GATAD2B – severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome

GATAD2B encodes p66β, a subunit of the NuRD complex critical for chromatin remodeling and transcriptional repression. Heterozygous pathogenic variants cause a syndromic intellectual disability with limited speech, hypotonia, and distinct dysmorphic features, inherited in an autosomal dominant manner with frequent de novo occurrence ([PMID:31205050]).

Initial reports described 17 unrelated probands with loss-of-function variants or microdeletions, and one paternal mosaic transmission ([PMID:31205050]). A 2020 cohort added 50 GAND cases harboring truncating, splice-site, and missense variants disrupting conserved CR1/CR2 domains ([PMID:31949314]).

Affected individuals consistently present with moderate to severe intellectual disability (HP:0001249), infantile hypotonia (HP:0008947), apraxia of speech (HP:0011098), macrocephaly (HP:0000256), and seizures (HP:0001250). Other features include strabismus, grimacing facies, and long digits, supporting a recognizable clinical profile across studies.

The variant spectrum is dominated by heterozygous truncating mutations (e.g., c.653_654dup (p.Gln219fs), c.346C>T (p.Arg116Ter)) and missense changes (e.g., c.1258T>C (p.Cys420Arg)). Segregation analyses confirm de novo occurrence in the majority, with one documented mosaic transmission event ([PMID:31205050]).

Functional studies demonstrate haploinsufficiency: Gatad2b haploinsufficient mice exhibit perinatal lethality when homozygous and recapitulate key neurodevelopmental and behavioral abnormalities when heterozygous. These models show abnormal cortical patterning and altered developmental transcriptomes in corticogenesis pathways ([PMID:38238293]).

In vitro immunoprecipitation assays reveal that missense variants within CR1/CR2 disrupt GATAD2B interaction with NuRD complex partners, impairing transcriptional repression and complex assembly ([PMID:31949314]).

Collectively, robust genetic and experimental evidence supports a Strong gene–disease association. GATAD2B variant testing provides high clinical utility for diagnosis, genetic counseling, and potential therapeutic development in this rare syndrome.

References

• Clinical dysmorphology • 2019 • GATAD2B-related intellectual disability due to parental mosaicism and review of literature. PMID:31205050
• Genetics in medicine • 2020 • GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder. PMID:31949314
• Translational psychiatry • 2024 • Gatad2b, associated with the neurodevelopmental syndrome GAND, plays a critical role in neurodevelopment and cortical patterning. PMID:38238293

Evidence Based Scoring (AI generated)