Copy number analysis of NIPBL in a cohort of 510 patients reveals rare copy number variants and a mosaic deletion

Yu‐Wei Cheng,Soma Das,Carrie Fitzpatrick,Latrice Wysinger,Beth A Kozel,Kelly Arndt,Dorothy K Grange,Daniela Del Gaudio,Christopher A Tan,Darrel Waggoner,Nathaniel H Robin,Agata Minor

doi:10.1002/mgg3.48

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.

Highlights

Cornelia de Lange syndrome (CdLS [MIM 122470]) is a multisystem disorder characterized by characteristic facial features, growth retardation, intellectual disability, limb reduction defects, hirsutism, and moderate-to-severe neurodevelopmental delay (Kline et al 1993)
We identified 13 copy number variations (CNVs) in a cohort of 510 CdLS cases
Copy number analysis was performed utilizing high-density array-comparative genomic hybridization (CGH) targeted to the NIPBL gene, whole-genome single nucleotide polymorphisms (SNPs) array, and Multiplex ligation-dependent probe amplification (MLPA)

Summary

Introduction

Cornelia de Lange syndrome (CdLS [MIM 122470]) is a multisystem disorder characterized by characteristic facial features, growth retardation, intellectual disability, limb reduction defects, hirsutism, and moderate-to-severe neurodevelopmental delay (Kline et al 1993). At one end of the spectrum are individuals with classical CdLS features exhibiting profound growth and neurodevelopmental delay, sometimes accompanied by severe limb defects. Genotype–phenotype correlation studies have demonstrated that NIPBL mutation-positive patients tend to have a more severe phenotype than mutation-negative patients with truncating mutations, generally causing a more severe phenotype than missense mutations based on limb differences, growth, and cognitive function (Gillis et al 2004). This suggests that NIPBL is a dosage-sensitive gene.

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Conclusion