Table 3.

Selected Genes of Interest in the Differential Diagnosis of SLC6A1-Related Neurodevelopmental Disorder

Gene(s)DisorderMOIClinical CharacteristicsComment
GABRA1
GABRB2
GABRB3
GABRG2 		GABAA receptor-related epilepsies (OMIM 137160, 600232, 137192, 137164)ADGeneralized epilepsy w/or w/o NDD. Some individuals have ASD, behavioral issues, or movement disorders. EEGs can have variable findings ranging from normal to abnormal w/focal or generalized spike-wave discharges, hypsarrhythmia, or burst-suppression pattern. Fever-related seizures are common. Eye abnormalities, incl nystagmus, can be seen.Persons w/SLC6A1-NDD are unlikely to have hypsarrhythmia or burst-suppression pattern on EEG & may be more likely to have NDD.
MECP2 Rett syndrome (See MECP2 Disorders.)XLProgressive NDD primarily affecting females characterized by apparently normal psychomotor development in 1st 6-18 mos of life, followed by short period of developmental stagnation, then rapid regression in language & motor skills, followed by long-term stability. During rapid regression phase, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings incl seizures & acquired microcephaly.Persons w/Rett syndrome typically have more severe DD/ID than those w/SLC6A1-NDD.
SCN1A
SCN2A
SCN8A 		Sodium channelopathies (See, e.g., SCN1A Seizure Disorders and SCN8A-Related Epilepsy w/Encephalopathy.)ADEpilepsy, ASD, & DD. Seizures are often exacerbated by heat & persons are prone to status epilepticus. May have encephalopathic features on EEG consistent w/DEE or LGS. Seizure onset is typically w/in 1st yr of life, & there is ↑ risk of SUDEP.Generalized tonic-clonic seizures & heat sensitivity are less prevalent in SLC6A1-NDD than in most sodium channel disorders.
UBE3A 1Angelman syndrome (AS)See footnote 2.Severe DD/ID, severe speech impairment, gait ataxia &/or tremulousness of limbs, & unique behavior w/apparently happy demeanor that incl frequent laughing, smiling, & excitability. Microcephaly & seizures are common. DDs are first noted at ~6 mos; however, unique clinical features of AS do not become manifest until >1 yr of age.Persons w/AS typically have more severe DD/ID than those w/SLC6A1-NDD; however, EEG abnormalities can be similar.

AD = autosomal dominant; ASD = autism spectrum disorder; DD = developmental delay; DEE = developmental and epileptic encephalopathy; ID = intellectual disability; LGS = Lennox-Gastaut syndrome; MOI = mode of inheritance; NDD = neurodevelopmental disorder; SUDEP = sudden unexpected death in epilepsy; XL = X-linked

1.

Angelman syndrome (AS) is associated with deficient expression or function of the maternally inherited UBE3A allele.

2.

Individuals with AS typically represent simplex cases and have the disorder as the result of a de novo genetic alteration associated with a very low recurrence risk.

From: SLC6A1-Related Neurodevelopmental Disorder

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