Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Novel Manifestations of Warburg Micro Syndrome Type 1 Caused by a New Splicing Variant of Rab3gap1: A Case Report Publisher Pubmed



Khalesi R1 ; Razmara E1 ; Asgaritarghi G2 ; Tavasoli AR3 ; Riazalhosseini Y4, 5 ; Auld D4, 5 ; Garshasbi M1
Authors
Show Affiliations
Authors Affiliations
  1. 1. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
  2. 2. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
  3. 3. Myelin Disorders Clinic, Pediatric Neurology Division, Children’s Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. McGill Genome Centre, Montreal, QC, Canada
  5. 5. Department of Human Genetics, McGill University, Montreal, QC, Canada

Source: BMC Neurology Published:2021


Abstract

Background: The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. Case presentation: A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant—NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)—in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes. Conclusions: Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the “RABopathies” term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1. © 2021, The Author(s).
Related Docs
View other Related Docs
1. A Novel Deletion Variant in Cln3 With Highly Variable Expressivity Is Responsible for Juvenile Neuronal Ceroid Lipofuscinoses, Acta Neurologica Belgica (2021)
2. A Novel Missense Variant in the Lmnb2 Gene Causes Progressive Myoclonus Epilepsy, Acta Neurologica Belgica (2022)
3. Novel Phenotype and Genotype Spectrum of Wdr62 in Two Patients With Associated Primary Autosomal Recessive Microcephaly, Irish Journal of Medical Science (2022)
4. Novel Imaging and Clinical Phenotypes of Condsias Disorder Caused by a Homozygous Frameshift Variant of Adprhl2: A Case Report, BMC Neurology (2020)
5. A Comprehensive Study of Mutation and Phenotypic Heterogeneity of Childhood Mitochondrial Leukodystrophies, Brain and Development (2024)
6. A Homozygote Variant in the Trna Splicing Endonuclease Subunit 54 Causes Pontocerebellar Hypoplasia in a Consanguineous Iranian Family, Molecular Genetics and Genomic Medicine (2020)
7. Expanding the Clinical and Neuroimaging Features of Nkx6-2-Related Hereditary Spastic Ataxia Type 8, European Journal of Medical Genetics (2020)
8. High Genetic Heterogeneity of Leukodystrophies in Iranian Children: The First Report of Iranian Leukodystrophy Registry, Neurogenetics (2023)
Experts (# of related papers)
View all Related Experts
Ali Reza Tavasoli (13)
Mahmoudreza Ashrafi (8)
Other Related Docs
9. Crystallographic Modeling of the Pnpt1:C.1453A>G Variant As a Cause of Mitochondrial Dysfunction and Autosomal Recessive Deafness; Expanding the Neuroimaging and Clinical Features, Mitochondrion (2021)
10. Three Iranian Patients With Rare Subtypes of Hereditary Spastic Paraplegia (Hsp): Spg76, Spg56, and Spg69, Neurogenetics (2025)
11. Identification of a Novel Homozygous Gls Gene Variant Associated With Developmental and Epileptic Encephalopathy (Dee) Type 71, Neurogenetics (2024)
12. Novel Stag3 Variant Associated With Primary Ovarian Insufficiency and Non-Obstructive Azoospermia in an Iranian Consanguineous Family, Gene (2022)
13. Functional Analysis of Reln S2486g Mutation and Its Contribution to Pathogenesis of Ankylosing Spondylitis, Archives of Iranian Medicine (2020)
14. A Novel Variant in the Pah Gene Causing Phenylketonuria in an Iranian Pedigree, Avicenna Journal of Medical Biotechnology (2017)
15. The First Iranian Patient With You-Hoover-Fong Syndrome and a Review of the Literature on 27 Cases: Expanding the Genotypic and Phenotypic Spectrum, Neurological Sciences (2024)
16. Extending and Outlining the Genotypic and Phenotypic Spectrum of Novel Mutations of Nalcn Gene in Ihprf1 Syndrome: Identifying Recurrent Urinary Tract Infection, Neurological Sciences (2023)
17. Novel Lama2 Gene Mutations Associated With Merosin-Deficient Congenital Muscular Dystrophy, Iranian Biomedical Journal (2018)
18. Catecholaminergic Polymorphic Ventricular Tachycardia (And Seizure) Caused by a Novel Homozygous Likely Pathogenic Variant in Casq2 Gene, Gene (2024)
19. A Panel of Six-Circulating Mirna Signature in Serum and Its Potential Diagnostic Value in Colorectal Cancer, Life Sciences (2020)
20. Endoplasmic Reticulum Aminopeptidase 2 Gene Single Nucleotide Polymorphisms in Association With Susceptibility to Ankylosing Spondylitis in an Iranian Population, Immunology Letters (2020)
21. Next Generation Sequencing Elucidated a Clinically Undiagnosed Metabolic Disorder - an Iranian Family With Hereditary Orotic Aciduria, Gene Reports (2019)
22. The Concept of Immunogenetics, Advances in Experimental Medicine and Biology (2022)
23. Structural Modeling of Human Akap3 Protein and in Silico Analysis of Single Nucleotide Polymorphisms Associated With Sperm Motility, Scientific Reports (2022)
24. The Genetic Perspective of Familial Glucocorticoid Deficiency: In Silico Analysis of Two Novel Variants, International Journal of Endocrinology (2020)
25. Biallelic Variants in Ogdh Encoding Oxoglutarate Dehydrogenase Lead to a Neurodevelopmental Disorder Characterized by Global Developmental Delay, Movement Disorder, and Metabolic Abnormalities, Genetics in Medicine (2023)
26. Association of the Genetic Variants in the Endoplasmic Reticulum Aminopeptidase 2 Gene With Ankylosing Spondylitis Susceptibility, International Journal of Rheumatic Diseases (2021)
27. Whole-Transcriptome Sequencing–Based Concomitant Detection of Viral and Human Genetic Determinants of Cutaneous Lesions, JCI Insight (2022)
28. Genetic Homozygosity in a Diverse Population: An Experience of Long Qt Syndrome, International Journal of Cardiology (2020)
29. Whole-Exome Sequencing Uncovers Novel Causative Variants and Additional Findings in Three Patients Affected by Glycogen Storage Disease Type Vi and Fanconi−Bickel Syndrome, Frontiers in Genetics (2021)
30. Comprehensive Review and Expanding the Genetic Landscape of Cornelia-De-Lange Spectrum: Insights From Novel Mutations and Skin Biopsy in Exome-Negative Cases, BMC Medical Genomics (2024)
31. Novel Mutation in Patients With Microcephalic Osteodysplastic Primordial Dwarfism Type Ii (Mopd Ii), Metabolic Brain Disease (2025)
32. Clinical and Molecular Findings of Autosomal Recessive Spastic Ataxia of Charlevoix Saguenay: An Iranian Case Series Expanding the Genetic and Neuroimaging Spectra, Cerebellum (2023)
33. Flt3l Governs the Development of Partially Overlapping Hematopoietic Lineages in Humans and Mice, Cell (2024)
34. Primary and Secondary Microcephaly, Global Developmental Delay, and Seizure in Two Siblings Caused by a Novel Missense Variant in the Znf335 Gene, Journal of Molecular Neuroscience (2022)
35. Acer3-Related Leukoencephalopathy: Expanding the Clinical and Imaging Findings Spectrum Due to Novel Variants, Human Genomics (2021)