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Published on: April 4, 2018
A Homozygous c.74A>G Variant in PRKRA Causes DYT-PRKRA: Extensive Familial Segregation and a Variant of Uncertain
Fatemeh Soleymani1, Fahimeh Piryaei2,3, Arezoo Farhadi4
1Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
Background:
DYT-PRKRA is a rare, autosomal recessive movement disorder caused by mutations in the PRKRA gene. While PRKRA mutations are recognized in DYT-PRKRA, a significant number of identified variants are still classified as "variant of uncertain significance" (VUS).
Objective:
In this study we identified a causative variant previously reported as a VUS.
Methods:
A 4.5-year-old female born to consanguineous, healthy parents presented with progressive neurodevelopmental regression, similar to two affected relatives. Whole-exome sequencing was performed, and segregation analysis was conducted across two generations.
Results:
A homozygous PRKRA c.74A>G (p.Lys25Arg) variant co-segregated with the DYT-PRKRA phenotype. Unaffected family members were identified as heterozygous carriers.
Conclusions:
This is the first report of DYT-PRKRA in the Iranian population. Strong evidence from familial segregation and in silico analyses support the reclassification of this variant to likely pathogenic. This reclassification has significant implications for the diagnosis and genetic counseling of families affected by DYT-PRKRA. © 2025 International Parkinson and Movement Disorder Society.
Insights
This study reclassifies a previously uncertain PRKRA gene variant as likely pathogenic, identifying it as the cause of DYT-PRKRA movement disorder in an Iranian family. This finding aids in diagnosing and counseling affected families.
Area of Science:
- Genetics
- Neuroscience
- Rare Diseases
Background:
- DYT-PRKRA is a rare autosomal recessive movement disorder linked to PRKRA gene mutations.
- Many identified PRKRA variants are currently classified as variants of uncertain significance (VUS).
Purpose of the Study:
- To identify a causative variant for DYT-PRKRA that was previously classified as VUS.
- To report the first case of DYT-PRKRA in the Iranian population.
Main Methods:
- Whole-exome sequencing was performed on a pediatric patient with progressive neurodevelopmental regression.
- Segregation analysis was conducted across two generations of a consanguineous family.
Main Results:
- A homozygous PRKRA c.74A>G (p.Lys25Arg) variant was identified and segregated with the DYT-PRKRA phenotype.
- Unaffected family members were heterozygous carriers of the variant.
Conclusions:
- The PRKRA c.74A>G variant is reclassified from VUS to likely pathogenic based on familial segregation and in silico data.
- This reclassification has significant implications for diagnosing and providing genetic counseling for DYT-PRKRA.
- This study marks the first report of DYT-PRKRA in the Iranian population.
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