UFC1 – Neurodevelopmental Disorder

UFC1 (HGNC:26941) has been implicated in a neurodevelopmental disorder (MONDO:0700092) characterized by neurodevelopmental delay, microcephaly, and seizures. A novel compound heterozygous mutation was identified in a Chinese patient; notably, one of the reported variants is c.19C>T (p.Arg7Ter) (PMID:39078589). This single‐proband finding, with variants classified as likely pathogenic per ACMG guidelines, suggests an autosomal recessive mode of inheritance but remains limited by the scarcity of additional unrelated cases or clear familial segregation (PMID:39078589). The clinical data, although detailed, require cautious interpretation given the isolated nature of the evidence, and thus, the overall gene–disease association is currently considered limited.

Functional studies provide biologically plausible support for this association by demonstrating that loss‐of‐function mutations in UFC1 disrupt the ufmylation pathway, which is essential for normal brain development. Experimental models have shown that impaired ufmylation leads to cellular and mitotic defects consistent with neurodevelopmental pathology (PMID:29868776; PMID:31914610). Although these mechanistic insights bolster the role of UFC1 in neurodevelopment, further multi‐patient studies and segregation analyses are necessary to elevate the clinical validity of this association. Key take‑home: While UFC1 mutations may contribute to neurodevelopmental disorder, additional confirmatory evidence is needed for robust clinical diagnostic application.

References

• Genes & Genomics • 2024 • A novel compound heterozygous mutation of UFC1 in a patient with neurodevelopmental disorder PMID:39078589
• Brain : a journal of neurology • 2018 • Biallelic UFM1 and UFC1 mutations expand the essential role of ufmylation in brain development PMID:29868776
• FASEB journal • 2020 • The UFM1 cascade times mitosis entry associated with microcephaly PMID:31914610

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