Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00669806%3A_____%2F25%3A10492951" target="_blank" >RIV/00669806:_____/25:10492951 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11140/25:10492951
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=3RFWkP0VQh" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=3RFWkP0VQh</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.5507/bp.2025.005" target="_blank" >10.5507/bp.2025.005</a>
Alternative languages
Result language
angličtina
Original language name
Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome
Original language description
AIMS/BACKGROUND: Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disease caused by pathogenic variants in the UBR1 gene. JBS is usually suspected based on characteristic anomalies, but only genetic testing provides a definitive diagnosis. Since most variants are inherited from the parents, we aimed to identify the causal variants in a Czech proband with clinically suspected JBS and perform segregation analysis. METHODS: A proband with clinically suspected JBS underwent clinical exome sequencing (CES). Sanger sequencing was used for the validation, characterization, and segregation of variants in the family. The variants were also characterized using quantitative real-time PCR (qPCR) and in silico analysis. RESULTS: Using CES in the proband, we identified two novel causal variants in the UBR1 gene, c.3482A>C and c.3509+6T>C. Although the variants were found in trans, neither was detected in the parents. Sanger sequencing of the cDNA revealed that the novel variant c.3509+6T>C caused activation of the non-canonical GC donor splice site. The inclusion of 70 bp of the intronic sequence generated a frameshift and a premature termination codon leading to nonsense-mediated decay, as detected by qPCR. In silico protein structural analysis showed that the novel missense variant c.3482A>C in the zinc-stabilized domain RING-H2 altered a highly conserved zinc-coordinating histidine by proline. CONCLUSION: To the best of our knowledge, we report the first molecular confirmation of JBS in the Czech Republic and the first identification of two de novo causal variants in two alleles. Our findings also expand the spectrum of pathogenic variants in the UBR1 gene.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30101 - Human genetics
Result continuities
Project
<a href="/en/project/LM2023067" target="_blank" >LM2023067: The National Center for Medical Genomic</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biomedical Papers
ISSN
1213-8118
e-ISSN
1804-7521
Volume of the periodical
169
Issue of the periodical within the volume
2
Country of publishing house
CZ - CZECH REPUBLIC
Number of pages
9
Pages from-to
98-106
UT code for WoS article
001423965700001
EID of the result in the Scopus database
2-s2.0-105008376747