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

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.