Diagnostic Utility of Collaborative Gene Matching Databases in Delineating a Novel Neurodevelopmental Syndrome Associated with a de novo NACC1 Mutation
Here, we describe seven children with a neurodevelopmental disorder characterized by microcephaly, profound developmental delays and/or intellectual disability, cataracts, severe epilepsy including infantile spasms, irritability, failure to thrive, and stereotypic hand movements. Brain imaging in these individuals reveals delay in myelination and cerebral atrophy (1).All patients were independently found to have a de novo, heterozygous, missense variant (c.892C>T, p.Arg298Trp) in the nucleus accumbens associated 1 (NACC1) gene. There was evidence for potential mosaicism of the variant in one patient who presented with a milder phenotype.
The seven patients enrolled by Duke, Baylor and UCLA were able to connect through the databases and online search functions of GeneMatcher and the Undiagnosed Disease Network (2).NACC1 encodes a transcriptional repressor implicated in gene expression and has not previously been associated with germline disorders,
The probability of finding the same missense NACC1 variant by chance in 7 out of 17,228 individuals who underwent WES for diagnoses of neurodevelopmental phenotypes is extremely small and achieves genome-wide significance (p =1.25x10^14). Selective constraint against missense variants in NACC1 makes this excess of an identical missense variant in all seven individuals more remarkable.