Solving Disease Mysteries

In an effort to address undiagnosed rare diseases, the Solve-Rare Diseases (Solve-RD) Consortium identified molecular diagnoses for 13 percent of previously unsolved cases through comprehensive genomic reanalysis. This pan-European initiative, detailed in Nature Medicine, systematically reanalyzed genomic data from 6,004 families affected by rare diseases, providing diagnostic clarity for 506 families (8 percent) through systematic reanalysis and an additional 4 percent via expert ad hoc reviews.

The study analyzed 9,874 datasets, detecting 552 disease-causing variants. Most (84 percent) were single-nucleotide variants (SNVs) or short insertions/deletions (InDels), with others including copy number variants (CNVs) and structural variants (SVs). Tools like SpliceAI and ExpansionHunter identified previously missed complex mutations.

Examples of Solve-RD success include:

• A neurological disorder was resolved with the discovery of a missense variant and deletion in B4GALT1, confirmed through functional testing.
• Pathogenic variants in PIK3CA and MN1 ended long diagnostic searches in intellectual disability cases.
• A mitochondrial mutation (MT-TL1) explained varying symptoms in a mother and son.

About 14 percent of diagnoses linked to actionable genes led to potential treatments or surveillance, including targeted therapies for neuromuscular conditions like limb-girdle myasthenic syndrome.

Solve-RD’s scalable framework demonstrates the potential of reanalysis to address undiagnosed rare diseases globally. The resource is open for future research, with plans to expand to additional rare diseases and adopt advanced sequencing technologies.