Clinical and Genetic Findings in Two Japanese Individuals With SET-Related Neurodevelopmental Disorder

SET-related neurodevelopmental disorder (OMIM #618106) is an emerging condition for which the phenotypic spectrum remains incompletely defined. We report two unrelated Japanese individuals with distinct genomic alterations affecting SET: a de novo frameshift variant and a heterozygous 9q34.11 microdeletion encompassing the gene. Both individuals presented with global developmental delay, intellectual disability, and overlapping craniofacial features, including a broad nasal bridge, broad nasal tip, wide mouth, and periorbital fullness. These features were broadly consistent with those described in previously reported individuals, suggesting a shared pattern of craniofacial characteristics associated with SET disruption. Both individuals exhibited a sociable behavioral tendency was observed in both individuals, whereas formal neurodevelopmental diagnoses such as autism spectrum disorder or attention-deficit/hyperactivity disorder were not consistently identified. Comparison with previously reported individuals, including those with protein-truncating variants, missense variants, and copy number alterations, showed that neurodevelopmental impairment is a consistent feature, while craniofacial and behavioral findings appear variable. In the individual with the microdeletion, contributions from neighboring genes cannot be fully excluded. These findings further delineate the clinical spectrum of SET-related neurodevelopmental disorder and support the importance of careful phenotypic characterization in its recognition.