AI Article Synopsis
- Objective: The study aimed to identify a unique mechanism for revealing recessive hereditary spastic paraplegias.
- Method: Researchers discovered 4 new homozygous FA2H mutations in non-related families using whole-exome sequencing and targeted gene analysis, confirming one parent as a mutation carrier.
- Results: All families exhibited uniparental disomy (UPD) leading to homozygous FA2H mutations, which is a rare mechanism in neurodegenerative diseases, emphasizing the necessity of segregation analysis in similar cases.
Article Abstract
Objective: Identifying an intriguing mechanism for unmasking recessive hereditary spastic paraplegias.
Method: Herein, we describe 4 novel homozygous FA2H mutations in 4 nonconsanguineous families detected by whole-exome sequencing or a targeted gene panel analysis providing high coverage of all known hereditary spastic paraplegia genes.
Results: Segregation analysis revealed in all cases only one parent as a heterozygous mutation carrier whereas the other parent did not carry FA2H mutations. A macro deletion within FA2H, which could have caused a hemizygous genotype, was excluded by multiplex ligation-dependent probe amplification in all cases. Finally, a microsatellite array revealed uniparental disomy (UPD) in all 4 families leading to homozygous FA2H mutations. UPD was confirmed by microarray analyses and methylation profiling.
Conclusion: UPD has rarely been described as causative mechanism in neurodegenerative diseases. Of note, we identified this mode of inheritance in 4 families with the rare diagnosis of spastic paraplegia type 35 (SPG35). Since UPD seems to be a relevant factor in SPG35 and probably additional autosomal recessive diseases, we recommend segregation analysis especially in nonconsanguineous homozygous index cases to unravel UPD as mutational mechanism. This finding may bear major repercussion for genetic counseling, given the markedly reduced risk of recurrence for affected families.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940069 | PMC |
| http://dx.doi.org/10.1212/WNL.0000000000002843 | DOI Listing |
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