Exome sequencing helps with HSP diagnosis

New gene-disease associations found


This Dutch study revealed new gene-disease associations and uncovered unanticipated rare disorders with 12 different gene variants identified in 16 HSPers.


Cerebellar ataxia (CA) and hereditary spastic paraplegia (HSP) are two of the most prevalent motor disorders with extensive locus and allelic heterogeneity.


We implemented clinical exome sequencing, followed by filtering data for a ‘movement disorders’ gene panel, as a generic test to increase variant detection in 76 patients with these disorders. Segregation analysis or phenotypic re-evaluation was utilized to substantiate findings.


Disease-causing variants were identified in 9 of 28 CA patients, and 8 of 48 HSP patients. In addition, possibly disease-causing variants were identified in 1 and 8 of the remaining CA and HSP patients, respectively. In 10 patients with CA, the total disease-causing or possibly disease-causing variants were detected in 8 different genes, whereas 16 HSP patients had such variants in 12 different genes.


In the majority of cases, the identified variants were compatible with the patient phenotype. Interestingly, in some patients variants were identified in genes hitherto related to other movement disorders, such as TH variants are in two siblings with HSP. In addition, rare disorders were uncovered, for example, a second case of HSP caused by a VCP variant. For some patients, exome sequencing results had implications for treatment, exemplified by the favorable L-DOPA treatment in a patient with HSP due to ATP13A2 variants (Parkinson type 9). Thus, clinical exome sequencing in this cohort of CA and HSP patients suggests broadening of disease spectra, revealed novel gene-disease associations, and uncovered unanticipated rare disorders. In addition, clinical exome sequencing results have shown their value in guiding practical patient management.


SOURCE: Eur J Hum Genet. 2016 May 11. doi: 10.1038/ejhg.2016.42. [Epub ahead of print] PMID: 27165006 [PubMed – as supplied by publisher]


Clinical exome sequencing for cerebellar ataxia and spastic paraplegia uncovers novel gene-disease associations and unanticipated rare disorders.


van de Warrenburg BP1, Schouten MI2, de Bot ST3, Vermeer S3, Meijer R2, Pennings M2, Gilissen C2, Willemsen MA1, Scheffer H2, Kamsteeg EJ2.


1 Department of Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.

2 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

3 Department of Human Genetics, University Medical Center Groningen, Groningen, The Netherlands.

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