Biallelic loss-of-function variants in DSCAM cause a neurodevelopmental syndrome with nystagmus and retinal dysfunction.

DSCAM occupies a 1-Mb locus in the original Down syndrome critical region on chromosome 21q22 and encodes a neuronal cell adhesion molecule of importance for brain and eye development. Singleton individuals, both born to first-cousin parents, with intellectual disability and homozygous DSCAM loss-of-function variants were reported in 2017 and in 2021, the latter also presenting with nystagmus and visual impairment. We present a cohort of five individuals, four new, including two sibling pairs with homozygosity or compound heterozygosity for predicted loss-of-function DSCAM variants. We identify a common clinical pattern of moderate to severe neurodevelopmental delay with poor language development, risk of focal seizures with onset in infancy, and nystagmus with poor vision. Electroretinography in two of the affected revealed cone-pathway dysfunction with a b-wave pattern indicating main dysfunction at the level of the cone-associated bipolar cells of the central retina. Our electroclinical findings are in line with previous DSCAM knockout chicken and mice studies that evidenced disturbed horizontal and vertical patterning of the retina. Taken together, we delineate a rare syndromic form of recessive intellectual disability with a distinctive type of visual impairment.