Wolf-Hirschhorn Syndrome with Epibulbar Dermoid: An Unusual Association in a Patient with 4p Deletion and Functional Xp Disomy

Bragagnolo, Silvia; Colovati, Mileny Esbravatti Stephano; Guilherme, Roberta Santos; Dantas, Anelisa Gollo; Souza, Malú Zamariolli de; Soares, Maria F. de; Melaragno, Maria Isabel; Pérez, Ana B.

doi:10.1159/000452237

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…In addition, the CNV algorithm enables the detection of terminal deletions/duplications, which are often associated with severe disorders. The two samples with terminal deletions, 1p36.33p36.32, and 4p16.3p15.31 included in this study were detected by OGM and are associated with chromosome 1p36 deletion syndrome (OMIM #607872) and Wolf-Hirschhorn syndrome [ 23 ], respectively.…”

Section: Discussionmentioning

confidence: 99%

Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing

Sahajpal

Mondal

Fee

et al. 2022

Preprint

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The standard-of-care (SOC) diagnostic prenatal testing includes a combination of cytogenetic methods such as karyotyping, fluorescence in situ hybridization (FISH), and chromosomal microarray (CMA) using either direct or cultured amniocytes or chorionic villi sampling (CVS). However, each technology has its limitations: karyotyping has a low resolution (>5Mb), FISH is targeted, and CMA does not detect balanced structural variants (SVs) or decipher complex rearrangements in the genome. These limitations necessitate the use of multiple tests, either simultaneously or sequentially to reach a genetic diagnosis. This long-standing prenatal testing workflow demonstrates the need for an alternative technology that can provide high-resolution results in a cost and time-effective manner. Optical genome mapping (OGM) is an emerging technology that has demonstrated its ability to detect all classes of SVs, including copy number variations (CNVs) and balanced abnormalities in a single assay, but has not been evaluated in the prenatal setting. This retrospective validation study analyzed 114 samples (including replicates), representing 94 unique and well-characterized samples that were received in our laboratory for traditional cytogenetic analysis with karyotyping, FISH, and/or CMA. Samples comprised 84 cultured amniocytes, and 10 phenotypically normal and cytogenetically negative controls. Six samples were run in triplicate to evaluate intra-run, inter-run, and inter-instrument reproducibility. Clinically relevant SVs and CNVs were reported using the Bionano Access software with standardized and built-in filtration criteria and phenotype-specific analysis. OGM was 100% concordant in identifying the 101 aberrations that included 29 interstitial/terminal deletions, 28 duplications, 26 aneuploidies, 6 absence of heterozygosity (AOH), 3 triploid genomes, 4 Isochromosomes, 1 translocation, and revealed the identity of 3 marker chromosomes, and 1 chromosome with additional material not determined by karyotyping. Additionally, OGM detected 64 additional clinically reportable SVs in 43 samples. OGM demonstrated high technical and analytical robustness and a limit of detection of 5% allele fraction for interstitial deletions and duplications, and 10% allele fraction for translocation and aneuploidy. This study demonstrates that OGM has the potential to identify unique genomic abnormalities such as CNVs, AOHs, and several classes of SVs including complex structural rearrangements. OGM has a standardized laboratory workflow and reporting solution that can be adopted in routine clinical laboratories and demonstrates the potential to replace the current SOC methods for prenatal diagnostic testing. We recommend its use as a first-tier genetic diagnostic test in a prenatal setting.

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Section: Discussionmentioning

confidence: 99%

Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing

Sahajpal

Mondal

Fee

et al. 2022

Preprint

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“…All samples used in this study were collected after written appropriate informed consent and approval of the local ethics committee (CONEP 36019314.9.0000.5505, CEP 0028/2015). Of note, clinical and cytogenomic evaluation for patients 1, 4, 5, 6, 7, 8, and 10 had previously been reported [6][7][8][9]. However, most rearrangements had not been mapped to sequence resolution, except for patients 6 and 8 who were previously described in clinical studies [8,9].…”

Section: Enrollmentmentioning

confidence: 99%

“…Of note, clinical and cytogenomic evaluation for patients 1, 4, 5, 6, 7, 8, and 10 had previously been reported [6][7][8][9]. However, most rearrangements had not been mapped to sequence resolution, except for patients 6 and 8 who were previously described in clinical studies [8,9]. The clinical description of all patients, the molecular characterization of their rearrangements and their expression profiles are described in detail in Supplementary Case Reports.…”

Section: Enrollmentmentioning

confidence: 99%

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Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes

et al. 2019

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Precise breakpoint mapping of balanced chromosomal rearrangements is crucial to identify disease etiology. Ten female patients with X-autosome balanced translocations associated with phenotypic alterations were evaluated, by mapping and sequencing their breakpoints. The rearrangements' impact on the expression of disrupted genes, and inferred mechanisms of formation in each case were assessed. For four patients that presented one of the chromosomal breaks in heterochromatic and highly repetitive segments, we combined cytogenomic methods and short-read sequencing to characterize, at nucleotide resolution, breakpoints that occurred in reference genome gaps. Most of rearrangements were possibly formed by nonhomologous end joining and have breakpoints at repeat elements. Seven genes were found to be disrupted in six patients. Six of the affected genes showed altered expression, and the functional impairment of three of them were considered pathogenic. One gene disruption was considered potentially pathogenic, and three had uncertain clinical significance. Four patients presented no gene disruptions, suggesting other pathogenic mechanisms. Four genes were considered potentially affected by position effect and the expression abrogation of one of them was confirmed. This study emphasizes the importance of breakpoint-junction characterization at nucleotide resolution in balanced rearrangements to reveal genetic mechanisms associated with the patients' phenotypes, mechanisms of formation that originated the rearrangements, and genomic nature of disrupted DNA sequences.

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Clinical and cytogenomic findings in OAV spectrum

Bragagnolo

Colovati

Souza

et al. 2018

American J of Med Genetics Pt A

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The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.

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Wolf-Hirschhorn Syndrome with Epibulbar Dermoid: An Unusual Association in a Patient with 4p Deletion and Functional Xp Disomy

Cited by 7 publications

References 27 publications

Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing

Clinical Validation and Diagnostic Utility of Optical Genome Mapping in Prenatal Diagnostic Testing

Breakpoint mapping at nucleotide resolution in X-autosome balanced translocations associated with clinical phenotypes

Clinical and cytogenomic findings in OAV spectrum

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