Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome

Krawczyńska, Natalia; Wierzba, Jolanta; Wasąg, Bartosz

doi:10.3389/fped.2019.00203

Cited by 15 publications

(10 citation statements)

References 23 publications

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“…Deep DNA sequencing. Mosaicism, defined as the presence of genetically different cells in an individual, has long been recognized to play a significant role in a subset of RGDs (12,74); for example, 30% of patients with Cornelia de Lange syndrome (49,62) and more than 85% of patients with PIK3CA-associated segmental overgrowth (76) carry mosaic variants as the cause of their disease. Mosaicism is technically and analytically challenging to detect.…”

Section: 21mentioning

confidence: 99%

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases

Hartley

Lemire

Kernohan

et al. 2020

Annu. Rev. Genom. Hum. Genet.

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Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: 21mentioning

confidence: 99%

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases

Hartley

Lemire

Kernohan

et al. 2020

Annu. Rev. Genom. Hum. Genet.

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“…Additionally, 23% of CdLS probands without detectable mutation in lymphocytes were found to carry a NIPBL mutation in buccal cells (Huisman et al, 2013). Furthermore, mosaic variants were found in 4 out of 13 (30.8%) patients negative for germline alterations (Krawczynska et al, 2019). In our study, all the variants appeared to be de novo mutations in the patients because they were absent in the blood of both parents.…”

Section: Discussionmentioning

confidence: 44%

Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients

Peng

Liang

et al. 2021

Front. Genet.

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Cornelia de Lange syndrome (CdLS) is a genetic disorder characterized by multisystemic malformations. Mutation in the NIPBL gene accounts for nearly 60% of the cases. This study reports the clinical and genetic findings of three cases of CdLS from unrelated Chinese families. Clinically, all the three cases were classified as classic CdLS based on the cardinal (distinctive facial features and limb malformations) and suggestive (developmental delay, growth retardation, microcephaly, hirsutism, etc.) manifestations. SNP array detected a novel de novo heterozygous microdeletion of 0.2 Mb [arr[GRCh37]5p13.2(36848530_37052821) × 1] that spans the first 43 exons of NIPBL in the fetus with nuchal translucency thickening in case 1. Whole-exome sequencing in family trios plus Sanger sequencing validation identified a de novo heterozygous NIPBL c.5566G>A (p.R1856G) mutation in the fetus with intrauterine growth retardation in case 2 and a novel de novo heterozygous NIPBL c.448dupA (p.S150Kfs*23) mutation in the proband (an 8-month-old girl) in case 3. The cases presented in this study may serve as references for increasing our understanding of the mutation spectrum of NIPBL in association with CdLS.

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“…Mosaicism is known to be a factor in a range of pediatric NDs ( Figure 2 ), including autism (estimated to contribute 3–5% of simplex ASD risk), Cornelia de Lange syndrome (MIM# 122470), Proteus syndrome (MIM# 176920), Sturge–Weber syndrome (MIM# 185300), MCAP syndrome (MIM# 602501), and some epilepsies [ 28 , 57 , 58 , 59 , 60 , 61 , 62 ]. It is also likely responsible for up to 30% of cases in disorders of neuronal migration [ 63 ].…”

Section: Maximizing the Use Of Information In Existing Sequence Datamentioning

confidence: 99%

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Kadlubowska

Schrauwen

2022

Genes

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During the last decade, genetic testing has emerged as an important etiological diagnostic tool for Mendelian diseases, including pediatric neurological conditions. A genetic diagnosis has a considerable impact on disease management and treatment; however, many cases remain undiagnosed after applying standard diagnostic sequencing techniques. This review discusses various methods to improve the molecular diagnostic rates in these genomic cold cases. We discuss extended analysis methods to consider, non-Mendelian inheritance models, mosaicism, dual/multiple diagnoses, periodic re-analysis, artificial intelligence tools, and deep phenotyping, in addition to integrating various omics methods to improve variant prioritization. Last, novel genomic technologies, including long-read sequencing, artificial long-read sequencing, and optical genome mapping are discussed. In conclusion, a more comprehensive molecular analysis and a timely re-analysis of unsolved cases are imperative to improve diagnostic rates. In addition, our current understanding of the human genome is still limited due to restrictions in technologies. Novel technologies are now available that improve upon some of these limitations and can capture all human genomic variation more accurately. Last, we recommend a more routine implementation of high molecular weight DNA extraction methods that is coherent with the ability to use and/or optimally benefit from these novel genomic methods.

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Genetic Mosaicism in a Group of Patients With Cornelia de Lange Syndrome

Cited by 15 publications

References 23 publications

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases

New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases

Case Report: Novel NIPBL Variants Cause Cornelia de Lange Syndrome in Chinese Patients

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

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