The NR2F1-Related 5q14.3-q21.1 deletion causing periventricular heterotopia with cerebral visual impairment: a...

Large interstitial deletions spanning chromosome 5q14.3 to q21.1 and encompassing NR2F1 are rare. Existing descriptions have largely focused on structural features and presenting manifestations, with fewer reports examining functional neurodevelopmental outcomes over time, particularly in individuals with large interstitial deletions. Here, we present a 16-year longitudinal analysis of an individual with a de novo 13.58 Mb interstitial deletion of 5q14.3 to q21.1 encompassing NR2F1 (ClinVar accession SCV007328941), consistent with NR2F1-related neurodevelopmental disorder, historically described under OMIM:615722 (Bosch-Boonstra-Schaaf optic atrophy syndrome). We integrate longitudinal clinical, visual, neurological, and developmental data to examine relationships between optic nerve findings, periventricular heterotopia (PH; OMIM:612881, chromosome 5q14.3 deletion syndrome), cerebral visual impairment (CVI), epilepsy, hypotonia, and long-term functional outcomes. The index case manifested PH and severe CVI from infancy, with profound hypotonia associated oromotor and airway dysfunction. Epilepsy first manifested during adolescence. Longitudinal in-depth analysis suggests that CVI may represent a key mediating factor underlying cognitive, behavioral, and communicative difficulties. Substantial latent cognitive capacity was revealed once visual complexity was reduced and environments appropriately adapted. Analysis of published cases indicates that PH is an uncommon but recurrent feature of NR2F1 haploinsufficiency and suggests that optic atrophy can be secondary to cerebral visual pathway dysfunction. This case highlights that longitudinal functional assessment can enhance genotype-phenotype interpretation in rare genomic disorders and provide clinically actionable insights for diagnosis, management, and outcome prediction.