Craniofrontonasal Syndrome Caused by Introduction of a Novel uATG in the 5′UTR of EFNB1

Tavares, Vanessa Luiza Romanelli; Kague, Érika; Musso, Camila Manso; Alegria, Thiago Gerônimo Pires; Freitas, Roseli Santos de; Bertola, Débora Romeo; Twigg, Stephen R. F.; Passos‐Bueno, Maria Rita

doi:10.1159/000490635

Cited by 11 publications

(4 citation statements)

References 47 publications

(61 reference statements)

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“…The 5ʹUTR variants that alter uORFs have been described in association with the etiology of Mendelian disorders. Such variants may create an uAUG resulting in new uORF (Romanelli Tavares et al, 2019; von Bohlen et al, 2017; Wright et al, 2021; Zhou et al, 2018), or may disrupt the existing uORFs (Occhi et al, 2013; Wen et al, 2009). Analysis of allele frequency spectrum of variants in 15,708 individual whole‐genome sequencing data from the Genome Aggregation Database (gnomAD) reveals that uAUG‐creating variants and variants that disrupt uORF stop codons are under strong negative selection (Whiffin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

et al. 2021

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Congenital aniridia (AN) is a severe autosomal dominant panocular disorder associated with pathogenic variants in the PAX6 gene. Previously, we performed a molecular genetic study of a large cohort of Russian patients with AN and revealed four noncoding nucleotide variants in the PAX6 5ʹUTR. 14 additional PAX6-5ʹUTR variants were also reported in the literature, but the mechanism of their pathogenicity remained unclear. In the present study, we experimentally analyze five patient-derived PAX6 5ʹUTR-variants: four variants that we identified in Russian patients (c.-128-2delA, c.-125dupG, c.-122dupG, c.-118_-117del) and one previously reported (c.-52+5G>C). We show that the variants lead to a decrease in the protein translation efficiency, while mRNA expression level is not significantly reduced. Two of these variants also affect splicing. Furthermore, we predict and experimentally validate the presence of an evolutionarily conserved small uORF in the PAX6 5ʹUTR.All studied variants lead to the frameshift of the uORF, resulting in its extension.This extended out-of-frame uORF overlaps with the downstream CDS and thereby reduces its translation efficiency. We conclude that the uORF frameshift may be the main mechanism of pathogenicity for at least 15 out of 18 known PAX6 5ʹUTR variants. Moreover, we predict additional uORFs in the PAX6 5ʹUTR.

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Section: Introductionmentioning

confidence: 99%

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

et al. 2021

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“…Such regions are often excluded in diagnostic screening, or poorly covered because of GC‐richness, but with the increased use of, and improvement in, whole genome sequencing, more potentially pathological non‐coding variants will be identified and require clinical interpretation. In craniosynostosis, pathological variants have been identified in the 5′ UTRs of EFNB1 (Romanelli Tavares et al., ; Twigg et al., ) and SMAD6 (E.C., unpublished data), highlighting the importance of screening these sequences in patients with a clear diagnosis and where a coding mutation or deletion cannot be identified.…”

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confidence: 99%

Disruption ofTWIST1translation by 5′ UTR variants in Saethre-Chotzen syndrome

et al. 2018

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Saethre‐Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss‐of‐function variants within the coding region. To determine whether non‐coding variants also contribute to SCS, we screened 14 genetically undiagnosed SCS patients using targeted capture sequencing, and identified novel single nucleotide variants (SNVs) in the 5′ untranslated region (UTR) of TWIST1 in two unrelated SCS cases. We show experimentally that these variants, which create translation start sites in the TWIST1 leader sequence, reduce translation from the main open reading frame (mORF). This is the first demonstration that non‐coding SNVs of TWIST1 can cause SCS, and highlights the importance of screening the 5′ UTR in clinically diagnosed SCS patients without a coding mutation. Similar 5′ UTR variants, particularly of haploinsufficient genes, may represent an under‐ascertained cause of monogenic disease.

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“…Although this region in TWIST1 is exonic, it is a region that may be excluded from analysis for various reasons: it is not necessarily included in customized panel designs, bioinformatic analysis often excludes these regions and finally it is poorly covered in exomes. Pathogenic variants in the 5′ UTR of two other craniosynostosis genes also create upstream ORF-creating variants, EFBN1 ( Twigg et al, 2013 ; Romanelli Tavares et al, 2019 ) and more recently, SMAD6 ( Calpena et al, 2020 ). Thus, variants within the 5′ UTR of genes, and especially in haploinsufficient genes, should be carefully assessed in patients in whom the molecular defect has not been identified.…”

Section: Discussionmentioning

confidence: 99%

Case report: A third variant in the 5′ UTR of TWIST1 creates a novel upstream translation initiation site in a child with Saethre-Chotzen syndrome

Díaz‐González

Sacedo-Gutiérrez²,

Twigg³

et al. 2023

Front. Genet.

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Introduction: Saethre-Chotzen syndrome, a craniosynostosis syndrome characterized by the premature closure of the coronal sutures, dysmorphic facial features and limb anomalies, is caused by haploinsufficiency of TWIST1. Although the majority of variants localize in the coding region of the gene, two variants in the 5′ UTR have been recently reported to generate novel upstream initiation codons.Methods: Skeletal dysplasia Next-generation sequencing (NGS) panel was used for genetic analysis in a patient with bicoronal synostosis, facial dysmorphisms and limb anomalies. The variant pathogenicity was assessed by a luciferase reporter promoter assay.Results: Here, we describe the identification of a third ATG-creating de novo variant, c.-18C>T, in the 5′ UTR of TWIST1 in the patient with a clinical diagnosis of Saethre-Chotzen syndrome. It was predicted to create an out-of-frame new upstream translation initiation codon resulting in a 40 amino acid larger functionally inactive protein. We performed luciferase reporter promoter assays to demonstrate that the variant does indeed reduce translation from the main open reading frame.Conclusion: This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5′ UTR of TWIST1 as a pathogenic mechanism in Saethre-Chotzen syndrome. This case report shows the necessity for performing functional characterization of variants of unknown significance within national health services.

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Craniofrontonasal Syndrome Caused by Introduction of a Novel uATG in the 5′UTR of EFNB1

Cited by 11 publications

References 47 publications

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

Disruption ofTWIST1translation by 5′ UTR variants in Saethre-Chotzen syndrome

Case report: A third variant in the 5′ UTR of TWIST1 creates a novel upstream translation initiation site in a child with Saethre-Chotzen syndrome

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