ARID1B
This is the mechanism and prevalence for ARID1B.
ARID1B makes a chromatin remodeler. Variants are de novo and AD. Prevalence: 550 cases of Coffin-Siris Syndrome worldwide.
This is the mechanism and prevalence of GRIN2B.
GRIN2B variants impact NMDA receptors (glutamate). Prevalence: 750 cases worldwide.
This is the mechanism and the prevalence for RNU4-2.
RNU4-2 makes a spliceosome (splicing issues in other neurons, introns/noncoding regions not properly removed from genes).
Most common gene implicated in genetic NDD cases.
This is the mechanism and prevalence for SCN2A.
SCN2A gene codes for the voltage gated Sodium channel in neurons. GOF: neurons fire too much. LOF: neurons don't fire enough.
Prevalence: 700 reported cases worldwide.
This is the mechanism and prevalence for SLC6A1.
SLC6A1 codes for the GABA reuptake receptor (too much GABA in the synaptic cleft, inhibitory signals too high in the next neuron).
Prevalence: only a few hundred cases confirmed worldwide.
Physical features and feeding for ARID1B.
Fifth fingernail or toenail is gone or underdeveloped. They have thick eyebrows, long eyelashes, atypical hair growth, and feeding difficulties (25%-50% on feeding tubes in childhood).
Physical features and feeding for GRIN2B.
Big smile, no other major facial dysmorphia.
Cortical visual impairment can happen.
Physical features and feeding for RNU4-2.
Severe feeding problems. Drooling, acid reflux, G-tubes are common. 60% have short stature. Deep set eyes, wide nasal bridge, bone development abnormalities.
Cerebral/optic nerve vision problems (can't be corrected by glasses)
Physical features and feeding for SCN2A.
Cortical visual impairment, some have cerebral palsy, feeding issues, orthopedic issues.
No distinctive physical features.
LOF is more common variant (80%).
Physical features and feeding of SLC6A1.
Developmental regression, no distinctive facial features.
Hypotonia, weight/height is low, delayed motor skill development.
Mobility in GRIN2B.
Hypotonia, movement disorders could be present.
Mobility in RNU4-2.
Delayed walking/inability to walk. 27% remain non-ambulatory (will be in a wheelchair).
Mobility in SCN2A.
Movement issues, hypo- or hyper-tonia.
Mobility in SLC6A1.
Tremors, unsteady gait/clumsy movement (ataxia), hypotonia
Behavior/Language in ARID1B.
75% have speech by age 5, 98% have DD/ID, 25% have behavior issues (hyperactivity/aggressiveness)
Behavior/Language in GRIN2B.
Stereotypic behaviors (stimming, sensory seeking). Restless-impulsive, oppositional, and hyperactive behavior. Friendly, social behavior. 85% have DD/ID (more common in the LOF variants). 90% are non-verbal or have limited speech communication.
Behavior/Language in RNU4-2.
Self-injurious/aggressive behavior. 60% have ASD. 65% have stereotypic behaviors (stimming, sensory seeking). 99% have DD/ID. 55% speak a few words, slower language development.
Happy, friendly, affectionate. Love music and water.
Behavior/Language in SCN2A.
GOF: severe ID/DD
LOF: later seizure onset (after 3 months of age), more likely to see behavioral features, ASD common.
Language impairment/disorder (74%)
Behavior and language in SLC6A1.
Anxiety/aggression/irritability (screaming, self injurious behavior, stereotypic behavior (sensory seeking/stimming))
Language development (specifically expressive language) often more delayed than motor.
This is the name for the syndrome associated with more severe phenotypes of ARID1B disorder.
Coffin Siris Syndrome
Epilepsy in GRIN2B.
30%-50% have experienced seizures. More prevalent seizures in GOF variants.
About half are medication-resistant.
Fun Fact (when was it identified, variant severity, etc.)
Most common, one of the more severe variants, likely a first target for clinical trials. Identified in 2024.
Epilepsy in SCN2A.
GOF: severe, early seizures (before 3 months of age), DEE (developmental and epileptic encephalopathy (severe, early onset seizures with abnormal brain activity and a genetic/biological cause that are often drug resistant))
LOF: later onset seizures (onset at around 3 months of age or later)
Epilepsy in SLC6A1.
85% have seizures. Absent, myoclonic, atonic seizures reported. Some don't respond to medication.
Absent seizures: look like dissociation/not responding
Myoclonic seizures: brief twitches/muscle movements
Myoclonic-atonic seizures: muscles seize and then go limp