SUFU Loss-of-Function Heterozygous Variants Cause a Distinct Neurodevelopmental Delay With Simultaneous Effects on Brain Size

Heterozygous loss-of-function variants in SUFU are associated with Gorlin syndrome (MIM:620343) and tumor predisposition, while biallelic missense variants underlie recessive Joubert syndrome (JS; MIM:617757). Interestingly, emerging evidence suggests that SUFU haploinsufficiency also contributes to neurodevelopmental disorders (NDDs). We investigated 5 unrelated families encompassing 4 singletons and 1 pair of monozygotic twins carrying heterozygous SUFU loss-of-function variants through clinical, neuropsychological, and neuroimaging assessments and compared their features with 47 published cases fulfilling NDDs inclusion criteria. A consistent neurodevelopmental phenotype was observed, characterized by global developmental delay, hypotonia, congenital ocular motor apraxia, macrocephaly, and mild cerebellar abnormalities, including vermian hypoplasia and posterior fossa anomalies, variably falling within the JS spectrum. Craniofacial features were variably observed in our cohort and are reported as supportive clinical observations. Intellectual disability was present in similar to 35% of affected individuals, while autism spectrum disorder and behavioral difficulties occurred less frequently. Notably, neoplastic manifestations were absent among our cases, indicating that oncological and neurodevelopmental outcomes may segregate independently. SUFU haploinsufficiency may underlie a distinct dominantly inherited neurodevelopmental syndrome spanning from isolated ocular motor apraxia to a mild Joubert-like phenotype with macrocephaly and variable cognitive/behavioral outcomes. These findings further refine the clinical description of the SUFU-related neurodevelopmental phenotype beyond tumor predisposition and support its inclusion in diagnostic panels for developmental delay, macrocephaly, and JS-spectrum disorders. Multidisciplinary surveillance, balancing neurodevelopmental and oncological aspects, is recommended.