| Summary: | <p><strong>Introduction:</strong> 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 <em>TWIST1</em>. 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.</p>
<p><strong>Methods:</strong> 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.</p>
<p><strong>Results:</strong> Here, we describe the identification of a third ATG-creating <em>de novo</em> variant, c.-18C>T, in the 5′ UTR of <em>TWIST1</em> 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.</p>
<p><strong>Conclusion:</strong> This is the third variant identified in this region and confirms the introduction of upstream ATGs in the 5′ UTR of <em>TWIST1</em> 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.</p>
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