BackgroundSLC6A1 encodes GAT-1, a major gamma-aminobutyric acid (GABA) transporter in the brain. GAT-1 maintains neurotransmitter homeostasis by removing excess GABA from the synaptic cleft. Pathogenic variants in SLC6A1 disrupt the reuptake of GABA and are associated with a neurobehavioural phenotype.MethodsMedical history interviews, seizure surveys, Vineland Adaptive Behavior Scales Second Edition and other behavioural surveys were completed by primary care givers of 28 participants in Simons Searchlight. All participants underwent clinical whole exome sequencing or gene panel sequencing. Additional cases from the medical literature with comparable data were included.ResultsWe identified 28 individuals with largely de novo pathogenic/likely pathogenic variants including missense (15/21 or 71%) and truncating variants (6/21 or 29%). Missense variants were largely clustered around the sixth and seventh transmembrane domains, which functions as a GABA binding pocket. The phenotype of individuals with pathogenic variants in SLC6A1 includes hypotonia, intellectual disability/developmental delay, language disorder/speech delay, autism spectrum disorder, sleep issues and seizures.ConclusionPathogenic variants in SLC6A1 are associated with a clinical phenotype of developmental delay, behaviour problems and seizures. Understanding of the genotype–phenotype correlation within SLC6A1 may provide opportunities to develop new treatments for GABA-related conditions.

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Background: De novo pathogenic variants in CHAMP1 (chromosome alignment maintaining phosphoprotein 1) that encodes kinetochore-microtubule associated protein on 13q34 cause a rare neurodevelopmental disorder. Methods:We enrolled 14 individuals with pathogenic variants in CHAMP1 that were documented by exome sequencing or gene panel sequencing. Medical history interviews, seizure surveys, Vineland Adapted Behavior Scales Second Edition, and other behavioral surveys were completed by primary care givers of available participants in Simons Searchlight. Clinicians extracted clinical data from the medical record for two participants. Results:We report on clinical features of fourteen individuals (ages 2-26) with de novo predicted loss of function variants in CHAMP1 and compare them with previously reported cases (total n=32). At least two individuals have the same de novo variant: p.(Ser181Cysfs*5), p.(Trp348*), p.(Arg398*), p.(Arg497*), or p.(Tyr709*). Common phenotypes include intellectual disability/developmental delay, language impairment, congenital and acquired microcephaly, behavioral problems including autism spectrum disorder, seizures, hypotonia, gastrointestinal issues of reflux and constipation, and ophthalmologic issues. Other rarely observed phenotypes include leukemia, failure to thrive and high pain tolerance. Conclusion:Pathogenic variants in CHAMP1 are associated with a variable clinical phenotype of developmental delay/intellectual disability and seizures.

Homozygous pathogenic variants in WDR45B were first identified in six subjects from three unrelated families with global development delay, refractory seizures, spastic quadriplegia, and brain malformations. Since the initial report in 2018, no further cases have been described. In this report, we present 12 additional individuals from seven unrelated families and their clinical, radiological, and molecular findings. Six different variants in WDR45B were identified, five of which are novel. Microcephaly and global developmental delay were observed in all subjects, and seizures and spastic quadriplegia in most. Common findings on brain imaging include cerebral atrophy, ex vacuo ventricular dilatation, brainstem volume loss, and symmetric under‐opercularization. El‐Hattab‐Alkuraya syndrome is associated with a consistent phenotype characterized by early onset cerebral atrophy resulting in microcephaly, developmental delay, spastic quadriplegia, and seizures. The phenotype appears to be more severe among individuals with loss‐of‐function variants whereas those with missense variants were less severely affected suggesting a potential genotype–phenotype correlation in this disorder. A brain imaging pattern emerges which is consistent among individuals with loss‐of‐function variants and could potentially alert the neuroradiologists or clinician to consider WDR45B‐related El‐Hattab‐Alkuraya syndrome.