UPF3B – X-linked intellectual disability with marfanoid habitus

Lujan-Fryns syndrome (LFS) is characterized by intellectual disability, marfanoid habitus with disproportionate tall stature, minor facial anomalies and hypernasal speech. Initial screening of UPF3B in 397 families identified truncating and missense variants in four unrelated pedigrees (PMID:19238151). The nonsense allele c.1081C>T (p.Arg361Ter) underwent nonsense-mediated decay resulting in complete absence of UPF3B protein in patient lymphoblasts, and neuronal localization studies demonstrated UPF3B expression in dendritic spines critical for synaptic function (PMID:19238151).

A follow-up study of 28 males with a clinical diagnosis of LFS did not detect any causative UPF3B variants (PMID:26358559), challenging the specificity of UPF3B for classical LFS. Although functional data support a loss-of-function mechanism, the absence of replication in a larger cohort limits the clinical validity of UPF3B as a primary LFS gene. Key Take-home: UPF3B loss-of-function can manifest with LFS-like features but is rare; genetic diagnosis of LFS should prioritize MED12 and demonstrable X-linked segregation or pathogenic variants.

References

• Molecular psychiatry • 2010 • Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism PMID:19238151
• American journal of medical genetics. Part A • 2016 • Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities? PMID:26358559

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