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

• Published in: Molecular genetics & genomic medicine 2017-11, Vol.5 (6), p.774-780
• Main Authors: Sukalo, Maja, Schäflein, Eva, Schanze, Ina, Everman, David B., Rezaei, Nima, Argente, Jesús, Lorda‐Sanchez, Isabel, Deshpande, Charu, Takahashi, Tsutomu, Kleger, Alexander, Zenker, Martin
• Format: Article
• Language: English
• Subjects: Adult; Alleles; Anus, Imperforate - diagnosis; Anus, Imperforate - genetics; autosomal recessive; Base Sequence; Child; Child, Preschool; Clinical Report; Clinical Reports; DNA - chemistry; DNA - isolation & purification; DNA - metabolism; DNA Mutational Analysis; Ectodermal Dysplasia - diagnosis; Ectodermal Dysplasia - genetics; Exons; Female; Gene Deletion; Gene Duplication; Genotype; Growth Disorders - diagnosis; Growth Disorders - genetics; Hearing Loss, Sensorineural - diagnosis; Hearing Loss, Sensorineural - genetics; Humans; Hypothyroidism - diagnosis; Hypothyroidism - genetics; Intellectual Disability - diagnosis; Intellectual Disability - genetics; Johanson‐Blizzard syndrome; Male; MLPA; multiplex ligation‐dependent probe amplification; Multiplex Polymerase Chain Reaction; Nose - abnormalities; Pancreatic Diseases - diagnosis; Pancreatic Diseases - genetics; Phenotype; Ubiquitin-Protein Ligases - genetics; UBR1
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.319

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. Johanson‐Blizzard syndrome is a very rare autosomal recessive disorder caused by mutations of the UBR1 gene. 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 multiplex ligation‐dependent probe amplification (MLPA) study, raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles).