SCAF4 – Fliedner-Zweier Syndrome

Fliedner-Zweier syndrome is a rare neurodevelopmental disorder characterized by mild intellectual disability, seizures, behavioral abnormalities, and skeletal anomalies. Serine/arginine-rich C-terminal domain–associated factor 4 (SCAF4) has been implicated in transcriptional regulation, and loss-of-function variants may underlie impaired neurodevelopment. To date, only a single family has been reported linking SCAF4 variants to Fliedner-Zweier syndrome, providing limited clinical validity for this association.

A 4-year-7-month-old boy presented with cognitive impairment, language delay, behavioral abnormalities, and distinctive facial features. Whole-exome sequencing identified a heterozygous nonsense variant, c.1693C>T (p.Arg565Ter), in exon 14 of SCAF4, which was confirmed to be paternally inherited by Sanger sequencing (PMID:40290495). RNA sequencing from the patient revealed widespread transcriptional dysregulation consistent with SCAF4 loss-of-function. No additional unrelated cases of Fliedner-Zweier syndrome with SCAF4 variants have been described, underscoring the current limited evidence base.

Key Take-home: While SCAF4 c.1693C>T (p.Arg565Ter) has been associated with Fliedner-Zweier syndrome in one family, further case accumulation and functional studies are required to confirm its diagnostic utility.

References

• Frontiers in genetics • 2025 • A novel nonsense mutation in SCAF4 associated with fliedner-zweier syndrome: a case report and review of the literature. PMID:40290495

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