FERRY3 – Intellectual Disability

This summary details the association between FERRY3 (HGNC:1184) and intellectual disability (MONDO_0001071), based on multiple lines of evidence. The condition is characterized by neurodevelopmental delay, behavioral abnormalities, and additional features such as infantile muscular hypotonia and dysmorphic facial traits (PMID:31334606).

Case reports from a consanguineous Armenian family and an Iranian family have demonstrated autosomal recessive inheritance of the disorder, with affected individuals presenting with severe intellectual disability, speech impairment, and atypical behavior. Detailed phenotyping in these families revealed features including infantile hypotonia and abnormal facial shape (PMID:31334606) (PMID:34967075).

Multi-patient studies further support this association. In particular, a founder missense variant, c.983T>C (p.Leu328Pro), was identified in seven affected individuals across two Finnish consanguineous families, with additional variants reported in Dutch and Arab families. These findings, along with observed segregation in multiple families, underscore the importance of FERRY3 in the etiology of intellectual disability (PMID:27311568).

The genetic evidence is compelling, with a variant spectrum that includes missense, loss‑of‑function, and splice site alterations. The autosomal recessive pattern and robust co‑segregation data across unrelated probands provide strong support for the pathogenicity of FERRY3 variants in this disorder (PMID:27311568) (PMID:34967075).

Functional studies lend additional support by demonstrating that disruption of the FERRY complex, which includes FERRY3, leads to defects in mRNA transport and lysosomal trafficking in neurons. These defects are consistent with the neurodevelopmental deficits observed in patients, thereby reinforcing the gene-disease correlation (PMID:40093117).

Although the clinical phenotype can be variable and extends beyond solely intellectual disability, the genetic and experimental data converge to confirm a strong association. This integrated evidence justifies the use of FERRY3 in diagnostic decision‑making and suggests its potential as a target for future therapeutic interventions.

Key Take‑home: Robust genetic and functional evidence supports FERRY3 as a causative gene in autosomal recessive intellectual disability, highlighting its clinical utility for diagnosis and potential future treatments.

References

• Molecular Genetics & Genomic Medicine • 2019 • A novel variant of C12orf4 in a consanguineous Armenian family confirms the etiology of autosomal recessive intellectual disability type 66 with delineation of the phenotype PMID:31334606
• The Journal of Gene Medicine • 2022 • A novel variant of C12orf4 linked to autosomal recessive intellectual disability type 66 with phenotype expansion PMID:34967075
• Clinical Genetics • 2017 • Identification of C12orf4 as a gene for autosomal recessive intellectual disability PMID:27311568
• bioRxiv : the preprint server for biology • 2025 • TBCK-deficiency leads to compartment-specific mRNA and lysosomal trafficking defects in patient-derived neurons PMID:40093117

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