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Genes encoding long non-coding RNAs (lncRNAs) comprise a large fraction of the human genome, yet haploinsufficiency of a lncRNA has not been shown to cause a Mendelian disease. is a highly conserved human lncRNA adjacent to a coding gene in which loss-of-function variants cause developmental and epileptic encephalopathy. Here we report three unrelated individuals each harboring an ultra-rare heterozygous deletion in the locus. We report similarities in severe developmental delay, facial dysmorphisms, and cerebral dysmyelination in these individuals, distinguishing them from the phenotypic spectrum of haploinsufficiency. We demonstrate reduced mRNA expression and corresponding increased mRNA and protein in whole blood and patient-derived cell lines-specifically increased expression of the allele in with the deletion, as predicted from a prior mouse model of haploinsufficiency. We show for the first time that structural variants facilitated by Alu-mediated non-allelic homologous recombination led to deletion of a non-coding element (the lncRNA ) to cause a rare syndromic neurodevelopmental disorder. We also demonstrate that has bidirectional dosage sensitivity in human disease. This work highlights the need to carefully evaluate other lncRNAs, particularly those upstream of genes associated with Mendelian disorders.