Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Many patients with rare movement disorders (MD) lack molecular diagnoses.
• Underlying genetic variants and genes for MDs remain largely unknown.

Purpose of the Study:

• Evaluate genetic testing diagnostic accuracy in ataxia, spastic paraplegia, and dystonia.
• Identify novel genetic causes for unsolved rare movement disorders.

Main Methods:

• Analyzed 2,811 individuals using exome and whole genome sequencing.
• Performed gene-burden analysis on unsolved cases.
• Conducted cellular and transcriptome studies on patient-derived cells.

Main Results:

• Exome sequencing yielded diagnoses in 19.3% of cases.
• Genome sequencing beyond the exome increased diagnostic yield by 7.5%.
• Identified loss-of-function variants in CD99L2 as a cause of spastic ataxia, impacting CAPN1 interaction and synaptic function.

Conclusions:

• Advanced genetic sequencing strategies significantly improve diagnostic rates for rare movement disorders.
• CD99L2 variants disrupting CAPN1 signaling are implicated in neurodegeneration and spastic ataxia.