Expanding the Mutational Spectrum in Johanson-Blizzard Syndrome: Identification of Whole Exon Deletions and Duplications in the Ubr1 Gene by Multiplex Ligation-Dependent Probe Amplification Analysis Publisher Pubmed



Sukalo M¹ ; Schaflein E^{2, 3} ; Schanze I¹ ; Everman DB⁴ ; Rezaei N^{5, 6} ; Argente J^{7, 8, 9} ; Lordasanchez I¹⁰ ; Deshpande C¹¹ ; Takahashi T¹² ; Kleger A¹³ ; Zenker M¹
Source: Molecular Genetics and Genomic Medicine Published:2017

Abstract

Background: Johanson-Blizzard syndrome (JBS, MIM #243800) is a very rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, nasal wing hypoplasia, hypodontia, and other abnormalities. JBS is caused by mutations of the UBR1 gene (MIM *605981), encoding a ubiquitin ligase of the N-end rule pathway. Methods: Molecular findings in a total of 65 unrelated patients with a clinical diagnosis of JBS who were previously screened for UBR1 mutations by Sanger sequencing were reviewed and cases lacking a disease-causing UBR1 mutation on either one or both alleles were included in this study. In order to discover mutations that are not detectable by Sanger sequencing, we designed a probe set for multiplex ligation-dependent probe amplification (MLPA) analysis of the UBR1 gene and analyzed the copy number status of all 47 UBR1 exons. Results: Our previous studies using Sanger sequencing could detect mutations in 93.1% of 130 disease-associated UBR1 alleles. Six patients with a highly suggestive clinical diagnosis of JBS and unsolved genotype were included in this study. MLPA analysis detected six alleles harboring exon deletions/duplications, thereby raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles). Conclusion: We conclude that single or multi-exon deletions or duplications account for a substantial proportion of JBS-associated UBR1 mutations. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.