Genetics

Penetrance is a dynamic probability shaped by diverse genetic modifiers

This review summarizes how coding, regulatory, and structural variants together modulate penetrance across human diseases. Examples in steatotic liver disease, chronic kidney disease, and Alzheimer’s disease illustrate contributions from rare, intermediate-frequency, and polygenic variation. The authors emphasize distinct molecular mechanisms across the allele frequency spectrum, including ancestry-enriched modifiers. They highlight current gaps in integrating variant classes, context dependence, and temporal windows into individualized risk models. Clinically, the work supports replacing static penetrance tables with multicomponent, ancestry-informed risk assessments. 1

Germline structural variants produce measurable, ancestry-linked cancer proteomic changes

This proteogenomic study links germline structural variants with nearby protein expression changes in tumors from 1,637 cancer patients. Rare and singleton SVs disrupting expression of known cancer susceptibility genes collectively involve 6% of patients. About 24% of genes with SV-associated cis mRNA alterations show concordant protein-level differences, supporting functional impact. Both rare and common SVs influence protein expression in tumor-type–specific or pan-cancer patterns, with some ancestry-enriched events. SVs altering CpG island or enhancer methylation also affect protein levels, underscoring regulatory mechanisms. These findings support viewing germline SVs, including non-coding events, as plausible contributors to cancer heterogeneity and risk. 2

STRIPE targeted long-read RNA-seq clarifies splicing and upgrades rare-disease diagnoses

STRIPE is a targeted long-read RNA-seq approach enabling deep sequencing of full-length transcripts for customized disease-gene panels. In 88 rare-disease patients, STRIPE accurately reidentified known pathogenic variants and revealed often unexpected transcript consequences. Among 15 splice-region variants, over half showed complex RNA processing defects beyond single exon skipping or cryptic splice activation. Donor splice variants frequently activated cryptic intronic polyadenylation, causing premature transcript termination. The method also resolved variants of uncertain significance and identified disease-causing variants in five previously undiagnosed individuals. These results support targeted long-read RNA-seq when splicing effects or transcript structures are central to variant interpretation. 3

Low-level somatic mosaicism contributes to apparently sporadic ALS and FTD

Deep targeted sequencing of 88 neurodegeneration genes was performed on brain and spinal cord from 399 sporadic ALS/FTD cases and 144 controls. Predicted deleterious somatic variants in ALS/FTD genes were found in 2.1% of sporadic cases lacking deleterious germline variants. These mutations typically had allele fractions below 2%, were focal, and enriched in clinically affected regions. RNA-seq identified additional deleterious somatic variants in DYNC1H1 and LMNA, and long-read sequencing detected a de novo somatic C9orf72 repeat expansion. Findings suggest rare focal somatic variants can initiate widespread neurodegeneration in a subset of sporadic ALS/FTD. Clinically, this highlights limitations of blood-only testing and complicates recurrence risk estimates for such families. 4