LAS1L and X-linked Intellectual Disability

Recent genetic investigations have identified LAS1L (HGNC:25726) as being associated with X-linked intellectual disability (MONDO_0100284). In a large-scale X‑exome sequencing study of 405 unresolved families with intellectual disability, likely pathogenic variants in several novel XLID genes were identified, including LAS1L. In this study, 19 families had variants that co‑segregated with the intellectual disability phenotype (PMID:25644381).

Genetic evidence comes from the identification of both protein‐truncating and missense variants, which were found in unrelated probands exhibiting intellectual disability. One representative variant reported is c.1243C>T (p.Arg415Trp), which meets stringent molecular criteria for reporting (PMID:25644381). The segregation data, with 19 affected families, further substantiates the gene‑disease link.

The inheritance pattern for this association is X‑linked, which matches the clinical presentation of intellectual disability in affected males. The study’s results provide strong support for LAS1L’s involvement via pathogenic variants, underscoring its relevance in diagnostic decision‑making and potential commercial applications in genetic testing.

While functional studies of LAS1L have extensively characterized its role in ribosomal biogenesis and have implicated it in autosomal recessive distal spinal muscular atrophy phenotypes, these experiments primarily focus on a distinct clinical context. Thus, although compelling for other disorders, the experimental data offer limited insight into the mechanism underlying the XLID phenotype.

In summary, the robust genetic findings, derived from multi‑family segregation analyses and the detection of both truncating and missense variants, establish a strong association between LAS1L and X‑linked intellectual disability. Ongoing research and further functional validation may refine the molecular mechanism; however, current evidence clearly supports the clinical utility of incorporating LAS1L variant screening in patients presenting with intellectual disability and related phenotypes.

Key Take‑home: The strong genetic evidence linking LAS1L variants to X‑linked intellectual disability reinforces its value in clinical diagnostics and genetic counseling.

References

• Molecular Psychiatry • 2016 • X‑exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes PMID:25644381
• Neurology • 2014 • Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis PMID:24647030
• The Journal of biological chemistry • 2020 • It takes two (Las1 HEPN endoribonuclease domains) to cut RNA correctly PMID:32220933
• Genes • 2022 • Severe Infantile Axonal Neuropathy with Respiratory Failure Caused by Novel Mutation in X‑Linked LAS1L Gene PMID:35627110

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