Genetics of anterior segment dysgenesis disorders

Reis, Linda M.; Semina, Elena V.

doi:10.1097/icu.0b013e328349412b

Cited by 141 publications

(132 citation statements)

References 93 publications

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“…Anterior segment dysgenesis and pediatric glaucoma are highly heterogeneous conditions. While a number of genes have been found to play a role in these disorders, including CYP1B1 (MIM: 601771), LTBP2 (MIM: 602091), MYOC (MIM: 601652), FOXC1 (MIM: 601090), PAX6 (MIM: 607108), and PITX2 (MIM: 601542) (Khan 2011; Reis and Semina 2011), many cases are still awaiting molecular diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole‐exome sequencing (WES) and whole‐genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37‐bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled‐coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult‐onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis‐regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss‐of‐function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu‐mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu‐mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role of this region, if any, in human disease.

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Section: Introductionmentioning

confidence: 99%

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Schilter

Reis

Сорокина

et al. 2015

Molec Gen & Gen Med

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“…Disease-causing mutations outside of the coding region have been identified in other genes; for example, deletion of the downstream regulatory region of PAX6 was found in a number of families affected with aniridia. 2,30 Disruption of the regulatory regions of genes should be considered as a mechanism for other conditions not fully explained by intragenic mutations.…”

Section: Foxc1 Mutations: Phenotypes and Genotypesmentioning

confidence: 99%

“…1,2 One common form of ASD is Axenfeld-Rieger syndrome (ARS), characterized by specific ocular anomalies with or without systemic abnormalities. Ocular findings include posterior embryotoxon, iris malformation, corectopia/polycoria, irido-corneal adhesions, and B50% risk for glaucoma.…”

Section: Introductionmentioning

confidence: 99%

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

Reis¹,

Tyler²,

et al. 2012

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Anterior segment dysgenesis (ASD) encompasses a broad spectrum of developmental conditions affecting anterior ocular structures and associated with an increased risk for glaucoma. Various systemic anomalies are often observed in ASD conditions such as Axenfeld-Rieger syndrome (ARS) and De Hauwere syndrome. We report DNA sequencing and copy number analysis of PITX2 and FOXC1 in 76 patients with syndromic or isolated ASD and related conditions. PITX2 mutations and deletions were found in 24 patients with dental and/or umbilical anomalies seen in all. Seven PITX2-mutant alleles were novel including c.708_730del, the most C-terminal mutation reported to date. A second case of deletion of the distant upstream but not coding region of PITX2 was identified, highlighting the importance of this recently discovered mechanism for ARS. FOXC1 deletions were observed in four cases, three of which demonstrated hearing and/or heart defects, including a patient with De Hauwere syndrome; no nucleotide mutations in FOXC1 were identified. Review of the literature identified several other patients with 6p25 deletions and features of De Hauwere syndrome. The 1.3-Mb deletion of 6p25 presented here defines the critical region for this phenotype and includes the FOXC1, FOXF2, and FOXQ1 genes. In summary, PITX2 or FOXC1 disruptions explained 63% of ARS and 6% of other ASD in our cohort; all affected patients demonstrated additional systemic defects with PITX2 mutations showing a strong association with dental and/or umbilical anomalies and FOXC1 with heart and hearing defects. FOXC1 deletion was also found to be associated with De Hauwere syndrome.

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“…In AM cases, the genetic basis, either monogenic or chromosomal, is identified in ∼20%-40% of individuals who undergo genetic testing (Slavotinek 2011;Chassaing et al 2014). ASD disorders encompass a wide variety of developmental conditions affecting the cornea, iris, and lens including corneal opacity, posterior embryotoxon, iris hypoplasia, corectopia or polycoria, and adhesions between the iris and cornea or lens and cornea (Reis and Semina 2011). 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).…”

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confidence: 99%

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

et al. 2016

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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.

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Genetics of anterior segment dysgenesis disorders

Cited by 141 publications

References 93 publications

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype

PITX2 and FOXC1 spectrum of mutations in ocular syndromes

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

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