Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share By
A Novel Mettl5 Variant Disrupting a Donor Splice Site Leads to Primary Microcephaly-Related Intellectual Disability in an Iranian Family: Clinical Features and Literature Review Publisher



Shakarami F1 ; Nouri Z1, 2 ; Khanahmad H1 ; Ghazavi M3 ; Tabatabaiefar MA1, 4
Authors

Source: Journal of Genetics Published:2023


Abstract

Intellectual disability (ID) is a highly heterogeneous disorder, affecting 1–3% of the world’s population, which is associated with a significant disorder in cognitive development, adaptive functioning and behavioural problems in human life. In this study, due to the genetic heterogeneity of the disease, the whole-exome sequencing (WES) was performed on a 13-year-old boy suffering from microcephaly. In addition, Sanger sequencing, cosegregation analysis, and structural modelling were performed to identify and verify the causative variant in the proband and obligate carriers in the family. WES revealed a novel, homozygote 10-bp deletion in the donor splice site of 2nd exon of METTL5 gene (NM_014168:c.223_224+8del), which was found segregating with the phenotype in the pedigree. This variant meets the criteria of being pathogenic according to the American College of Medical Genetics (ACMG) variant interpretation guideline. Up to now, four pathogenic homozygous variants of the METTL5 gene have been reported that are associated with ID. A comparison of the clinical characteristics of our patient with previously reported cases revealed variability in the disease severity and some clinical presentations, including overall growth, dysmorphic facial features and behavioural psychiatric manifestations. The clinical findings of the case reported in this study extend the spectrum of genetic variations and phenotypes associated with ID and provide a better insight of the disease pathogenesis. © 2023, Indian Academy of Sciences.
Related Docs
View other Related Docs
1. Proband-Only Exome Sequencing for Intellectual Disability in Iran: Diagnostic Yield and Genetic Insights, American Journal of Medical Genetics, Part A (2024)
2. Clinical and Genetic Profile of Children With Unexplained Intellectual Disability/Developmental Delay and Epilepsy, Epilepsy Research (2021)
3. Clinical and Genetic Delineation of Autosomal Recessive and Dominant Actl6b-Related Developmental Brain Disorders, Genetics in Medicine (2025)
Experts (# of related papers)
View all Related Experts
Mohammad Amin Tabatabaiefar (8)
Majid Kheirollahi (3)
Other Related Docs
4. Molecular and Phenotypical Findings of a Novel De Novo Syngap1 Gene Variant in an 11-Year-Old Iranian Boy With Intellectual Disability, Lab Medicine (2024)
5. X-Linked Mental Retardation-Hypotonic Facies Syndrome: Exome Sequencing Identifies Novel Clinical Characteristics Associated With C.5182G>C Mutation in the Atrx Gene, Molecular Genetics and Genomic Medicine (2022)
6. A Novel Pathogenic Variant in the Lrtomt Gene Causes Autosomal Recessive Non-Syndromic Hearing Loss in an Iranian Family, BMC Medical Genetics (2020)
7. A Novel Mutation in Hld-5 With a Comprehensive Literature Review, Basic and Clinical Neuroscience (2025)
8. Whole Exome Sequencing Revealed Variants in Four Genes Underlying X-Linked Intellectual Disability in Four Iranian Families: Novel Deleterious Variants and Clinical Features With the Review of Literature, BMC Medical Genomics (2023)
9. The Identification of Two Pathogenic Variants in a Family With Mild and Severe Forms of Developmental Delay, Journal of Human Genetics (2021)
10. Next-Generation Sequencing Reveals a Novel Pathological Mutation in the Tmc1 Gene Causing Autosomal Recessive Non-Syndromic Hearing Loss in an Iranian Kindred, International Journal of Pediatric Otorhinolaryngology (2019)
11. A Novel Heterozygous Truncating Variant in the Ago1 Gene in an Iranian Family With Schizophrenia As an Unreported Symptom, Annals of Human Genetics (2023)
12. Autozygosity-Driven Genetic Diagnosis in Consanguineous Families From Italy and the Greater Middle East, Human Genetics (2020)
13. A Novel Biallelic Variant in Cdh23 Gene in a Family With Atypical Ush1d Manifestation: A Literature Review and Investigation of Genotype-Phenotype Correlation, Audiology and Neurotology (2023)
14. Sox10 Mutation Causes Waardenburg Syndrome Associated With Distinctive Phenotypic Features in an Iranian Family: A Clue for Phenotype-Directed Genetic Analysis, International Journal of Pediatric Otorhinolaryngology (2017)
15. Loss of Ank3 Function Causes a Recessive Neurodevelopmental Disorder With Cerebellar Ataxia, Movement Disorders (2025)
16. Phenotype and Genotype Heterogeneity of Pla2g6-Associated Neurodegeneration in a Cohort of Pediatric and Adult Patients, Orphanet Journal of Rare Diseases (2023)
17. Two Novel Homozygous Rab3gap1 Mutations Cause Warburg Micro Syndrome, Human Genome Variation (2015)
18. Identification of a Missense Variant in the Eif2b3 Gene Causing Vanishing White Matter Disease With Antenatal-Onset But Mild Symptoms and Long-Term Survival, Journal of Molecular Neuroscience (2021)
19. A Rare Case of Spinocerebellar Ataxia Autosomal Recessive 21 Presented With Liver Disease, Advanced Biomedical Research (2023)
20. Clinical Characterizations and Molecular Genetic Study of Two Co-Segregating Variants in Pdzd7 and Pde6c Genes Leading Simultaneously to Non-Syndromic Hearing Loss and Achromatopsia, BMC Medical Genomics (2024)