SCFD1 and Amyotrophic Lateral Sclerosis

Recent genetic studies have implicated SCFD1 (HGNC:20726) in susceptibility to amyotrophic lateral sclerosis (ALS) (MONDO_0004976). Several genome‐wide analyses have demonstrated that SCFD1 is the only gene showing genome‑wide significance in expression quantitative trait loci (eQTL) mediation of ALS risk (PMID:34708205). This finding underlines the important role of regulatory variation in modulating SCFD1 expression within ALS pathogenesis.

In addition, a focused study in a large Chinese cohort evaluated the SCFD1 rs10139154 variant and found that although there was no significant association with overall disease risk, the genotype correlated with an earlier age at onset for ALS (PMID:29260601). This suggests that genetic variation within SCFD1 may influence clinical heterogeneity, offering potential utility in stratifying patients according to disease onset.

Evidence from familial or segregational studies specifically examining SCFD1 in ALS is currently limited, with no clear count of additional affected relatives reported. Nonetheless, the aggregate genetic association data across multiple populations provides a strong signal, further supported by robust eQTL analyses and large sample sizes.

Functional data addressing the pathogenic mechanism of SCFD1 in neurodegeneration remain less direct. While experimental studies in other systems underscore SCFD1’s role in vesicle trafficking and membrane fusion, there is only limited functional evidence from neural tissues. Post‐mortem analyses of motor cortex from ALS patients have indicated differential expression profiles that align with the proposed genetic risk mechanism, although mechanistic studies in relevant neuronal models are still emerging.

Integrating these findings, the genetic evidence—driven by genome‑wide significance via eQTL mediation and modulation of age at onset—strongly supports an association between SCFD1 and ALS, even though detailed familial segregation and direct neural functional assays are not yet fully established. Importantly, these data emphasize the potential of including SCFD1 in genetic diagnostic strategies for ALS, particularly for patient stratification and risk prediction.

Key take‑home sentence: The strong genetic association between SCFD1 and ALS underscores its clinical relevance as a biomarker for diagnosis and prognostic assessments, warranting further research into its pathogenic mechanisms.

References

• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2018 • An association study between SCFD1 rs10139154 variant and amyotrophic lateral sclerosis in a Chinese cohort PMID:29260601
• Journal of neurology, neurosurgery, and psychiatry • 2021 • Value of systematic genetic screening of patients with amyotrophic lateral sclerosis PMID:34708205

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