Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11140/25:10492951

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome

Popis výsledku v původním jazyce

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&gt;C and c.3509+6T&gt;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&gt;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&gt;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.

Název v anglickém jazyce

Two de novo UBR1 variants in trans as a cause of Johanson-Blizzard syndrome

Popis výsledku anglicky

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&gt;C and c.3509+6T&gt;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&gt;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&gt;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30101 - Human genetics

Projekt

<a href="/cs/project/LM2023067" target="_blank" >LM2023067: Národní centrum lékařské genomiky</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Biomedical Papers

ISSN

1213-8118

e-ISSN

1804-7521

Svazek periodika

169

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

CZ - Česká republika

Počet stran výsledku

9

Strana od-do

98-106

Kód UT WoS článku

001423965700001

EID výsledku v databázi Scopus

2-s2.0-105008376747