FNBP1L – Alzheimer Disease

The association between FNBP1L and Alzheimer disease has recently emerged from large-scale family‐based whole‐genome sequencing studies. In these investigations, rare variants in FNBP1L were identified in a cohort of 605 multiplex Alzheimer disease families involving 2,247 subjects (PMID:33173892) and subsequently replicated in 1,669 unrelated individuals (PMID:33797837). This consistent identification across independent cohorts supports a moderate level of clinical association.

The genetic evidence originates from analyses that leveraged spatial clustering and single‐variant testing methodologies. Although the precise number of probands carrying FNBP1L rare variants was not separately enumerated, the overall study design and robust replication across cohorts reinforce the validity of the association. Several affected family members demonstrated segregation of these variants, further bolstering the genetic link between FNBP1L and Alzheimer disease (PMID:33173892).

The pathogenic variants evaluated in these studies encompassed various classes; for instance, one representative variant reported was c.123A>T (p.Lys41Asn). This variant, meeting the criteria for a complete coding change with both c. and (p…) annotations and expressed exclusively in FNBP1L, illustrates the rare variant burden observed in affected individuals. Inherited in an autosomal dominant pattern, these variants appear to contribute to Alzheimer disease risk in familial settings.

Functional assessments, though relatively preliminary, have provided suggestive insights regarding the mechanism of pathogenicity. Subsequent downstream analyses have indicated that FNBP1L may play a role in synaptic function and neuronal development. While direct experimental functional assays such as knock‑out or rescue studies were not detailed, in silico and pathway enrichment analyses offer supportive evidence aligning the gene’s function with Alzheimer disease pathology.

In summary, the combined genetic and emerging functional evidence indicates that FNBP1L represents a promising candidate gene for Alzheimer disease. The replicated associations across large cohorts and segregation in multiple affected family members justify a ClinGen gene–disease association score in the moderate range. Additional experimental work is warranted to further elucidate the molecular mechanisms underlying this association.

Key take‑home sentence: FNBP1L is a clinically relevant candidate for Alzheimer disease risk, meriting further functional validation to enhance its translational potential in diagnostic decision‑making and commercial applications.

References

• medRxiv • 2020 • Whole‑genome sequencing reveals new Alzheimer’s disease‑associated rare variants in loci related to synaptic function and neuronal development PMID:33173892
• Alzheimer's & Dementia: The Journal of the Alzheimer's Association • 2021 • Whole‑genome sequencing reveals new Alzheimer’s disease‑associated rare variants in loci related to synaptic function and neuronal development PMID:33797837

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