17q11.2 Duplication (includes NF1 gene): A Scoping Review

Several neurodevelopmental disorder (NDD)-associated copy-number variants (CNVs) show reciprocal dosage effects, where deletions and duplications produce mirroring phenotypes. While NF1 microdeletion syndrome is well-characterized, the reciprocal NF1 microduplication remains poorly defined. This scoping review assesses whether NF1 microduplications constitute a recognizable syndrome with reciprocal features to NF1 microdeletion syndrome.

We conducted a scoping review following reporting guidelines, extracting clinical and molecular data from publications reporting individuals with 17q11.2 microduplications involving NF1. We queried DECIPHER using identical criteria and applied Bayesian statistics to recalculate NDD penetrance estimates.

Across 14 studies, 37 individuals were identified. Among those with duplications reciprocal to type 1 or 2 NF1 microdeletions, NDD/neurobehavioral disorders were observed in 85%, including developmental delay (85%), intellectual disability or learning difficulties (57%), and autism spectrum disorder (29%). Growth abnormalities more commonly mirrored the deletion phenotype, with short stature (35%) and microcephaly (29%). Penetrance estimates for NDDs (25-40%) were markedly lower than recently reported (74%).

NF1 microduplications confer NDD risk and show partially reciprocal but heterogeneous phenotypic features compared to NF1 microdeletion syndrome, without defining a distinct syndrome. They are best interpreted as moderate-penetrance neurodevelopmental-susceptibility CNVs. Population-based studies are needed to refine estimates and inform genetic counseling.