Abstract
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.
Uniparental disomy, the inheritance of two copies of a chromosomal region from one parent, may generate homozygosity for a deleterious recessive variant when the chromosomal region is from the same parental allele (isodisomy). In this study, we identified chromosomal uniparental isodisomy from one proband's whole‐exome sequencing (WES) while screening 96 simplex, non‐consanguineous families of patients affected by hereditary ataxia and a spectrum of motoneuron diseases including ALS, ALS‐FTD and Hereditary Spastic Paraplegia (HSP).
