SF3B4 Frameshift Variants Represented a More Severe Clinical Manifestation in Nager Syndrome

Abstract

Nager syndrome (NS) is a rare disease marked with craniofacial and preaxial limb anomalies. In this report, we summarized the current evidence to determine a possible genotype-phenotype association among NS individuals. Twenty-four articles comprising of 84 NS (including 9 patients with a severe form of NS [Rodriguez syndrome]) patients were examined, of which 76% were caused by variants in <i>SF3B4</i> (OMIM *605593, Splicing Factor 3B, Subunit 4). Within the <i>SF3B4</i> gene, variants located in exon 3 commonly occurred (20%) from a total identified variant, while hotspot location was identified in exon 1 (12%), and primarily occurred as frameshift variants (64%). Thirty-five distinct pathogenic variants within <i>SF3B4</i> gene were identified with two common sites, c.1A > G and c.1060dupC in exons 1 and 5, respectively. Although no significant genotype-phenotype association was found, it is notable that patients with frameshift <i>SF3B4</i> variants and predicted to lead to nonsense-mediated RNA decay (NMD) of the transcripts tended to have a more severe clinical manifestation. Additionally, patients harboring variants in exons 2 and 3 displayed a higher proportion of cardiac malformations. Taken together, this article summarizes the pathogenic variants observed in <i>SF3B4</i> and provides a possible genotype-phenotype relationship in this disease.

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