2017
DOI: 10.1093/brain/awx095
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Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia

Abstract: Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequenc… Show more

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Cited by 93 publications
(153 citation statements)
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“…6 It is also well established that hypomyelination on brain MRI is not obligate in POLR3-related disorder. [27][28][29][30] Therefore, we cannot exclude that the 5 patients with TCS attributed to variants in POLR1C could have a mild form of POLR3-HLD, with only subtle neurologic manifestations, if any. We suspect that there is a spectrum of disease severity for both the hypomyelination and the non-neurologic manifestations in POLR3-HLD caused by biallelic POLR1C variants, as it is the case in patients carrying pathogenic variants in POLR3A or POLR3B.…”
Section: Discussionmentioning
confidence: 99%
“…6 It is also well established that hypomyelination on brain MRI is not obligate in POLR3-related disorder. [27][28][29][30] Therefore, we cannot exclude that the 5 patients with TCS attributed to variants in POLR1C could have a mild form of POLR3-HLD, with only subtle neurologic manifestations, if any. We suspect that there is a spectrum of disease severity for both the hypomyelination and the non-neurologic manifestations in POLR3-HLD caused by biallelic POLR1C variants, as it is the case in patients carrying pathogenic variants in POLR3A or POLR3B.…”
Section: Discussionmentioning
confidence: 99%
“…Despite all progress with NGS, z50% of patients with the clinical suspicion of ARCA remain without a molecular diagnosis. This may reflect not only new ARCA genes but also mutations in established genes that escape current diagnostic strategies such as deep intronic mutations, mutations in regulatory regions, epigenetic changes, gene dosage effects, or digenic modes of inheritance (for examples, see Bonifert et al, 2014;Minnerop et al, 2017).…”
Section: Arca: a Rapidly Growing Number Of Genes And Expanding Phenotmentioning
confidence: 99%
“…However, deep intronic pathogenic variants that have been described in some individuals with hereditary ataxia are not reliably detected by clinical exome sequencing. 8 How to compare molecular genetic testing options? If the clinical features or family history suggest a specific hereditary ataxia, single gene testing can be considered.…”
Section: Clinical Exome Sequencingmentioning
confidence: 99%