Clinical and genetic spectrum ofRNF216-related disorder: a new case and literature review

Abstract

BackgroundCases ofRNF216-related disorder have been reported sporadically. However, the clinical and genetic spectrum of this disorder has not been fully studied.MethodsWe identified an individual with a novel causativeRNF216variant in our institution and reviewed all individuals with causativeRNF216variants in previous reports. The clinical and genetic features of all the described individuals were analysed and summarised.ResultsTwenty-four individuals from 17 families with causativeRNF216variants were identified. The mean age at the onset of neurological symptoms was 29.2 years (range 18–49 years). Ataxia (57%) was the most frequent initial symptoms in individuals under 30 years old, while chorea (63%) was the most frequent initial symptom in individuals over 30 years old. Over 90% of individuals presented with cognitive impairment and hypogonadotropic hypogonadism throughout the disease. White matter lesions (96%) and cerebellar atrophy (92%) were the most common imaging findings. Twenty pathogenic variants inRNF216were detected. The variants in 12 (71%) families were inherited in a monogenic recessive pattern, whereas the variants in 5 (29%) were inherited in a digenic pattern by acting with variants in other genes. The majority of theRNF216variants (85%) resulted in amino acid changes or the truncation of the ‘RING between RING’ (RBR) domain or C-terminal extension.ConclusionRNF216-related disorder is an inherited neuroendocrine disease characterised by cerebellar ataxia, chorea, cognitive impairment and hypogonadotropic hypogonadism. Most causative variants in patients withRNF216-related disorder influence the RBR domain or C-terminal extension of RNF216.