Expanding Clinical and Genetic Landscape of SATB2-Associated Syndrome

SATB2-associated syndrome (SAS), also known as Glass syndrome, is a neurodevelopmental disorder (NDD) characterized by intellectual disability, developmental delay, absent or limited speech, and distinctive craniofacial and dental anomalies. It is caused by autosomal dominant pathogenic variants in the SATB2 gene, which plays a crucial role in brain, dental, and jaw development. Due to its variable phenotype, clinical diagnosis can be challenging, necessitating genetic confirmation.

We present six new cases of SAS with SATB2 germline variants identified through next generation sequencing (NGS) technologies, expanding the known genetic and clinical spectrum of the syndrome. Detailed clinical phenotyping was performed for all patients.

Our cohort exhibits a broad range of clinical manifestations consistent with SAS, encompassing severe intellectual disability, profound speech delay, various palatal and dental abnormalities. We report the oldest adult patient (56 years old) carrying an in-frame duplication, and a pediatric patient with a missense variant who presented a significant reduction in visual acuity, likely of neurological or cortical origin, in the absence of ophthalmological abnormalities. SATB2 variants include three missenses, two in-frame deletion/duplication and one frameshift variant, several of which are novel and classified as likely pathogenic or pathogenic according to ACMG guidelines.

This report provides new clinical and genetic insights into the landscape of SAS. Our findings confirm the phenotypic heterogeneity of SAS and highlight the critical role of comprehensive genetic testing for accurate diagnosis in NDD patients.