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<p>Background rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder primarily affecting females, predominantly caused by pathogenic variants in the MECP2 gene. This study investigates the genetic and phenotypic spectrum of RTT in Iran, a population characterized by high genetic diversity and consanguinity. Methods twenty-five Iranian RTT patients (24 females, 1 male; aged 2–17 years), including 11 newly diagnosed and 14 previously reported cases, were analyzed. Clinical evaluation, pedigree analysis, and bidirectional sequencing of all MECP2 coding exons (NM_004992.3) were performed. Variant pathogenicity was assessed using ACMG criteria and in silico tools (MutationTaster, VarSome, Franklin). Structural impact of the novel variant was modeled using RoseTTAFold. Results a novel frameshift variant, c.1268_1269insGGGCACTC; p. Leu424GlyfsTer61, was identified in exon 4 and classified as likely pathogenic. Fifteen distinct MECP2 variants were detected, with 87% pathogenic/likely pathogenic; exon 4 emerged as a mutational hotspot. All patients showed psychomotor regression, loss of purposeful hand use, and communication impairment. Common features included locomotion difficulties (96%), microcephaly (64%), seizures (60%), and abnormal EEG (64%). Truncating variants (nonsense/frameshift) correlated with severe phenotypes (e.g., quadriplegia, feeding difficulties), though statistical significance was limited by sample size (Fisher’s exact test, p = 1.00). Conclusions this study reveals a distinct MECP2 mutation profile in Iranian RTT patients, including a novel pathogenic variant, and highlights genotype–phenotype associations influenced by regional genetic factors. Targeted MECP2 exon 4 sequencing is recommended for efficient diagnosis. These findings support the development of personalized diagnostic and therapeutic approaches in high-consanguinity populations and lay the foundation for future genomic and functional studies in Iran.</p>

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MECP2 Variant Spectrum and Genotype–Phenotype Correlations in Iranian Rett Syndrome Patients: Identification of a Novel Frameshift Mutation

  • 期刊论文

  • 发表日期：

    2026年5月29日

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  • Parnoush Booalizadeh,
  • Iman Salahshourifar,
  • Bahareh Rabbani,
  • Morteza Rezvani,
  • Mahmoud Reza Ashrafi,
  • Nejat Mahdieh

摘要

Background rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder primarily affecting females, predominantly caused by pathogenic variants in the MECP2 gene. This study investigates the genetic and phenotypic spectrum of RTT in Iran, a population characterized by high genetic diversity and consanguinity. Methods twenty-five Iranian RTT patients (24 females, 1 male; aged 2–17 years), including 11 newly diagnosed and 14 previously reported cases, were analyzed. Clinical evaluation, pedigree analysis, and bidirectional sequencing of all MECP2 coding exons (NM_004992.3) were performed. Variant pathogenicity was assessed using ACMG criteria and in silico tools (MutationTaster, VarSome, Franklin). Structural impact of the novel variant was modeled using RoseTTAFold. Results a novel frameshift variant, c.1268_1269insGGGCACTC; p. Leu424GlyfsTer61, was identified in exon 4 and classified as likely pathogenic. Fifteen distinct MECP2 variants were detected, with 87% pathogenic/likely pathogenic; exon 4 emerged as a mutational hotspot. All patients showed psychomotor regression, loss of purposeful hand use, and communication impairment. Common features included locomotion difficulties (96%), microcephaly (64%), seizures (60%), and abnormal EEG (64%). Truncating variants (nonsense/frameshift) correlated with severe phenotypes (e.g., quadriplegia, feeding difficulties), though statistical significance was limited by sample size (Fisher’s exact test, p = 1.00). Conclusions this study reveals a distinct MECP2 mutation profile in Iranian RTT patients, including a novel pathogenic variant, and highlights genotype–phenotype associations influenced by regional genetic factors. Targeted MECP2 exon 4 sequencing is recommended for efficient diagnosis. These findings support the development of personalized diagnostic and therapeutic approaches in high-consanguinity populations and lay the foundation for future genomic and functional studies in Iran.