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RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder

Patrick Santens (UGent) , Tim Van Damme (UGent) , Wouter Steyaert (UGent) , Andy Willaert (UGent) , Bernard Sablonnière, Anne De Paepe (UGent) , Paul Coucke (UGent) and Bart Dermaut (UGent)
(2015) NEUROLOGY. 84(17). p.1760-1766
Author
Organization
Abstract
Objective: To identify the genetic cause in 2 Belgian families with autosomal recessive Huntington-like disorder (HDL). Methods: Homozygosity mapping and whole-exome sequencing in a consanguineous family as well as Sanger sequencing of the candidate gene in an independent family with HDL followed by genotype-phenotype correlation studies. Results: We identified a homozygous mutation in the gene RNF216 p.(Gly456Glu) within a shared 4.8-Mb homozygous region at 7p22.3 in 2 affected siblings of a consanguineous HDL family. In an independent family, 2 siblings with HDL were compound heterozygous for mutations in RNF216 p.(Gln302*) and p.(Tyr539Cys). Chorea, behavioral problems, and severe dementia were the core clinical signs in all patients. Brain imaging consistently showed white matter lesions. Low gonadotropin serum levels and cerebellar atrophy could be demonstrated in the index family. Conclusions: Mutations in RNF216 have recently been found in families with Gordon Holmes syndrome, a condition defined by hypogonadotropic hypogonadism and cerebellar ataxia. The mode of inheritance was proposed to be oligogenic for most families. We describe novel RNF216 mutations causing an HDL phenotype with pure monogenic recessive inheritance. Subclinical serum evidence of hypogonadotropic hypogonadism links this disorder to Gordon Holmes syndrome. Our study thus challenges the oligogenic inheritance model and emphasizes chorea as an essential clinical feature in RNF216-mediated neurodegeneration.
Keywords
REPEAT EXPANSION, DISEASE PHENOCOPY, DEGENERATION

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MLA
Santens, Patrick et al. “RNF216 Mutations as a Novel Cause of Autosomal Recessive Huntington-like Disorder.” NEUROLOGY 84.17 (2015): 1760–1766. Print.
APA
Santens, P., Van Damme, T., Steyaert, W., Willaert, A., Sablonnière, B., De Paepe, A., Coucke, P., et al. (2015). RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. NEUROLOGY, 84(17), 1760–1766.
Chicago author-date
Santens, Patrick, Tim Van Damme, Wouter Steyaert, Andy Willaert, Bernard Sablonnière, Anne De Paepe, Paul Coucke, and Bart Dermaut. 2015. “RNF216 Mutations as a Novel Cause of Autosomal Recessive Huntington-like Disorder.” Neurology 84 (17): 1760–1766.
Chicago author-date (all authors)
Santens, Patrick, Tim Van Damme, Wouter Steyaert, Andy Willaert, Bernard Sablonnière, Anne De Paepe, Paul Coucke, and Bart Dermaut. 2015. “RNF216 Mutations as a Novel Cause of Autosomal Recessive Huntington-like Disorder.” Neurology 84 (17): 1760–1766.
Vancouver
1.
Santens P, Van Damme T, Steyaert W, Willaert A, Sablonnière B, De Paepe A, et al. RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. NEUROLOGY. 2015;84(17):1760–6.
IEEE
[1]
P. Santens et al., “RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder,” NEUROLOGY, vol. 84, no. 17, pp. 1760–1766, 2015.
@article{6858874,
  abstract     = {Objective: To identify the genetic cause in 2 Belgian families with autosomal recessive Huntington-like disorder (HDL).
Methods: Homozygosity mapping and whole-exome sequencing in a consanguineous family as well as Sanger sequencing of the candidate gene in an independent family with HDL followed by genotype-phenotype correlation studies.
Results: We identified a homozygous mutation in the gene RNF216 p.(Gly456Glu) within a shared 4.8-Mb homozygous region at 7p22.3 in 2 affected siblings of a consanguineous HDL family. In an independent family, 2 siblings with HDL were compound heterozygous for mutations in RNF216 p.(Gln302*) and p.(Tyr539Cys). Chorea, behavioral problems, and severe dementia were the core clinical signs in all patients. Brain imaging consistently showed white matter lesions. Low gonadotropin serum levels and cerebellar atrophy could be demonstrated in the index family.
Conclusions: Mutations in RNF216 have recently been found in families with Gordon Holmes syndrome, a condition defined by hypogonadotropic hypogonadism and cerebellar ataxia. The mode of inheritance was proposed to be oligogenic for most families. We describe novel RNF216 mutations causing an HDL phenotype with pure monogenic recessive inheritance. Subclinical serum evidence of hypogonadotropic hypogonadism links this disorder to Gordon Holmes syndrome. Our study thus challenges the oligogenic inheritance model and emphasizes chorea as an essential clinical feature in RNF216-mediated neurodegeneration.},
  author       = {Santens, Patrick and Van Damme, Tim and Steyaert, Wouter and Willaert, Andy and Sablonnière, Bernard and De Paepe, Anne and Coucke, Paul and Dermaut, Bart},
  issn         = {0028-3878},
  journal      = {NEUROLOGY},
  keywords     = {REPEAT EXPANSION,DISEASE PHENOCOPY,DEGENERATION},
  language     = {eng},
  number       = {17},
  pages        = {1760--1766},
  title        = {RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder},
  url          = {http://dx.doi.org/10.1212/WNL.0000000000001521},
  volume       = {84},
  year         = {2015},
}

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