METTL23 – Intellectual developmental disorder, autosomal recessive 44

METTL23 is a lysine methyltransferase implicated in non-histone protein methylation and human neurodevelopment. Biallelic variants in METTL23 cause intellectual developmental disorder, autosomal recessive 44, characterized by global developmental delay, intellectual disability, and variable dysmorphic features. The inheritance is autosomal recessive, with affected individuals harboring homozygous or compound heterozygous loss-of-function or missense changes in METTL23. This summary integrates genetic and functional data to support diagnostic decision-making and future research.

In a consanguineous Arab pedigree, seven members exhibited intellectual disability and mild dysmorphic features. Linkage and homozygosity mapping identified a homozygous 4-bp deletion resulting in c.169_172del (p.His57ValfsTer11) ([PMID:24501276]), predicted to truncate the protein. Segregation analysis confirmed co-segregation of this frameshift variant with disease in all affected siblings, providing strong genetic evidence for METTL23 deficiency.

A 2020 study reported two additional consanguineous families with autosomal recessive intellectual disability. Each family harbored a homozygous missense change, c.310T>C (p.Phe104Leu), validated by segregation in all available relatives ([PMID:32878022]). In silico modeling suggested disruption of the methyltransferase domain, supporting a deleterious effect.

A recent case report described a Chinese girl with global developmental delay, thin vermilion border, and flat occiput. Whole-exome sequencing revealed a novel splice donor site variant, c.322+1del, classified as pathogenic by ACMG criteria and absent from population databases ([PMID:39026940]).

The variant spectrum in METTL23 includes splice-site (c.322+1del), frameshift (c.169_172del (p.His57ValfsTer11)), and missense changes (c.310T>C (p.Phe104Leu)). No recurrent or founder alleles have been reported. Reported variants consistently segregate recessively, and carrier frequency is exceedingly low in public databases.

Functional studies demonstrate that METTL23 localizes to nucleus and cytoplasm and interacts with the transcription factor GABPA. Overexpression enhances GABPA-driven promoter activity at THPO, while METTL23 knockdown decreases ATP5B expression, revealing a role in transcriptional regulation important for cognitive development ([PMID:24501276]).

Overall, ten probands across three independent studies exhibit METTL23 variants with autosomal recessive inheritance, segregation in multiple families, and concordant functional data. This strong evidence supports METTL23 testing in undiagnosed intellectual disability and informs variant interpretation in clinical and research settings.

References

• Human molecular genetics • 2014 • METTL23, a transcriptional partner of GABPA, is essential for human cognition. PMID:24501276
• Genes • 2020 • Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants. PMID:32878022
• Frontiers in pediatrics • 2024 • Identification of a novel METTL23 gene variant in a patient with an intellectual development disorder: a literature review and case report. PMID:39026940

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