A series of 38 novel germline and somatic mutations of <i><scp>NIPBL</scp></i> in Cornelia de Lange syndrome

Nizon, Mathilde; Henry, Marcia; Michot, Caroline; Baumann, Clarisse; Bazin, Anne; Bessières, Bettina; Blesson, Sophie; Cordier-Alex, Marie-Pierre; David, Albert; Delahaye‐Duriez, Andrée; Delezoide, Anne‐Lise; Dieux-Coëslier, Anne; Doco‐Fenzy, Martine; Faivre, Laurence; Goldenberg, Alice; Layet, Valérie; Loget, Philippe; Marlin, Sandrine; Martinovic, Jéléna; Odent, Sylvie; Pasquier, Laurent; Plessis, Ghislaine; Prieur, Fabienne; Putoux, Audrey; Rio, Marlène; Testard, H.; Bonnefont, Jean‐Paul; Cormier‐Daire, Valérie

doi:10.1111/cge.12720

Cited by 21 publications

(19 citation statements)

References 19 publications

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“…No large rearrangements of the NIPBL were identified in the patients analyzed. The frequency of alterations detected in this study was lower compared to the previous reports (31,9% vs. 60–80%) (2, 16–18). This low rate of detected alterations can be explained by selection bias since 15 previously NIPBL -negative patients were included in the study (10).…”

Section: Discussioncontrasting

confidence: 94%

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

2019

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Background: Cornelia de Lange Syndrome (CdLS) is a heterogeneous disorder. Diverse expression of clinical symptoms can be caused by a variety of pathogenic variants located within the sequence of different genes correlated with the cohesin complex. Methods: Sixty-nine patients with confirmed clinical diagnosis of CdLS were enrolled in the study. Blood and buccal swab samples were collected for molecular studies. Mutational analysis was performed using the Next Generation (deep) Sequencing (NGS) covering 24 genes. In addition, the MLPA technique was applied to detect large rearrangements of NIPBL . Results: MLPA and NGS analysis were performed in 66 (95,7%) and 67 (97,1%) patients, respectively. Large rearrangements of NIPBL were not identified in the studied group. Germline pathogenic variants were detected in 18 (26,1%) patients. Fourteen variants (20,3%) were identified in NIPBL , two (2,9%) in SMC1A , and two (2,9%) in HDAC8 . In total, 13 (18,8%) buccal swabs were suitable for deep sequencing. Mosaic variants were found in four (30,8%; 4/13) patients negative for germline alterations. Three mosaic substitutions were detected in NIPBL while one in KMT2A gene. Conclusions: Comprehensive and sensitive molecular techniques allow detecting novel pathogenic variants responsible for the molecular basis of CdLS. In addition, molecular testing of different tissues should be applied since such an approach allows detect mosaic variants specific for a subgroup of CdLS patients. Finally, to test possible pathogenicity of intronic variants, RNA analysis should be conducted.

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Section: Discussioncontrasting

confidence: 94%

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

2019

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“…In a questionnaire study, GERD was more common in individuals with NIPBL variants (71%) than in those with SMC1A variants (60%) 3 . In a small series of 38 individuals with NIPBL variants, 55% had GERD 91 , and in a series of 43 clinically diagnosed individuals, the disease was more common in those with classic phenotypes (known to be caused predominantly by NIPBL variants) 92 . In this study group, aged 6-32 years, 65% of participants demonstrated inflammation of the lining of the oesophagus (oesophagitis) at endoscopy.…”

Section: Organ System Manifestations Gastroenterologymentioning

confidence: 97%

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

et al. 2018

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Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

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“…It is caused by genetic alterations in NIPBL , SMC1A , SMC3 , HDAC8 , and RAD21 ( Krantz et al, 2004 ; Tonkin et al, 2004 ; Musio et al, 2006 ; Deardorff et al, 2007 , 2012a , b ). To date, genetic alterations in NIPBL have been detected in approximately 70% of CdLS patients (OMIM: 608667) ( Nizon et al, 2016 ). Genetic variants affecting gene splicing account for 15% of NIPBL mutations ( Mannini et al, 2013 ; Teresa-Rodrigo et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Mosaic Intronic NIPBL Variant in a Family With Cornelia de Lange Syndrome

et al. 2018

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Cornelia de Lange Syndrome (CdLS) is a well described multiple malformation syndrome caused by alterations in genes encoding subunits or regulators of the cohesin complex. In approximately 70% of CdLS patients, pathogenic NIPBL variants are detected and 15% of them are predicted to affect splicing. Moreover, a large portion of genetic variants in NIPBL was shown to be somatic mosaicism. Here we report two family members with different expression of the CdLS phenotype. In both individuals, a c.869-2A>G (r.869_1495del) substitution was detected, affecting a conserved splice-acceptor site. Deep sequencing revealed the presence of somatic mosaicism in the mother. The substitution was detected in 23% of the sequencing reads using DNA derived from blood samples and 51% in DNA from buccal swabs. The analysis of blood DNA of the son excluded the presence of somatic mosaicism. Correlation of molecular and clinical data revealed that various distribution of genetic alteration in different cell types had an impact on the expression of observed clinical features in both individuals.

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

Cited by 21 publications

References 19 publications

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

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

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement

Mosaic Intronic NIPBL Variant in a Family With Cornelia de Lange Syndrome

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