Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder.

Genetics in medicine : official journal of the American College of Medical Genetics 2023 Sep

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5-methylcytosine RNA modifications are driven by NSUN methyltransferases. Although variants in NSUN2 and NSUN3 were associated with neurodevelopmental diseases, the physiological role of NSUN6 modifications on transfer RNAs and messenger RNAs remained elusive. We combined exome sequencing of consanguineous families with functional characterization to identify a new neurodevelopmental disorder gene. We identified 3 unrelated consanguineous families with deleterious homozygous variants in NSUN6. Two of these variants are predicted to be loss-of-function. One maps to the first exon and is predicted to lead to the absence of NSUN6 via nonsense-mediated decay, whereas we showed that the other maps to the last exon and encodes a protein that does not fold correctly. Likewise, we demonstrated that the missense variant identified in the third family has lost its enzymatic activity and is unable to bind the methyl donor S-adenosyl-L-methionine. The affected individuals present with developmental delay, intellectual disability, motor delay, and behavioral anomalies. Homozygous ablation of the NSUN6 ortholog in Drosophila led to locomotion and learning impairment. Our data provide evidence that biallelic pathogenic variants in NSUN6 cause one form of autosomal recessive intellectual disability, establishing another link between RNA modification and cognition. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Francesca Mattioli, Lina Worpenberg, Cai-Tao Li, Nazia Ibrahim, Shagufta Naz, Saima Sharif, Saghar G Firouzabadi, Shohreh Vosoogh, Radoslava Saraeva-Lamri, Laure Raymond, Carlos Trujillo, Nicolas Guex, Stylianos E Antonarakis, Muhammad Ansar, Hossein Darvish, Ru-Juan Liu, Jean-Yves Roignant, Alexandre Reymond. Biallelic variants in NSUN6 cause an autosomal recessive neurodevelopmental disorder. Genetics in medicine : official journal of the American College of Medical Genetics. 2023 Sep;25(9):100900