FTSJ1 – X‑Linked Intellectual Disability

FTSJ1 (HGNC:13254) is a conserved 2'-O-methyltransferase that plays a critical role in modifying tRNAs, particularly at positions essential for proper translation. Its disruption has been robustly associated with X‑linked intellectual disability (MONDO:0100284), as evidenced by multiple independent studies utilizing case reports, multi‐patient screenings, and functional assessments.

The overall clinical validity for this gene–disease association is rated as Strong. Several independent families, including at least one detailed case report featuring the pathogenic variant c.76G>C (p.Ala26Pro) (PMID:36720500), as well as multi‐patient studies reporting copy-number variations and splicing mutations (PMID:20613765; PMID:18081026), provide compelling segregation evidence. In all instances, affected individuals show clear transmission patterns, with additional affected relatives corroborating the genetic findings (PMID:18081026).

Genetic evidence is equally convincing. The mode of inheritance is X‑linked, and detailed segregation analyses have identified multiple variant classes in FTSJ1, including missense, nonsense, and splicing mutations. For instance, the variant c.76G>C (p.Ala26Pro) is one of the reported causative alleles, reinforcing the link between deleterious mutations in FTSJ1 and the intellectual disability phenotype (PMID:36720500).

Functional studies provide strong experimental support for the pathogenicity of FTSJ1 mutations. In vitro assays, transcript analyses, and model organism studies (yeast, Drosophila, and mouse) have demonstrated that loss-of-function mutations disrupt tRNA anticodon loop methylation. These alterations impair neuronal morphology and function, correlating with the cognitive deficits observed in patients (PMID:15162322; PMID:26310293; PMID:30557699).

While some studies have linked FTSJ1 abnormalities to other conditions such as cancer, the collective genetic and functional data specifically support its primary role in X‑linked intellectual disability. Confounding observations do not diminish the robust correlation between loss-of-function alleles in FTSJ1 and neurocognitive impairment.

In conclusion, the integration of genetic segregation and extensive functional evidence substantiates a strong gene–disease association between FTSJ1 and X‑linked intellectual disability. This comprehensive evaluation aids in diagnostic decision‑making, supports commercial applications, and lays a solid foundation for future publication.

References

• Life Science Alliance • 2023 • The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance PMID:36720500
• Journal of Human Genetics • 2010 • Copy-number variations on the X chromosome in Japanese patients with mental retardation detected by array-based comparative genomic hybridization analysis PMID:20613765
• American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics • 2008 • A loss-of-function mutation in the FTSJ1 gene causes nonsyndromic X-linked mental retardation in a Japanese family PMID:18081026
• American Journal of Human Genetics • 2004 • Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation PMID:15162322
• Human Mutation • 2015 • Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1 PMID:26310293

Evidence Based Scoring (AI generated)