UFC1 – Intellectual Disability

The gene UFC1 (HGNC:26941) has emerged as a candidate for intellectual disability (MONDO:0001071) through genomic studies in cohorts with recessive neurodevelopmental disorders. Genetic screening in individuals with intellectual disability has identified recessively inherited mutations in UFC1, thereby extending the morbid genome of this heterogeneous clinical condition (PMID:27431290).

The overall clinical validity of the UFC1–intellectual disability association is assessed as strong. Multiple unrelated probands from consanguineous cohorts have been found to harbor pathogenic variants in UFC1, with segregation analysis supporting recessive inheritance. Such evidence underscores its utility in diagnostic decision‑making.

Genetic evidence is highlighted by the recurrent identification of the variant c.317C>T (p.Thr106Ile) in independent cases. This complete coding change, noted in both case reports and multi‐patient studies, strongly supports the role of altered UFC1 function in the pathogenesis of intellectual disability (PMID:27431290).

Complementary functional studies have demonstrated that mutations in UFC1 impair the ufmylation cascade, a post‑translational modification process critical for proper neuronal development. In experimental models, disrupted ufmylation due to UFC1 mutations results in cellular phenotypes consistent with neurodevelopmental deficits, thereby providing a biological mechanism that aligns with the human intellectual disability phenotype (PMID:39078589).

There is currently no compelling conflicting evidence; however, as additional cases are identified and further experimental validations are pursued, nuanced genotype‑phenotype correlations may emerge. At present, the genetic and functional data provide a coherent narrative linking UFC1 dysfunction to cognitive impairment in affected individuals.

Key take‑home sentence: The robust genetic recurrence and clear mechanistic insights into ufmylation support the clinical utility of UFC1 as a diagnostic marker for intellectual disability.

References

• Molecular Psychiatry • 2017 • Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield PMID:27431290
• Genes & Genomics • 2024 • A novel compound heterozygous mutation of UFC1 in a patient with neurodevelopmental disorder PMID:39078589

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