NONO was first reported in relation to X-linked syndromic intellectual disability in 2015 (Mircsof et al., PMID: 26571461). Common phenotypes include global developmental delay, relative macrocephaly, corpus callosum anomalies, non-compaction ventricular cardiomyopathy, dysmorphic facies, and hypotonia. At least 15 variants have been reported in 19 male probands which are included in this curation (PMIDs: 26571461, 27329731, 27550220, 30773818, 31883306, 34549882, 36426740, 36653413). Most reported variants are truncating (nonsense, frameshift and splicing), including several recurrent variants. Additionally, a Xq13.1 deletion involving the first three coding exons of NONO was described in one male. A recurrent missense variant leading to mild loss-of-function was reported in two families (PMID: 36894578). Both de novo and maternally inherited variants have been described. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.
The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by Nono-deficient mice which have a flattened nose, mimicking the facial anomalies observed in patients, and a smaller cerebellum, also observed in patients (PMID: 26571461). Mutant mice showed impaired learning and memory, anxiety-like behavior, and defects at inhibitory synapses, where Nono regulates synaptic transcription (PMID: 26571461).
In summary, there is definitive evidence to support the relationship between NONO and X-linked syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 5, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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