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Objective <p>This study aims to present the clinical and genetic findings of two siblings carrying a homozygous c.470_471del (p.Leu157<b>Arg</b>fsTer4) frameshift mutation in the METTL23 gene, and to compare their phenotypes with previously reported cases.</p> Materials and methods <p>Two female siblings from a consanguineous family were clinically assessed. Developmental history, dysmorphic features, neurological examination, brain MRI, and EEG findings were systematically reviewed. Genetic analysis was performed using exome sequencing (ES), and the mutation was confirmed by Sanger sequencing.</p> Results <p>Both patients exhibited severe intellectual disability, marked delay in speech and self-care, epileptic seizures, and facial dysmorphism (depressed nasal bridge, thin upper lip, high hairline, prognathism, prominent mandibular angle), along with mitral valve prolapse. One patient had nummular eczematous skin lesions. Brain MRI findings were normal. The identified mutation had previously only been reported in compound heterozygous form; this study presents the first known homozygous case.</p> Conclusion <p>These cases represent one of the most severe phenotypic presentations of METTL23-related intellectual disability reported to date. The co-occurrence of profound intellectual impairment, epilepsy, systemic involvement (mitral valve prolapse), and dermatologic findings (nummular eczema) suggests that the homozygous form of this frameshift mutation may be associated with a more severe clinical expression. Furthermore, this is the first report of the c.470_471del (p.Leu157<b>Arg</b>fsTer4) variant in a homozygous state, providing novel insights into genotype–phenotype correlations. Our findings significantly broaden the known clinical spectrum of METTL23-associated disorders.</p> Graphical abstract <p></p>

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“Severe intellectual disability with cardiac and dermatologic involvement due to homozygous METTL23 frameshift mutation: a case report of two Turkish sisters”

  • 期刊论文

  • 发表日期：

    2026年7月20日

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  • Mücahid Besnek,
  • Büşra Aynekin,
  • Ayten Güleç,
  • Stephanie Efthymiou,
  • Hüseyin Per

摘要

Objective

This study aims to present the clinical and genetic findings of two siblings carrying a homozygous c.470_471del (p.Leu157ArgfsTer4) frameshift mutation in the METTL23 gene, and to compare their phenotypes with previously reported cases.

Materials and methods

Two female siblings from a consanguineous family were clinically assessed. Developmental history, dysmorphic features, neurological examination, brain MRI, and EEG findings were systematically reviewed. Genetic analysis was performed using exome sequencing (ES), and the mutation was confirmed by Sanger sequencing.

Results

Both patients exhibited severe intellectual disability, marked delay in speech and self-care, epileptic seizures, and facial dysmorphism (depressed nasal bridge, thin upper lip, high hairline, prognathism, prominent mandibular angle), along with mitral valve prolapse. One patient had nummular eczematous skin lesions. Brain MRI findings were normal. The identified mutation had previously only been reported in compound heterozygous form; this study presents the first known homozygous case.

Conclusion

These cases represent one of the most severe phenotypic presentations of METTL23-related intellectual disability reported to date. The co-occurrence of profound intellectual impairment, epilepsy, systemic involvement (mitral valve prolapse), and dermatologic findings (nummular eczema) suggests that the homozygous form of this frameshift mutation may be associated with a more severe clinical expression. Furthermore, this is the first report of the c.470_471del (p.Leu157ArgfsTer4) variant in a homozygous state, providing novel insights into genotype–phenotype correlations. Our findings significantly broaden the known clinical spectrum of METTL23-associated disorders.

Graphical abstract