Comprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscape

Dávid, Dezső; Freixo, João Parente; Fino, Joana; Carvalho, Inês; Marques, M.; Cardoso, Manuela; Piña-Aguilar, Raúl E.

doi:10.1007/s00439-020-02121-x

Cited by 9 publications

(16 citation statements)

References 47 publications

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“…Recently, a large‐insert genome sequencing study identified an apparently balanced translocation disrupting ANKS1B and WDR26 in a proband with a WDR26 ‐disease phenotype compatible 3 …”

Section: Introductionmentioning

confidence: 99%

Skraban‐Deardorff syndrome: Six new cases of WDR26‐related disease and expansion of the clinical phenotype

et al. 2021

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Skraban‐Deardorff syndrome (a disease related to variations in the WDR26 gene; OMIM #617616) was first described in a cohort of 15 individuals in 2017. The syndrome comprises intellectual deficiency, severe speech impairment, ataxic gait, seizures, mild hypotonia with feeding difficulties during infancy, and dysmorphic features. Here, we report on six novel heterozygous de novo pathogenic variants in WDR26 in six probands. The patients' phenotypes were consistent with original publication. One patient displayed marked hypotonia with an abnormal muscle biopsy; this finding warrants further investigation. Gait must be closely monitored, in order to highlight any musculoskeletal or neurological abnormalities and prompt further examinations. Speech therapy and alternative communication methods should be initiated early in the clinical follow‐up, in order to improve language and oral eating and drinking.

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“…Recently, a large‐insert genome sequencing study identified an apparently balanced translocation disrupting ANKS1B and WDR26 in a proband with a WDR26 ‐disease phenotype compatible 3 …”

Section: Introductionmentioning

confidence: 99%

Skraban‐Deardorff syndrome: Six new cases of WDR26‐related disease and expansion of the clinical phenotype

et al. 2021

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“…For CNVs, SVInterpreter offers an option of performing an overlap search between the query CNV and those curated in several public CNV databases and published datasets ( Supplementary Figure S2 ). The overlap specifications are similar to our previously published CNV-Content Tool ( David et al, 2020 ), which retrieves the best hit by database, with the respective overlap percentage and variant frequency. In addition to the SVInterpreter standard output table, a detailed overlap table is available for download on the output web page.…”

Section: Methodsmentioning

confidence: 99%

“…For clinical outcome prediction of a gene disruption, SVInterpreter retrieves gene-specific annotation data such as the LoF sensitivity, Genomics England PanelApp 15 data, its association with disorders and respective phenotypic overlap, animal model data, gene expression patters, and GWAS data. Concomitantly, the disruption of major genes by de novo BCA breakpoints leading to major AD developmental disorders, as retrieved by SVInterpreter, indicated the pathogenicity of ANKRD11 (OMIM *611192; proband DGRC0016) and WDR26 (OMIM *617424; proband DGRC0025) (David et al, 2020). In the abovementioned cases, the calculated similarity between the inputted phenotypes and of gene-associated disorders localized within the analyzed regions played a major part on the interpretation, where ANKRD11 PhenSSc was 2.64 (p 0.02; MaxSSc 4.01) and WDR26 PhenSSc was 2.31 (p 0.…”

Section: Retrospective Reevaluation Of Published Svsmentioning

confidence: 96%

“…These were randomly selected among those referral for clinical diagnosis, of which genomic variants were identified by CytoScan 750K (nine cases), CytoScan HD microarrays (six cases), and long-insert genomic sequencing (liGS) (five cases). Microarray and liGS analysis was carried out as previously described (David et al, 2018(David et al, , 2020.…”

Section: Svs and Clinical Casesmentioning

confidence: 99%

“…To assist the evaluation of balanced and unbalanced SVs, we previously published two useful bioinformatic tools: TAD-GConTool and CNV-ConTool . TAD-GConTool automatically defines the regions for following analysis, based on TADs affected by the breakpoints, and retrieves relevant information, whereas CNV-ConTool performs an overlap search against curated CNV databases ( David et al, 2020 ). However, they are still limited in their scope.…”

Section: Introductionmentioning

confidence: 99%

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SVInterpreter: A Comprehensive Topologically Associated Domain-Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants

et al. 2021

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With the advent of genomic sequencing, a number of balanced and unbalanced structural variants (SVs) can be detected per individual. Mainly due to incompleteness and the scattered nature of the available annotation data of the human genome, manual interpretation of the SV’s clinical significance is laborious and cumbersome. Since bioinformatic tools developed for this task are limited, a comprehensive tool to assist clinical outcome prediction of SVs is warranted. Herein, we present SVInterpreter, a free Web application, which analyzes both balanced and unbalanced SVs using topologically associated domains (TADs) as genome units. Among others, gene-associated data (as function and dosage sensitivity), phenotype similarity scores, and copy number variants (CNVs) scoring metrics are retrieved for an informed SV interpretation. For evaluation, we retrospectively applied SVInterpreter to 97 balanced (translocations and inversions) and 125 unbalanced (deletions, duplications, and insertions) previously published SVs, and 145 SVs identified from 20 clinical samples. Our results showed the ability of SVInterpreter to support the evaluation of SVs by (1) confirming more than half of the predictions of the original studies, (2) decreasing 40% of the variants of uncertain significance, and (3) indicating several potential position effect events. To our knowledge, SVInterpreter is the most comprehensive TAD-based tool to identify the possible disease-causing candidate genes and to assist prediction of the clinical outcome of SVs. SVInterpreter is available at http://dgrctools-insa.min-saude.pt/cgi-bin/SVInterpreter.py.

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Congenital heart defects in molecularly confirmed KBG syndrome patients

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Calcagni

Gnazzo

et al. 2021

American J of Med Genetics Pt A

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Congenital heart defects (CHDs) are known to occur in 9%-25% of patients with KBG syndrome. In this study we analyzed the prevalence and anatomic types of CHDs in 46 personal patients with KBG syndrome, carrying pathogenetic variants in ANKRD11 or 16q24.3 deletion, and reviewed CHDs in patients with molecular diagnosis of KBG syndrome from the literature. CHD was diagnosed in 15/40 (38%) patients with ANKRD11 variant, and in one patient with 16q24.3 deletion. Left ventricular outflow tract obstructions have been diagnosed in 9/15 (60%), subaortic or muscular ventricular septal defect in 5/15 (33%), dextrocardia in 1/15 (8%). The single patient with 16q24.3 deletion and CHD had complete atrioventricular septal defect (AVSD) with aortic coarctation. Review of KBG patients from the literature and present series showed that septal defects have been diagnosed in 44% (27/61) of the cases, left ventricular tract obstructions in 31% (19/61), AVSD in 18% (11/61).Septal defects have been diagnosed in 78% of total patients with 16q24.3 deletion.Valvar anomalies are frequently diagnosed, prevalently involving the left side of the heart. A distinctive association with AVSD is identifiable and could represent a marker to suggest the diagnosis in younger patients. In conclusion, after precise molecular diagnosis and systematic cardiological screening the prevalence of CHD in KBG syndrome seems to be higher than previously reported in clinical articles. In addition to septal defects, left-sided anomalies and AVSD should be considered. Clinical management of KBG syndrome should include accurate and detailed echocardiogram at time of diagnosis.

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Comprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscape

Abstract: Comprehensive clinically oriented workflow for nucleotide level resolution and interpretation in prenatal diagnosis of de novo apparently balanced chromosomal translocations in their genomic landscape. Human Genetics.

Cited by 9 publications

References 47 publications

Skraban‐Deardorff syndrome: Six new cases of WDR26‐related disease and expansion of the clinical phenotype

Skraban‐Deardorff syndrome: Six new cases of WDR26‐related disease and expansion of the clinical phenotype

SVInterpreter: A Comprehensive Topologically Associated Domain-Based Clinical Outcome Prediction Tool for Balanced and Unbalanced Structural Variants

Congenital heart defects in molecularly confirmed KBG syndrome patients

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