A Missense Mutation in the HMNT Gene Responsible for Autosomal Recessive Intellectual Disability in an Iranian Family with Consanguineous Marriage

Seyed Hamidreza  Mirabutalebi; Mohammadreza  Dehghani; Nasrin  Ghasemi; Mohammad yahya  Vahidi Mehjardi; Mojtaba  Movahedinia; Seyed Mehdi  Kalantar

doi:10.18502/ijml.v9i3.10907

Seyed Hamidreza Mirabutalebi Department of Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Mohammadreza Dehghani Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Nasrin Ghasemi Abortion Research Center, Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Mohammad yahya Vahidi Mehjardi Medical Genetics Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Mojtaba Movahedinia Department of Pediatrics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
Seyed Mehdi Kalantar Department of Genetics, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

DOI: https://doi.org/10.18502/ijml.v9i3.10907

Keywords: Consanguineous family, HNMT gene, Intellectual disability, Whole exome sequencing

Abstract

Background and Aims: One of the neurotransmitters in the brain is Histamine which acts as several biological mechanism regulators like inflammation, gastric acid secretion, and neuromodulation. Inactivation of Histamine occurs by histamine N-methyltransferase (HNMT) enzyme. The HNMT transfers a methyl group from S-adenosyl-L-methionine to Histamine and is the main process for the termination of neurotransmission actions of Histamine in the mammalian central nervous system.

Materials and Methods: In this case, a family was referred to the genetic clinic to diagnose the cause of their disorder. The clinical form, pedigree, and questionnaire were completed for the family, and the parents gave their written consent for all tests and photographs publication. Both siblings have moderate learning and intellectual disability. Whole exome sequencing was performed and Sanger sequencing for co-segregation was used.

Results: Bioinformatics analysis revealed a homozygous missense variant in HNMT (c.623T>C p.Leu208Pro) which causes non-syndromic autosomal recessive intellectual disability in this consanguineous family. Analysis of segregation confirmed this mutation. P.Leu208Pro mutation reduces the stability of the protein, which reduces the inactivation of Histamine.

Conclusion: HNMT should be considered an important gene in the genetic evaluation of consanguineous families with intellectual disability.