Whole‐genome copy number variation analysis in anophthalmia and microphthalmia

Schilter, Kala F.; Reis, Linda M.; Schneider, Adele; Bardakjian, Tanya; Abdul‐Rahman, Omar; Kozel, Beth A.; Zimmerman, Holly H.; Broeckel, Ulrich; Semina, Elena V.

doi:10.1111/cge.12202

Cited by 44 publications

(42 citation statements)

References 45 publications

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“…2013). The Database of Genomic Variants (http://projects.tcag.ca/variation/) was used as a control population along with 30 unaffected in‐house controls; a control population specifically matched to the patient's Trinidad and Tobago ancestry was not available.…”

Section: Methodsmentioning

confidence: 99%

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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: Methodsmentioning

confidence: 99%

“…Data were evaluated for mutations in 203 genes known to be involved in ocular development (Schilter et al. 2013) through the Geospiza GeneSifter Analysis program hosted through Perkin Elmer Bioinformatics. The entire exome was analyzed using the SNP & Variation Suite (SVS; Golden Helix, Bozeman, MT) as previously described (Deml et al.…”

Section: Methodsmentioning

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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“…Whereas mental (with often behavioral) impairment is almost always present, obesity, microcephaly, facial dysmorphism, skeletal and heart anomalies were observed with lower frequencies. Moreover, a single case with the typical dup3q29 presented with isolated anophthalmia , enlarging the clinical heterogeneity associated with the duplication 3q29 syndrome. In another patient with hemifacial microsomia (OMIM %164210) the 0.7 Mb duplication also affected region 3q29, but located proximal to the typical region .…”

Section: Phenotypic Features Of Patients With ‘Pure’ Duplication 3qmentioning

confidence: 96%

“…The female reported by Rosenberg et al also showed a paternally inherited dup3q29, associated with MI, facial dysmorphism and ataxia. Subsequently, Lisi et al , defined the dup3q29 syndrome and at least 25 patients have been described yet . However, several patients showed overlapping or smaller duplications or a dup3q29, that only bordered the common deleted region and these were excluded in a phenotype review provided by Fernández‐Jaén et al .…”

Section: Phenotypic Features Of Patients With ‘Pure’ Duplication 3qmentioning

confidence: 99%

Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32‐q27.2

et al. 2016

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Partial duplications of the long arm of chromosome 3, dup(3q), are a rare but well-described condition, sharing features of Cornelia de Lange syndrome. Around two thirds of cases are derived from unbalanced translocations, whereas pure dup(3q) have rarely been reported. Here, we provide an extensive review of the literature on dup(3q). This search revealed several patients with caudal malformations and anomalies, suggesting that caudal malformations or anomalies represent an inherent phenotypic feature of dup(3q). In this context, we report a patient with a pure de novo duplication 3q26.32-q27.2. The patient had the clinical diagnosis of Currarino syndrome (CS) (characterized by the triad of sacral anomalies, anorectal malformations and a presacral mass) and additional features, frequently detected in patients with a dup(3q). Mutations within the MNX1 gene were found to be causative in CS but no MNX1 mutation could be detected in our patient. Our comprehensive search for candidate genes located in the critical region of the duplication 3q syndrome, 3q26.3-q27, revealed a so far neglected phenotypic overlap of dup(3q) and the Pierpont syndrome, associated with a mutation of the TBL1XR1 gene on 3q26.32.

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“…Thus, such analysis benefits from additional biological insights through iSyTE . Indeed, several studies have successfully applied iSyTE in their investigations of eye and lens defects in human patients, namely for: 1) prioritization of novel candidate genes for pediatric cataract (Aldahmesh et al, 2012); 2) prioritization of promising candidates for anophthalmia and microphthalmia (Schilter et al, 2013); 3) linking ADAMTS18 in ocular syndrome in microcornea and myopia (Aldahmesh et al, 2013), 4) linking STX3 to congenital cataract (Chograni et al, 2014), and 5) identifying ASPH mutations that are associated with Traboulsi syndrome with ocular lens dislocation (Patel et al, 2014). Further, in 2012 iSyTE correctly predicted SIPA1l3 as a cataract-linked gene (Fig.…”

Section: Future Of Lens Research: Toward Lens Systems Biologymentioning

confidence: 99%

Systems biology of lens development: A paradigm for disease gene discovery in the eye

Anand

Lachke

2017

Experimental Eye Research

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Over the past several decades, the biology of the developing lens has been investigated using molecular genetics-based approaches in various vertebrate model systems. These efforts, involving target gene knockouts or knockdowns, have led to major advances in our understanding of lens morphogenesis and the pathological basis of cataracts, as well as of other lens related eye defects. In particular, we now have a functional understanding of regulators such as Pax6, Six3, Sox2, Oct1 (Pou2f1), Meis1, Pnox1, Zeb2 (Sip1), Mab21l1, Foxe3, Tfap2a (Ap2-alpha), Pitx3, Sox11, Prox1, Sox1, c-Maf, Mafg, Mafk, Hsf4, Fgfrs, Bmp7, and Tdrd7 in this tissue. However, whether these individual regulators interact or their targets overlap, and the significance of such interactions during lens morphogenesis, is not well defined. The arrival of high-throughput approaches for gene expression profiling (microarrays, RNA-sequencing (RNA-seq), etc.), which can be coupled with chromatin immunoprecipitation (ChIP) or RNA immunoprecipitation (RIP) assays, along with improved computational resources and publically available datasets (e.g. those containing comprehensive protein-protein, protein-DNA information), presents new opportunities to advance our understanding of the lens tissue on a global systems level. Such systems-level knowledge will lead to the derivation of the underlying lens gene regulatory network (GRN), defined as a circuit map of the regulator-target interactions functional in lens development, which can be applied to expedite cataract gene discovery. In this review, we cover the various systems-level approaches such as microarrays, RNA-seq, and ChIP that are already being applied to lens studies and discuss strategies for assembling and interpreting these vast amounts of high-throughput information for effective dispersion to the scientific community. In particular, we discuss strategies for effective interpretation of this new information in the context of the rich knowledge obtained through the application of traditional single-gene focused experiments on the lens. Finally, we discuss our vision for integrating these diverse high-throughput datasets in a single web-based user-friendly tool iSyTE (integrated Systems Tool for Eye gene discovery) – a resource that is already proving effective in the identification and characterization of genes linked to lens development and cataract. We anticipate that application of a similar approach to other ocular tissues such as the retina and the cornea, and even other organ systems, will significantly impact disease gene discovery.

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Whole‐genome copy number variation analysis in anophthalmia and microphthalmia

Cited by 44 publications

References 45 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

Comprehensive review of the duplication 3q syndrome and report of a patient with Currarino syndrome and de novo duplication 3q26.32‐q27.2

Systems biology of lens development: A paradigm for disease gene discovery in the eye

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