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This summary evaluates the association between LZTS3 and amyotrophic lateral sclerosis (ALS) as reported in a study of homozygous rare variants in a North‐African Jewish ALS cohort (PMID:31108397). Although several candidate genes were investigated through whole‐exome sequencing, LZTS3 emerged as a potential contributor to disease risk based on its inclusion in a panel of recessively inherited genes. No unique, clearly deleterious variant was directly linked to LZTS3 in this study, and the evidence relies on its identification in candidate screening rather than on robust variant‐specific segregation data.
The clinical validity of the LZTS3–ALS association is currently best characterized as Limited according to ClinGen criteria. In the evaluated cohort of 43 probands (PMID:31108397), while a subset of 13 patients carried at least one homozygous rare in‑silico damaging variant, there was no clear segregation evidence supporting a definitive role for LZTS3 in disease pathogenesis.
Genetic evidence for LZTS3 in ALS is constrained by the absence of a clearly reported coding change in this gene. Unlike other ALS‐associated genes in the study, LZTS3 was noted as part of the broader analysis, with no individual variant (i.e. a complete coding change such as a c. sequence with an accompanying p. annotation) being reported. Consequently, the genetic support remains inferential, derived solely from burden testing within a multi‐gene screening strategy.
Functional data directly linking LZTS3 to ALS are also lacking. Although separate functional studies in colorectal cancer (PMID:37806182) have demonstrated that LZTS3 can modulate cell proliferation and migration, these findings in a non‐ALS context do not provide disease‑specific support. No experiments have yet validated a mechanism in motor neurons or other ALS‑relevant models, leaving the pathogenic mechanism for LZTS3 in ALS unconfirmed.
No conflicting evidence has been reported that refutes a role for LZTS3; however, the current data neither conclusively establish its involvement in ALS nor provide sufficient segregation or variant-specific proof. This underscores the need for further investigation, including detailed variant analysis and functional assays in ALS models.
In conclusion, while preliminary candidate gene screening suggests that LZTS3 may participate in the recessive burden contributing to ALS pathogenesis, the lack of clear variant and functional data currently limits its clinical validity. Nonetheless, ongoing studies to elucidate its role could enhance diagnostic decision-making and enable more precise genetic counseling for ALS patients in the future.
Gene–Disease AssociationLimitedThe association is based on candidate gene screening in a cohort of 43 ALS patients (PMID:31108397), without a report of a definitive LZTS3 coding variant or robust segregation evidence. Genetic EvidenceLimitedNo direct coding variant in LZTS3 was identified; the evidence relies on its nominal inclusion among several candidate genes from a burden analysis of homozygous rare variants. Functional EvidenceLimitedFunctional studies in ALS-relevant models are lacking; although LZTS3 has been functionally characterized in colorectal cancer, these findings are not directly applicable to ALS. |