grave, em paciente com diversas alterações oftalmológicas e sistêmicas, ressaltando a importância do reconhecimento precoce da SAR a fim de proporcionar um manejo clínico e cirúrgico adequados, com intuito de preservar a função visual dos pacientes e evitar prognóstico desfavorável. Palavras-chave: Glaucoma secundário, Disgenesia do segmento anterior, Embriotoxon posterior, atrofia iriana, microcornea, anodontia, Síndrome de Axenfeld Rieger.

show abstract

Whole exome sequencing reveals a novel de novo FOXC1 mutation in a patient with unrecognized Axenfeld–Rieger syndrome and glaucoma

Cited by 12 publications

References 44 publications

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants

Targeted resequencing identifies PTCH1 as a major contributor to ocular developmental anomalies and extends the SOX2 regulatory network

Síndrome de Axenfeld-Rieger: a importância do diagnóstico precoce e da avaliação oftalmológica

Contact Info

Product

Resources

About