SATB2-associated syndrome

Zarate YA, Kaylor J, Fish J. SATB2-Associated Syndrome. 2017 Oct 12. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK458647/

Excerpt

CLINICAL CHARACTERISTICS:

SATB2-associated syndrome (SAS) is a multisystem disorder characterized by significant neurodevelopmental compromise with limited to absent speech, behavioral issues, and craniofacial anomalies. All individuals described to date have manifest developmental delay / intellectual disability, with severe speech delay. Affected individuals often have hypotonia and feeding difficulties in infancy. Behavioral issues may include autistic features, hyperactivity, and aggressiveness. Craniofacial anomalies may include palatal abnormalities (cleft palate, high-arched palate, and bifid uvula), micrognathia, and abnormal shape or size of the upper central incisors. Less common features include skeletal anomalies (osteopenia, pectus deformities, kyphosis/lordosis, and scoliosis), growth restriction, strabismus/refractive errors, congenital heart defects, genitourinary anomalies, and epilepsy. While dysmorphic features have been described in individuals with this condition, these features are not typically distinctive enough to allow for a clinical diagnosis of SAS.

DIAGNOSIS/TESTING:

The diagnosis of SATB2-associated syndrome (SAS) is established in a proband by detection of one of the following: A heterozygous intragenic SATB2 pathogenic variant (61%). A heterozygous deletion at chromosome 2q33.1 that includes SATB2 (22%). An intragenic deletion or duplication of SATB2 (9%). A chromosome translocation with a chromosome 2q33.1 breakpoint that disrupts SATB2 (8%).

MANAGEMENT:

Treatment of manifestations: Treatment is symptomatic. Nutritional support for feeding difficulties and management by a cleft/craniofacial team for those with palatal anomalies early in life. Early referral for developmental support/special education; standard treatment for dental anomalies, sleep disturbance, skeletal anomalies, seizure disorders, genitourinary anomalies, strabismus and refractive errors, and congenital heart defects. Surveillance: Evaluation of nutritional status, growth, and developmental progress at each visit; routine monitoring by a neurologist for those with epilepsy; annual sleep study in those with a history of sleep disturbance; evaluation for scoliosis/spine deformity at each visit and consideration of screening for osteopenia; routine evaluations by dentistry and ophthalmology.

GENETIC COUNSELING:

SATB2-associated syndrome (SAS) is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a de novo genetic event. In two families, parental mosaicism seemed likely (given recurrence of SAS in sibs and failure to detect the genetic alteration in parental blood samples).To date, individuals with SAS are not known to reproduce. Once an SATB2 intragenic pathogenic variant, a 2q33.1 deletion that includes SATB2, or a chromosome translocation affecting SATB2 has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Zarate YA, Fish JL. SATB2-associated syndrome: Mechanisms, phenotype, and practical recommendations. Am J Med Genet A. 2017 Feb;173(2):327-337. doi:10.1002/ajmg.a.38022.

Abstract

The SATB2-associated syndrome is a recently described syndrome characterized by developmental delay/intellectual disability with absent or limited speech development, craniofacial abnormalities, behavioral problems, dysmorphic features, and palatal and dental abnormalities. Alterations of the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point mutations. The multisystemic nature of this syndrome demands a multisystemic approach and we propose evaluation and management guidelines. The SATB2-associated syndrome registry has now been started and that will allow gathering further clinical information and refining the provided surveillance recommendations.

Bayraktar OA, Bartels T, Holmqvist S, Kleshchevnikov V, Martirosyan A, Polioudakis D, Ben Haim L, Young AMH, Batiuk MY, Prakash K, Brown A, Roberts K, Paredes MF, Kawaguchi R, Stockley JH, Sabeur K, Chang SM, Huang E, Hutchinson P, Ullian EM, Hemberg M, Coppola G, Holt MG, Geschwind DH, Rowitch DH. Astrocyte layers in the mammalian cerebral cortex revealed by a single-cell in situ transcriptomic map. Nat Neurosci. 2020 Mar 16. doi: 10.1038/s41593-020-0602-1.

[Epub ahead of print]

Abstract

Although the cerebral cortex is organized into six excitatory neuronal layers, it is unclear whether glial cells show distinct layering. In the present study, we developed a high-content pipeline, the large-area spatial transcriptomic (LaST) map, which can quantify single-cell gene expression in situ. Screening 46 candidate genes for astrocyte diversity across the mouse cortex, we identified superficial, mid and deep astrocyte identities in gradient layer patterns that were distinct from those of neurons. Astrocyte layer features, established in the early postnatal cortex, mostly persisted in adult mouse and human cortex. Single-cell RNA sequencing and spatial reconstruction analysis further confirmed the presence of astrocyte layers in the adult cortex. Satb2 and Reeler mutations that shifted neuronal post-mitotic development were sufficient to alter glial layering, indicating an instructive role for neuronal cues. Finally, astrocyte layer patterns diverged between mouse cortical regions. These findings indicate that excitatory neurons and astrocytes are organized into distinct lineage-associated laminae.