Copy Number Analysis of NIPBL in a Cohort of 510 Patients Reveals Rare Copy Number Variants and a Mosaic Deletion

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2014 Apr 2

PMID 24689074

Citations 5

Authors

Yu-Wei Cheng

Christopher A Tan

Agata Minor

Kelly Arndt

Latrice Wysinger

Dorothy K Grange

Beth A Kozel

Nathaniel H Robin

Darrel Waggoner

Carrie Fitzpatrick

Soma Das

Daniela Del Gaudio

Affiliations

Soon will be listed here.

Abstract

Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of intragenic NIPBL copy number variations (CNVs) in a cohort of 510 NIPBL sequence-negative patients with suspected CdLS. Copy number analysis was performed by custom exon-targeted oligonucleotide array-comparative genomic hybridization and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene. We identified NIPBL CNVs in 13 patients (2.5%) including one intragenic duplication and a deletion in mosaic state. Breakpoint sequences in two patients provided further evidence of a microhomology-mediated replicative mechanism as a potential predominant contributor to CNVs in NIPBL. Patients for whom clinical information was available share classical CdLS features including craniofacial and limb defects. Our experience in studying the frequency of NIBPL CNVs in the largest series of patients to date widens the mutational spectrum of NIPBL and emphasizes the clinical utility of performing NIPBL deletion/duplication analysis in patients with CdLS.

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References

Gervasini C, Parenti I, Picinelli C, Azzollini J, Masciadri M, Cereda A . Molecular characterization of a mosaic NIPBL deletion in a Cornelia de Lange patient with severe phenotype. Eur J Med Genet. 2013; 56(3):138-43. DOI: 10.1016/j.ejmg.2012.12.009. View

Deardorff M, Kaur M, Yaeger D, Rampuria A, Korolev S, Pie J . Mutations in cohesin complex members SMC3 and SMC1A cause a mild variant of cornelia de Lange syndrome with predominant mental retardation. Am J Hum Genet. 2007; 80(3):485-94. PMC: 1821101. DOI: 10.1086/511888. View

Lupski J . Genomic rearrangements and sporadic disease. Nat Genet. 2007; 39(7 Suppl):S43-7. DOI: 10.1038/ng2084. View

Tonkin E, Wang T, Lisgo S, Bamshad M, Strachan T . NIPBL, encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B, is mutated in Cornelia de Lange syndrome. Nat Genet. 2004; 36(6):636-41. DOI: 10.1038/ng1363. View

Huisman S, Redeker E, Maas S, Mannens M, Hennekam R . High rate of mosaicism in individuals with Cornelia de Lange syndrome. J Med Genet. 2013; 50(5):339-44. DOI: 10.1136/jmedgenet-2012-101477. View

Musio A, Selicorni A, Focarelli M, Gervasini C, Milani D, Russo S . X-linked Cornelia de Lange syndrome owing to SMC1L1 mutations. Nat Genet. 2006; 38(5):528-30. DOI: 10.1038/ng1779. View

Kline A, Stanley C, Belevich J, Brodsky K, Barr M, Jackson L . Developmental data on individuals with the Brachmann-de Lange syndrome. Am J Med Genet. 1993; 47(7):1053-8. DOI: 10.1002/ajmg.1320470724. View

Schoumans J, Wincent J, Barbaro M, Djureinovic T, Maguire P, Forsberg L . Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients. Eur J Hum Genet. 2006; 15(2):143-9. DOI: 10.1038/sj.ejhg.5201737. View

Krantz I, McCallum J, DeScipio C, Kaur M, Gillis L, Yaeger D . Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B. Nat Genet. 2004; 36(6):631-5. PMC: 4902017. DOI: 10.1038/ng1364. View

10.

Kline A, Krantz I, Sommer A, Kliewer M, Jackson L, Fitzpatrick D . Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance. Am J Med Genet A. 2007; 143A(12):1287-96. DOI: 10.1002/ajmg.a.31757. View

11.

Deardorff M, Wilde J, Albrecht M, Dickinson E, Tennstedt S, Braunholz D . RAD21 mutations cause a human cohesinopathy. Am J Hum Genet. 2012; 90(6):1014-27. PMC: 3370273. DOI: 10.1016/j.ajhg.2012.04.019. View

12.

Gervasini C, Picinelli C, Azzollini J, Rusconi D, Masciadri M, Cereda A . Genomic imbalances in patients with a clinical presentation in the spectrum of Cornelia de Lange syndrome. BMC Med Genet. 2013; 14:41. PMC: 3626829. DOI: 10.1186/1471-2350-14-41. View

13.

Bhuiyan Z, Stewart H, Redeker E, Mannens M, Hennekam R . Large genomic rearrangements in NIPBL are infrequent in Cornelia de Lange syndrome. Eur J Hum Genet. 2007; 15(4):505-8. DOI: 10.1038/sj.ejhg.5201776. View

14.

Borck G, Redon R, Sanlaville D, Rio M, PRIEUR M, Lyonnet S . NIPBL mutations and genetic heterogeneity in Cornelia de Lange syndrome. J Med Genet. 2004; 41(12):e128. PMC: 1735640. DOI: 10.1136/jmg.2004.026666. View

15.

Russo S, Masciadri M, Gervasini C, Azzollini J, Cereda A, Zampino G . Intragenic and large NIPBL rearrangements revealed by MLPA in Cornelia de Lange patients. Eur J Hum Genet. 2012; 20(7):734-41. PMC: 3376273. DOI: 10.1038/ejhg.2012.7. View

16.

Rollins R, Korom M, Aulner N, Martens A, Dorsett D . Drosophila nipped-B protein supports sister chromatid cohesion and opposes the stromalin/Scc3 cohesion factor to facilitate long-range activation of the cut gene. Mol Cell Biol. 2004; 24(8):3100-11. PMC: 381657. DOI: 10.1128/MCB.24.8.3100-3111.2004. View

17.

Deardorff M, Bando M, Nakato R, Watrin E, Itoh T, Minamino M . HDAC8 mutations in Cornelia de Lange syndrome affect the cohesin acetylation cycle. Nature. 2012; 489(7415):313-7. PMC: 3443318. DOI: 10.1038/nature11316. View

18.

Stankiewicz P, Inoue K, Bi W, Walz K, Park S, Kurotaki N . Genomic disorders: genome architecture results in susceptibility to DNA rearrangements causing common human traits. Cold Spring Harb Symp Quant Biol. 2004; 68:445-54. DOI: 10.1101/sqb.2003.68.445. View

19.

Srour M, Schwartzentruber J, Hamdan F, Ospina L, Patry L, Labuda D . Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am J Hum Genet. 2012; 90(4):693-700. PMC: 3322222. DOI: 10.1016/j.ajhg.2012.02.011. View

20.

Castronovo P, Delahaye-Duriez A, Gervasini C, Azzollini J, Minier F, Russo S . Somatic mosaicism in Cornelia de Lange syndrome: a further contributor to the wide clinical expressivity?. Clin Genet. 2010; 78(6):560-4. DOI: 10.1111/j.1399-0004.2010.01408.x. View