P370: Expanding the phenotypic spectrum of Warburg Micro syndrome

Discussion: Our patient's phenotype, including severe intellectual disability, autism, and dysmorphic features, strongly aligns with GABRA4-related NDD.While the frameshift variant is a VUS, its absence in population databases and predicted truncating effect provide strong evidence for pathogenicity.This case is significant as it reports a frameshift variant, a mechanism not previously described for this NDD, suggesting loss-of-function as a disease mechanism.Conclusion: Our case report expands the GABRA4-related NDD mutational spectrum beyond missense variants to include truncating, loss-of-function variants.These findings provide crucial evidence to support reclassification of this novel variant and underscore the utility of genome sequencing in diagnosing patients with complex NDDs.Further reporting of individuals with similar variants is essential to delineate the clinical spectrum and establish definitive genotype-phenotype correlations. Introduction:The GABRA4 gene encodes the 4 subunit of the GABA-A receptor, critical for inhibitory neurotransmission.De novo missense variants in GABRA4 are associated with a syndromic neurodevelopmental disorder (NDD) featuring developmental delay, epilepsy, and behavioral abnormalities.The mutational spectrum reported to date consists almost exclusively of missense variants.There are no reported nonsense or truncating variants in GABRA4 to date.We present a 21-year-old male with a complex NDD phenotype in whom genome sequencing identified a previously unreported heterozygous frameshift variant in GABRA4.Case Presentation: Our patient is a 21-year-old White male referred for evaluation of severe intellectual disability (IQ 50-55), autism, and dysmorphic features.The pregnancy was conceived by donor sperm and complicated by preeclampsia and gestational diabetes.He showed early developmental regression in motor and speech skills and was on lamotrigine for a long period.His clinical course includes OCD, schizoaffective disorder, depression, psychosis, diplopia, and balance issues.Physical examination revealed short stature (below 3rd %), moderate bilateral kinetic tremors, and severe articulation.Dysmorphic features include arched dark eyebrows, deep-set eyes, small ears with underdeveloped auricles, generalized joint laxity, distorted nails, and long toes.Diagnostic Workup: Chromosome microarray was normal.GS was performed for patient and his mother, identifying a heterozygous 11 base-pair duplication in GABRA4 (c.1299_1309dup NM_000809.3),resulting in a frameshift and premature stop codon (p.Ser437Lysfs*54).This variant of uncertain significance was not inherited from his mother.The biological father was reportedly intelligent.A maternally inherited pathogenic heterozygous variant in SLC39A8 (c.112G>C, p.Gly38Arg NM_022154.5)was also found, consistent with carrier status for a recessive disorder, which did not explain the primary phenotype.