SF3B4 – Nager Acrofacial Dysostosis

Nager syndrome (acrofacial dysostosis type 1) is a rare disorder characterized by mandibulofacial hypoplasia, micrognathia, and preaxial limb anomalies including thumb hypoplasia or aplasia. In an international cohort, heterozygous loss-of-function variants in SF3B4 were discovered by exome sequencing in 20 of 35 unrelated families, implicating haploinsufficiency as the primary pathogenic mechanism (PMID:22541558). Among these, the recurrent start-loss variant c.1A>G (p.Met1Val) was observed in multiple probands and segregates with disease (PMID:22541558).

Segregation analysis in a multiplex family with a novel synonymous exon 3 variant demonstrated co-segregation in three affected relatives, and hybrid minigene assays confirmed creation of a cryptic splice site and a hypomorphic allele (PMID:27966544). Functional studies in Sf3b4+/- mice recapitulated key skeletal features—vertebral homeotic transformations, flattened calvaria, and reduced forebrain proliferation—supporting a haploinsufficiency model (PMID:31900962). In zebrafish, sf3b4 deficiency led to craniofacial and segmentation defects that were rescued by exogenous Fgf8, linking disrupted FGF signalling to Nager syndrome pathogenesis (PMID:39288852).

Collectively, genetic evidence from >20 probands across 35 families, segregation in a three-member pedigree, and concordant functional data in mammalian and fish models underpin a Definitive autosomal dominant gene–disease association for SF3B4 and Nager acrofacial dysostosis. Clinical sequencing of SF3B4 for heterozygous loss-of-function variants is recommended to confirm diagnosis, inform recurrence risk, and guide multidisciplinary management.

References

• American Journal of Human Genetics • 2012 • Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome PMID:22541558
• European Journal of Human Genetics • 2017 • A synonymous splicing mutation in the SF3B4 gene segregates in a family with highly variable Nager syndrome PMID:27966544
• Developmental Dynamics • 2020 • Heterozygous mutation of the splicing factor Sf3b4 affects development of the axial skeleton and forebrain in mouse PMID:31900962
• International Journal of Biological Macromolecules • 2024 • Fgf8 contributes to the pathogenesis of Nager syndrome PMID:39288852

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