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Histamine (HA) acts as a neurotransmitter in the brain, which participates in the regulation of many biological processes including inflammation, gastric acid secretion and neuromodulation. The enzyme histamine  N -methyltransferase (HNMT) inactivates HA by transferring a methyl group from  S -adenosyl- l -methionine to HA, and is the only well-known pathway for termination of neurotransmission actions of HA in mammalian central nervous system. We performed autozygosity mapping followed by targeted exome sequencing and identified two homozygous  HNMT  alterations, p.Gly60Asp and p.Leu208Pro, in patients affected with nonsyndromic autosomal recessive intellectual disability from two unrelated consanguineous families of Turkish and Kurdish ancestry, respectively. We verified the complete absence of a functional HNMT in patients using  in vitro  toxicology assay. Using mutant and wild-type DNA constructs as well as  in silico  protein modeling, we confirmed that p.Gly60Asp disrupts the enzymatic activity of the protein, and that p.Leu208Pro results in reduced protein stability, resulting in decreased HA inactivation. Our results highlight the importance of inclusion of  HNMT  for genetic testing of individuals presenting with intellectual disability.

Mutations in the histamine N -methyltransferase gene, HNMT , are associated with nonsyndromic autosomal recessive intellectual disability