Somatic mosaicism in a Cornelia de Lange syndrome patient with <i><scp>NIPBL</scp></i> mutation identified by different next generation sequencing approaches

Baquero-Montoya, Carolina; Gil-Rodríguez, María Concepción; Braunholz, Diana; Teresa-Rodrigo, María Esperanza; Obieglo, Carolin; Gener, Blanca; Schwarzmayr, Thomas; Strom, Tim M.; Gómez‐Puertas, Paulino; Puisac, Beatriz; Gillessen‐Kaesbach, Gabriele; Musio, Antonio; Ramos, Feliciano J.; Kaiser, Frank J.; Pié, Juan

doi:10.1111/cge.12333

Cited by 18 publications

(22 citation statements)

References 5 publications

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“…Other reports support a postzygotic event. Indeed, somatic mosaicism has already been identified on leukocytes for four different NIPBL mutations, namely a large intragenic deletion, a frame shift, a nonsense and a missense mutation, by array‐comparative genomic hybridisation, pyrosequencing and exome sequencing, respectively . Almost 50% of patients negative for NIPBL mutation in leucocytes are predicted to have a somatic mosaicism Embryological data are in agreement with these results.…”

Section: Discussionsupporting

confidence: 61%

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome

et al. 2016

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Cornelia de Lange syndrome is a multisystemic developmental disorder mainly related to de novo heterozygous NIPBL mutation. Recently, NIPBL somatic mosaicism has been highlighted through buccal cell DNA study in some patients with a negative molecular analysis on leukocyte DNA. Here, we present a series of 38 patients with a Cornelia de Lange syndrome related to a heterozygous NIPBL mutation identified by Sanger sequencing. The diagnosis was based on the following criteria: (i) intrauterine growth retardation and postnatal short stature, (ii) feeding difficulties and/or gastro-oesophageal reflux, (iii) microcephaly, (iv) intellectual disability, and (v) characteristic facial features. We identified 37 novel NIPBL mutations including 34 in leukocytes and 3 in buccal cells only. All mutations shown to have arisen de novo when parent blood samples were available. The present series confirms the difficulty in predicting the phenotype according to the NIPBL mutation. Until now, somatic mosaicism has been observed for 20 cases which do not seem to be consistently associated with a milder phenotype. Besides, several reports support a postzygotic event for those cases. Considering these elements, we recommend a first-line buccal cell DNA analysis in order to improve gene testing sensitivity in Cornelia de Lange syndrome and genetic counselling.

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Section: Discussionsupporting

confidence: 61%

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome

et al. 2016

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“…Mutation analyses by Ion AmpliSeq‐Ion PGM were performed as described previously [Ansari et al., ; Baquero‐Montoya et al., ; Braunholz et al., ]. Briefly, 10–20 ng of genomic DNA were amplified using custom‐designed gene panels (Ion AmpliSeq ™ ; Life Technologies, Darmstadt, Germany) to cover the coding exons of the known CdLS genes, including approximately 90% of the coding sequence of SMC3 (NC_000010) and its splice junctions in particular.…”

Section: Methodsmentioning

confidence: 99%

“…Almost all cases are sporadic with de novo heterozygous loss‐of‐function mutations in NIPBL (MIM #608667) being the most common genetic finding in typical CdLS [Gillis et al., ; Krantz et al., ; Tonkin et al., ; Selicorni et al., ; Pie et al., ; Wierzba et al., ]. A proportion of the “ NIPBL ‐negative” cases with typical CdLS have recently been shown to have mosaic NIPBL mutations, often undetected in the blood by Sanger‐based screening [Huisman et al., ; Ansari et al., ; Baquero‐Montoya et al., ; Braunholz et al., ]. Mutations in four other genes have been reported to account for a smaller proportion of mostly atypical cases; SMC1A (MIM #300040) on chromosome Xp11 (∼4%–6%), SMC3 (MIM #606062) on chromosome 10q25 (<1%), RAD21 (MIM #606462) on chromosome 8q24 (<1%), and HDAC8 (MIM #300269) on chromosome Xq13 (4%) [Musio et al., ; Deardorff et al., , , ; Kaiser et al., ; Minor et al., ].…”

Section: Introductionmentioning

confidence: 99%

De NovoHeterozygous Mutations inSMC3Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

et al. 2015

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“…Recent findings indicate a high percentage of CdLS‐causing mosaic mutations in NIPBL that were previously excluded by conventional Sanger sequencing approaches using DNA isolated from blood samples [Castronovo et al., ; Huisman et al., ; Baquero‐Montoya et al., ]. Huisman et al.…”

Section: Application and Analysis Of Different Sequencing Methods In mentioning

confidence: 99%

Hidden Mutations in Cornelia de Lange Syndrome Limitations of Sanger Sequencing in Molecular Diagnostics

et al. 2014

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Cornelia de Lange syndrome (CdLS) is a well-characterized developmental disorder. The genetic cause of CdLS is a mutation in one of five associated genes (NIPBL, SMC1A, SMC3, RAD21, and HDAC8) accounting for about 70% of cases. To improve our current molecular diagnostic and to analyze some of CdLS candidate genes, we developed and established a gene panel approach. Because recent data indicate a high frequency of mosaic NIPBL mutations that were not detected by conventional sequencing approaches of blood DNA, we started to collect buccal mucosa (BM) samples of our patients that were negative for mutations in the known CdLS genes. Here, we report the identification of three mosaic NIPBL mutations by our high-coverage gene panel sequencing approach that were undetected by classical Sanger sequencing analysis of BM DNA. All mutations were confirmed by the use of highly sensitive SNaPshot fragment analysis using DNA from BM, urine, and fibroblast samples. In blood samples, we could not detect the respective mutation. Finally, in fibroblast samples from all three patients, Sanger sequencing could identify all the mutations. Thus, our study highlights the need for highly sensitive technologies in molecular diagnostic of CdLS to improve genetic diagnosis and counseling of patients and their families.

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Somatic mosaicism in a Cornelia de Lange syndrome patient with NIPBL mutation identified by different next generation sequencing approaches

Cited by 18 publications

References 5 publications

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome

A series of 38 novel germline and somatic mutations of NIPBL in Cornelia de Lange syndrome

De NovoHeterozygous Mutations inSMC3Cause a Range of Cornelia de Lange Syndrome-Overlapping Phenotypes

Hidden Mutations in Cornelia de Lange Syndrome Limitations of Sanger Sequencing in Molecular Diagnostics

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