In:
Frontiers in Genetics, Frontiers Media SA, Vol. 13 ( 2023-1-4)
Abstract:
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 & gt;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.
Type of Medium:
Online Resource
ISSN:
1664-8021
DOI:
10.3389/fgene.2022.1089417
DOI:
10.3389/fgene.2022.1089417.s001
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2023
detail.hit.zdb_id:
2606823-0
