Genetics

Targeted long-read WGS improves diagnosis and cost-effectiveness in hypotonia and muscle weakness

In 227 hypotonia patients, standard testing achieved a 42% diagnostic yield with substantial delays from sequential assays. A targeted long-read whole-genome workflow accurately detected known pathogenic SNVs, CNVs, SVs, repeat expansions, and methylation defects in a positive reference cohort. Applied to unsolved cases, long-read sequencing provided one definitive and one possible additional diagnosis, adding 14% yield in that subgroup. Modeling in patients diagnosed after sequential testing suggested long-read WGS could cut time-to-diagnosis by about 85% with projected healthcare cost savings. Across the full cohort, the long-read approach was predicted to reduce overall testing costs by 6.5%, saving approximately $105 per patient. 1

Integrated functional data enables high-accuracy classification of BRCA2 DBD variants

This study combined functional results from two saturation genome editing datasets covering 6,383 BRCA2 DNA-binding domain single nucleotide variants. An integrated VarCall model using raw functional scores achieved 98.8% accuracy against variants with known clinical classifications, outperforming the original studies. Using ClinGen BRCA1/2 expert panel rules, incorporation of these functional data enabled classification of 5,926 variants as pathogenic or benign. In total, 735 variants were classified as pathogenic and 5,191 as benign, substantially reducing variants of uncertain significance for the BRCA2 DBD. 2

Population-scale STR analysis links repeat size to disease risk and preclinical neurodegeneration

Investigators analyzed repeat lengths at 37 disease-associated STR loci in 1,020,833 exomes and genomes from diverse populations. They confirmed that pathogenic repeat alleles are generally more frequent than the diagnosed prevalence of their associated neurologic diseases. Repeat length showed expected associations with multiple traits, including Huntington disease with HTT and myotonic disorders with DMPK expansions. Carriers of several expansions had elevated neurofilament light chain levels and focal brain volume loss before clinical diagnosis. HTT expansion carriers showed a 22.1% reduction in putamen volume, and CACNA1A expansion carriers had a 24.6% cerebellar volume loss. 3

Saturation editing of RNU4-2 refines ReNU syndrome region and reveals a recessive disorder

Researchers performed saturation genome editing across the noncoding RNU4-2 gene, which encodes U4 snRNA of the major spliceosome. Function scores based on cell fitness separated known ReNU syndrome variants from population variants and outperformed in silico predictors. The data redefined the critical ReNU syndrome region at single-nucleotide resolution and helped resolve pathogenicity for multiple VUS. Function scores correlated with phenotypic severity and degree of splicing disruption, providing graded evidence for clinical interpretation. Variants affecting U4 interactions with other spliceosomal components were shown to cause a distinct recessive neurodevelopmental disorder. 4