NFIX – Marshall-Smith syndrome

Marshall-Smith syndrome (MSS) is a rare autosomal dominant skeletal dysplasia characterized by postnatal failure to thrive, dysmorphic craniofacial features, accelerated osseous maturation, respiratory insufficiency, and neurodevelopmental impairment.

Pathogenic NFIX variants were first identified in nine sporadic MSS cases via array comparative genomic hybridization and sequencing, revealing distinct frameshift and splice-site mutations clustering in exons 6–10 that escape nonsense-mediated mRNA decay (PMID:20673863).

The variant spectrum in MSS comprises predominantly protein-truncating alleles, including nonsense changes (e.g., c.637C>T (p.Gln213Ter)) and small insertions/deletions, all preserving the N-terminal DNA-binding/dimerization domain but disrupting the C-terminal region critical for transcriptional regulation (PMID:20673863).

All reported MSS NFIX mutations have arisen de novo; no familial segregation beyond index cases has been documented, consistent with an autosomal dominant inheritance and a dominant-negative mechanism.

Functional studies using CRISPR-Cas9–generated Nfix Del2/Del2 mice recapitulate key MSS features—growth retardation, kyphosis, vertebral porosity, reduced bone mineral content, and cortical brain enlargement—demonstrating that NMD-escaping NFIX truncations exert deleterious dominant-negative effects in vivo (PMID:37283649).

In summary, NFIX is definitively established as the causative gene for MSS, with strong genetic evidence from multiple unrelated de novo truncating variants and concordant in vivo functional modeling. Key take-home: NFIX sequencing should be prioritized in patients presenting with the MSS clinical spectrum to enable accurate diagnosis and anticipatory management.

References

• American journal of human genetics • 2010 • Distinct effects of allelic NFIX mutations on nonsense-mediated mRNA decay engender either a Sotos-like or a Marshall-Smith syndrome PMID:20673863
• JBMR plus • 2023 • A Mouse Model with a Frameshift Mutation in the Nuclear Factor I/X (NFIX) Gene Has Phenotypic Features of Marshall-Smith Syndrome PMID:37283649

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