A Clinical Study of Nine Patients With ReNU Syndrome

ReNU syndrome, also known as neurodevelopmental disorder with hypotonia, brain anomalies, distinctive facies, and absent language (NEDHAFA), is characterized by hypotonia, global developmental delay, intellectual disability with poor or absent speech, delayed motor development, feeding difficulties, short stature, seizures, and dysmorphic features. Neuroradiological abnormalities, including ventriculomegaly, hypoplasia of the corpus callosum, and a decreased white matter volume, are observed in many individuals. Most individuals have the same highly recurrent single base insertion (n.64_65insT) in RNU4-2. RNU4-2 encodes U4 small nuclear RNA, which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome. We reviewed exome sequencing and genome sequencing data from previous patients with neurodevelopmental disorders that matched the clinical features of ReNU syndrome and performed a hotspot analysis using the Sanger method. A recurrent variant in RNU4-2 was identified in eight patients, while the rare variant, n.66A>G, was detected in one patient. Nine patients aged between 3 and 29 years all showed severe developmental delay and/or intellectual disability. Independent walking was achieved by five patients. In six patients, meaningful words had not been acquired, even after the age of 5 years. All patients showed a distinctive pattern of dysmorphic features, including hooded upper eyelids, full cheeks, a tented philtrum, and a mouth constantly slightly open with an everted lower lip vermilion. All patients had neuroradiological abnormalities. The identification of nine patients at a single institution reaffirmed that ReNU syndrome is an important cause of ID. ReNU syndrome is considered a clinically recognizable syndrome. If clinically suspected, it is reasonable to examine the 18-base pair region using the Sanger method.