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This summary reviews the evidence linking the LRFN5 gene to intellectual disability. The association is built on detailed molecular investigations in which de novo chromosomal rearrangements and submicroscopic deletions have been identified in affected individuals. Multiple lines of evidence, including both genetic alterations and functional studies, contribute to our understanding of the gene’s role in neurodevelopmental impairment.
In the 2010 case report (PMID:20648246), a 19‑year‑old patient with severe autism and intellectual disability was found to carry a balanced de novo translocation along with a 2.6‑Mb deletion spanning 15 protein‑coding genes. Importantly, analysis revealed that only LRFN5 expression was significantly altered, with patient fibroblasts showing a 10‑fold reduction in transcript levels. The study also identified distinct epigenetic changes at the LRFN5 promoter region, supporting a mechanism of haploinsufficiency.
A complementary multi‐patient study reported in 2011 (PMID:22031302) identified eight patients with small intragenic or total gene deletions that encompassed LRFN5 among several neurodevelopmental genes. Although these deletions affect multiple genes, the recurrent involvement of LRFN5 in patients presenting with intellectual disability and related neurodevelopmental issues bolsters its candidacy as a contributing factor. The collective genetic evidence, however, is tempered by the limited number of probands and the confounding influence of multi‑gene deletions.
The genetic findings indicate that the alterations in LRFN5 typically occur de novo, suggesting an autosomal dominant effect. While no additional affected relatives with segregating variants were reported (segregation = 0), the de novo nature of the pathogenic alterations and the detection of similar copy number variants in unrelated individuals provide preliminary support for a gene‑disease association. Nevertheless, the sample size remains small and detailed segregation analysis is lacking.
Functional assessments have provided moderate evidence for the pathogenicity of LRFN5 alteration. The 10‑fold reduction in LRFN5 expression observed in patient-derived fibroblasts, coupled with marked epigenetic modifications at the promoter, are consistent with a loss‑of‑function mechanism. These experimental outcomes reinforce the hypothesis that haploinsufficiency of LRFN5 may contribute to the intellectual disability phenotype, even as the genetic evidence is yet limited by small numbers and overlapping genomic events.
In conclusion, while the current evidence consists of one detailed de novo case and a multi‑patient study totaling nine probands, the strong functional data support that dysregulation of LRFN5 is involved in the etiology of intellectual disability. Clinicians should consider evaluation of LRFN5 alterations during diagnostic workups for intellectual disability, particularly when functional data indicate a loss‑of‑function mechanism.
Gene–Disease AssociationLimitedEvidence from one de novo case (PMID:20648246) and eight patients from a multi‑patient CNV study (PMID:22031302) results in a total of nine probands. However, the involvement of additional genes in the reported deletions limits the specificity of the association. Genetic EvidenceLimitedGenetic data are based on de novo events and recurrent CNVs that include LRFN5, yet the small number of probands and the presence of multi‑gene deletions restrict the strength of the genetic evidence. Functional EvidenceModerateFunctional assays demonstrated a 10‑fold reduction in LRFN5 expression in patient-derived fibroblasts along with significant epigenetic alterations at the promoter, supporting a mechanism of haploinsufficiency (PMID:20648246). |