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This summary integrates evidence from case reports, multi‐patient studies, and functional analyses that support a strong association between METTL5 and intellectual disability. METTL5 variants have been implicated in syndromic presentations that include not only intellectual disability but also microcephaly and atypical behavior, underscoring a specific and consistent clinical phenotype (PMID:37731250). The reported studies span different ethnic groups and employ a combination of whole‐exome sequencing, segregation analysis, and structural modeling to establish a genetic link between METTL5 disruption and the observed neurodevelopmental outcomes (PMID:31564433). The integration of these approaches provides robust genetic and experimental support for this gene‐disease association.
In a detailed case report, a 13‑year‑old boy from an Iranian family was found to harbor a novel homozygous 10‑bp deletion disrupting a donor splice site in exon 2 of METTL5. This variant was detected by WES and further validated through Sanger sequencing and cosegregation analyses in the family (PMID:37731250). The case report emphasized that the identified variant meets ACMG pathogenicity criteria and expands the mutational spectrum of METTL5 in intellectual disability. The segregation of the variant with the phenotype in obligate carriers supports its pathogenic role. In addition, the clinical findings highlight variability in severity and behavioral manifestations among affected individuals.
Multi‐patient studies have identified several pathogenic variants in METTL5, with evidence of autosomal recessive inheritance. In one such study, two frameshift variants, including the recurrent variant c.571_572del (p.Arg115AsnfsTer19), were identified in families of Pakistani and Yemenite origin. These variants segregated with moderate to severe intellectual disability and microcephaly in multiple families (PMID:31564433). The identification of different variant types, such as frameshift and missense mutations, further substantiates the broad variant spectrum contributing to the disorder. The consistent genetic findings across diverse cohorts add significant weight to the gene‐disease association.
Functional assessments have provided critical insights into the pathogenic mechanisms underlying METTL5‐related intellectual disability. Experimental studies demonstrate that truncating mutations in METTL5, including c.571_572del (p.Arg115AsnfsTer19), disrupt protein expression and function in cellular models. Moreover, knockdown experiments in zebrafish recapitulated the microcephaly phenotype, thereby linking impaired METTL5 function with neural developmental defects (PMID:31564433; PMID:35005123). These functional data reinforce the biological plausibility of the genetic findings and suggest that perturbations in METTL5-mediated methylation processes contribute directly to neurodevelopmental abnormalities.
The genetic and functional evidence converge to support a strong gene‑disease association for METTL5 with intellectual disability. The autosomal recessive inheritance pattern is consistently observed across both case reports and cohort studies, and the robust segregation data further validate the pathogenicity of the variants. Although the clinical spectrum includes overlapping features such as microcephaly and behavioral abnormalities, the reproducibility of findings across independent studies emphasizes the clinical relevance of METTL5 testing for diagnostic decision‑making. Additional evidence from larger cohorts may further extend the clinical spectrum, but current data already exceed the minimal threshold for a strong association.
Key take‑home: Comprehensive genomic and experimental analyses confirm that pathogenic, autosomal recessive variants in METTL5 are strongly associated with intellectual disability and related neurodevelopmental features, supporting its utility in clinical diagnostics and future therapeutic research.
Gene–Disease AssociationStrongThe association is supported by a case report with a novel METTL5 variant in one proband (PMID:37731250) and multi‐patient studies demonstrating segregation in multiple families (PMID:31564433), providing consistent genetic evidence. Genetic EvidenceStrongMultiple pathogenic variants including the recurrent c.571_572del (p.Arg115AsnfsTer19) have been reported across independent cohorts with clear autosomal recessive segregation, satisfying ClinGen criteria for strong genetic evidence (PMID:31564433). Functional EvidenceModerateFunctional studies in cellular models and zebrafish clearly demonstrate that truncating METTL5 variants result in loss of normal protein function, consistent with the human phenotype and supporting the pathogenic mechanism (PMID:31564433; PMID:35005123). |