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<p>Membrane-bound O-acyltransferase domain-containing member 7 (MBOAT7) plays an irreplaceable role in lipogenesis and neural development. Over the past decade, a few variants in <i>MBOAT7</i> have been associated with intellectual disability (ID), and a spectrum of clinical symptoms, including seizures, autism spectrum disorders (ASD), and speech impairment. DNA samples from two of the three affected members of a large Iranian Azeri family with moderate ID and no major dysmorphic features were investigated by whole exome sequencing (WES). Bioinformatic tools were used to identify and evaluate the pathogenicity of the candidate variants. The most likely causative variant was pursued by Sanger sequencing in patients and their relatives. ACMG guidelines and in silico analysis, including molecular modeling, were used to validate the identified variant of uncertain significance (VUS). An in-frame deletion, NM_024298.5: c.37_39 del (p.Leu13del) in the <i>MBOAT7</i> gene, which had not been previously reported with homozygous genotype, was identified as a possible cause of the clinical conditions in patients. Sanger analysis confirmed the recessive inheritance pattern of this variant in probands and 14 relatives. In-silico modeling of the mutant protein revealed structural changes resulting from removing a highly conserved amino acid. The current study&#xa0;has expanded the <i>MBOAT7</i> gene variant spectrum and clarified variable phenotypic features to the associated ID criteria. Meanwhile, we have provided insights into the importance of the MBOAT7 protein’s first alpha helix in terms of its functionality and solid evidence regarding a VUS’s pathogenicity. Additionally, this study presents the oldest recorded case of <i>MBOAT7</i>-related ID in a 51-year-old female to date.</p>

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A Deleterious Variant in MBOAT7 Causes Intellectual Disability in an Iranian Family: An Example of Reassignment of Variants of Uncertain Significance

  • 期刊论文

  • 发表日期：

    2025年10月16日

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  • Naghmeh Saba,
  • Maryam Naghinejad,
  • Mahmoud Shekari Khaniani,
  • Shahram Sadeghvand,
  • Sima Mansoori Derakhshan,
  • Mohammad Taheri

摘要

Membrane-bound O-acyltransferase domain-containing member 7 (MBOAT7) plays an irreplaceable role in lipogenesis and neural development. Over the past decade, a few variants in MBOAT7 have been associated with intellectual disability (ID), and a spectrum of clinical symptoms, including seizures, autism spectrum disorders (ASD), and speech impairment. DNA samples from two of the three affected members of a large Iranian Azeri family with moderate ID and no major dysmorphic features were investigated by whole exome sequencing (WES). Bioinformatic tools were used to identify and evaluate the pathogenicity of the candidate variants. The most likely causative variant was pursued by Sanger sequencing in patients and their relatives. ACMG guidelines and in silico analysis, including molecular modeling, were used to validate the identified variant of uncertain significance (VUS). An in-frame deletion, NM_024298.5: c.37_39 del (p.Leu13del) in the MBOAT7 gene, which had not been previously reported with homozygous genotype, was identified as a possible cause of the clinical conditions in patients. Sanger analysis confirmed the recessive inheritance pattern of this variant in probands and 14 relatives. In-silico modeling of the mutant protein revealed structural changes resulting from removing a highly conserved amino acid. The current study has expanded the MBOAT7 gene variant spectrum and clarified variable phenotypic features to the associated ID criteria. Meanwhile, we have provided insights into the importance of the MBOAT7 protein’s first alpha helix in terms of its functionality and solid evidence regarding a VUS’s pathogenicity. Additionally, this study presents the oldest recorded case of MBOAT7-related ID in a 51-year-old female to date.