GAND

GATAD2B-associated neurodevelopmental disorder (GAND) is a rare, recently recognized syndrome characterized by a distinct combination of features, most notably severe neurodevelopmental delay with profound language impairment. It is classified as a Nucleosome Remodeling and Deacetylase (NuRD)-related disorder.

Most cases of GAND are due to de novo (new) mutations in GATAD2B gene, and the disorder is inherited in an autosomal dominant manner.

GAND is caused by heterozygous pathogenic variants in the GATAD2B gene, located on chromosome 1q21.3 – OMIM ID: 614998

https://www.omim.org/entry/614998?search=GATAD2B&highlight=gatad2b

The GATAD2B gene encodes a transcriptional repressor protein that is a subunit of the NuRD complex. This complex is crucial for controlling transcription of a large number of genes necessary for proper neurodevelopment and cortical patterning by coupling histone deacetylase and chromatin remodeling activities.

The pathogenic variants, including loss-of-function (e.g., truncating frameshift, nonsense, deletions) and missense subtypes typically result in haploinsufiency – where a single functional copy of the gene is insufficient for normal cell function – making it a suitable clinical target for gene augmentation (gene addition) therapeutic strategies.

The core clinical features of GAND include:

• Neurological & Developmental: Intellectual disability (ID), severe developmental delay, and predominant language impairment (most affected individuals are non-verbal). Other neurological features include infantile hypotonia (low muscle tone), apraxia of speech, and sometimes epilepsy.
• Craniofacial & Physical: While macrocephaly (large head size) is a prominent finding, patients also often exhibit distinctive facial features (e.g., hypertelorism, prominent nasal tip, pointed chin).
• Gastrointestinal & Other: Neonatal feeding difficulties, polyhydramnios (excess amniotic fluid) during pregnancy, cardiac abnormalities (e.g., bicuspid aortic valves), ophthalmological abnormalities, and psychiatric issues like anxiety and irritability are frequently reported.

• Epilepsy: Seizures occur in a minority of individuals (around 17%), with a mean age of onset of 15 months. Seizure types are variable and can include atypical absences or focal seizures.

Clinicians consider GAND when a child presents with a combination of the following features:

Core clinical signs

• Global developmental delay

• Intellectual disability (typically moderate to severe)
• Hypotonia (often present from infancy)
• Speech delay or minimal speech
• Macrocephaly or relative macrocephaly

Additional commonly reported features

• Distinctive facial features (frontal bossing, large ears, wide-set eyes, broad forehead)

• Behavioral concerns (autism spectrum features, hyperactivity)
• Feeding difficulties
• Motor delay
• Seizures (in a minority of individuals)

Clinical features can raise suspicion but are not diagnostic. GAND is diagnosed exclusively through genetic testing identifying a pathogenic or likely pathogenic variant in GATAD2B.

Recommended tests include:

1. Whole-Exome Sequencing (WES)
   • Most common and effective testing method.
   • Detects sequence variants and small indels in GATAD2B.
2. Whole-Genome Sequencing (WGS)
   • Useful if WES is nondiagnostic.
   • Can detect structural variants or intronic changes affecting GATAD2B.
3. Targeted Neurodevelopmental Gene Panel
   • Some panels include GATAD2B.
   • Faster turnaround but limited to included genes.
4. Chromosomal Microarray (CMA)
   • May detect larger deletions involving GATAD2B (rare).
   • Not sufficient alone, but supportive.
5. Sanger Sequencing / Familial Testing
   • Used to confirm variants identified by WES/WGS.
   • Allows parental testing for recurrence risk and mosaicism assessment.

No biochemical test can diagnose GAND—genetic confirmation is essential.

Currently recommended disease management is limited to multidisciplinary support, focusing on maximizing developmental potential.

• Therapies: Intensive speech and language therapy is critical due to the prominent communication deficit. Physical and occupational therapies are necessary to address gross and fine motor delays and hypotonia. Augmentative and alternative communication (AAC) strategies are essential for non-verbal individuals.
• Medical Care: A pediatric neurologist should manage any present epilepsy. Other specialists may be involved to address feeding difficulties, cardiac defects, and ophthalmological abnormalities.