Phenotypic and Genetic Insights Into CNOT3-Related Intellectual Developmental Disorder of Speech Delay, Autism, and...

Intellectual Developmental Disorder with Speech Delay, Autism, and Dysmorphic Faces (IDDSADF) is a rare neurodevelopmental disorder caused by heterozygous variants in CNOT3. Although several cohorts have been documented worldwide, no Japanese patients have been reported to date. Here, we present the first two Japanese cases of IDDSADF, an 8-year-old girl and a 19-year-old boy, both presenting with developmental delay, characteristic facial features, and short stature. Both individuals exhibited a thin, tented upper lip, a morphology that has been rarely reported in other cohorts and may represent an ethnicity-associated trait. Growth impairment was observed either from early childhood or emerging after puberty and may represent an underrecognized aspect of the phenotype. Trio-exome sequencing identified pathogenic CNOT3 variants in both patients, including a recurrent frameshift (c.732dup, p.Ser245fs) and a novel splice-site substitution (c.837+1G>A). Our findings expand the phenotypic and mutational spectrum of IDDSADF, highlighting the importance of longitudinal auxological assessment and recognition of potential ethnicity-associated facial traits in its clinical diagnosis and management.