SATB2 – 2q32-q33 Deletion Syndrome

Chromosome 2q32-q33 microdeletion syndrome is characterized by intellectual disability, dental anomalies, growth delay, and behavioral problems. Heterozygous deletions spanning SATB2 (Special AT-rich binding protein 2) have been implicated in this syndrome, consistent with a haploinsufficiency mechanism.

Three unrelated individuals carrying 173.1–185.2 kb deletions that partially span SATB2 presented with severe developmental delay, tooth abnormalities, and behavioral features, one with cleft palate (PMID:19668335). Additionally, a 37-year-old female with an 8.6 Mb 2q32.2q33.1 deletion encompassing SATB2 exhibited characteristic behavioral phenotype and secondary cognitive decline (PMID:26811410). These four probands all harbored de novo deletions implicating SATB2 haploinsufficiency.

A de novo monoallelic frameshift variant c.1135del (p.Gln379LysfsTer34) was identified in a 13-year-old girl with developmental delay and behavioral problems, further supporting a loss-of-function mechanism for SATB2 (PMID:39300047).

In Satb2 mutant mice, heterozygous and conditional knockouts exhibit impaired hippocampus-dependent long-term potentiation, reduced dendritic spine density and branching in CA1 neurons, and decreased expression of immediate early genes (Fos, FosB, Egr1), mirroring human cognitive deficits (PMID:28421537).

Mechanistic studies demonstrate that SATB2 activates UPF3B transcription by direct promoter binding. Patient leukocytes with SATB2 nonsense mutations show reduced UPF3B expression; Satb2 knockout embryonic tissue replicates this decrease, indicating a dominant-negative effect on a shared neurodevelopmental pathway (PMID:23925499).

No conflicting evidence has been reported that disputes the role of SATB2 haploinsufficiency in 2q32-q33 deletion syndrome.

Together, these data support a haploinsufficiency model in which heterozygous loss of SATB2 causes the core neurodevelopmental, craniofacial, and dental features of 2q32-q33 microdeletion syndrome. Genetic testing including CNV analysis and sequence screening of SATB2 is essential for definitive diagnosis and tailored management. Key take-home: SATB2 haploinsufficiency is a primary driver of the phenotype in 2q32-q33 deletion syndrome.

References

• PLoS One • 2009 • Small deletions of SATB2 cause some of the clinical features of the 2q33.1 microdeletion syndrome. PMID:19668335
• The Journal of international medical research • 2016 • Specific behavioural phenotype and secondary cognitive decline as a result of an 8.6 Mb deletion of 2q32.2q33. PMID:26811410
• International journal of developmental neuroscience • 2024 • Novel variant related to SATB2-associated syndrome. PMID:39300047
• Molecular neurobiology • 2017 • Satb2 Ablation Impairs Hippocampus-Based Long-Term Spatial Memory and Short-Term Working Memory and Immediate Early Genes (IEGs)-Mediated Hippocampal Synaptic Plasticity. PMID:28421537
• Human genetics • 2013 • Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene. PMID:23925499

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