Uniparental disomy determined by whole-exome sequencing in a spectrum of rare motoneuron diseases and ataxias

Background: The genetic causes of many rare inherited motoneuron diseases and ataxias (MND and ATX) remain largely unresolved, especially for sporadic patients, despite tremendous advances in gene discovery. Whole exome data is often available for patients, but it is rarely evaluated for unusual inheritance patterns, such as uniparental disomy (UPD). UPD is the inheritance of two copies of a chromosomal region from one parent, which may generate homozygosity for a deleterious recessive variant from only one carrier-parent. Detection of UPD-caused homozygous disease-causing variants is detrimental to accurate genetic counseling. Whole-exome sequencing can allow for the detection of such events.

Methods: We systematically studied the exomes of a phenotypically heterogeneous cohort of unresolved cases (n = 96 families) to reveal UPD events hindering a diagnosis and to evaluate the prevalence of UPD in recessive MND and ATX.

Results: One hereditary spastic paraplegia case harbored homozygous regions spanning 80% of chromosome 16. A homozygous disease-causing mutation in the SPG35 disease gene was then identified within this region.

Conclusion: This study demonstrates the ability to detect UPD in exome data of index patients. Our results suggest that UPD is a rare mechanism for recessive MND and ATX.