Duplications at 19q13.33 in patients with neurodevelopmental disorders.

OBJECTIVE

After the recent publication of the first patients with disease-associated missense variants in the gene, we evaluate the effect of copy number variants (CNVs) overlapping this gene toward the presentation of neurodevelopmental disorders (NDDs).

METHODS

We explored ClinVar (number of CNVs = 50,794) and DECIPHER (number of CNVs = 28,085) clinical databases of genomic variations for patients with copy number changes overlapping the gene at the 19q13.33 locus and evaluated their respective phenotype alongside their frequency, gene content, and expression, with publicly available reference databases.

RESULTS

We identified 11 patients with microduplications at the 19q13.33 locus. The majority of CNVs arose de novo, and comparable CNVs are not present in control databases. All patients were reported to have NDDs and dysmorphic features as the most common clinical phenotype (N = 8/11), followed by seizures (N = 6/11) and intellectual disability (N = 5/11). All duplications shared a consensus region of 405 kb overlapping 13 genes. After screening for duplication tolerance in control populations, positive gene brain expression, and gene dosage sensitivity analysis, we highlight 4 genes for future evaluation: , , , and , which are promising candidates for disease causality. Furthermore, investigation of the literature especially supports as the best candidate gene.

CONCLUSIONS

Our study presents dup19q13.33 as a novel duplication syndrome locus associated with NDDs. , , , and are promising candidates for functional follow-up.