Related Experiment Video
Updated: Jul 30, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Exome sequencing identifies a novel pathogenic variant in RAB3GAP1 causing Warburg Micro syndrome in a Pakistani
Wahid Ullah1, Muhammad Ilyas1,2, Muhammad Tariq3
1Centre for Omic Sciences, Islamia College University, Peshawar, Pakistan.
Background:
Warburg Micro (WARBM) syndrome is a rare heterogeneous recessive genetic disorder characterized by ocular, neurological, and endocrine problems. To date, disease-causing variants in four genes have been identified to cause this syndrome; of these, RAB3GAP1 variants are the most frequent. Very little is known about WARBM syndrome in rural populations.
Objectives:
This study aims to investigate the genetics underpinnings of WARBM syndrome in a Pashtun family with two patients from Pakistan. The patients presented with spastic diplegia, severe intellectual disability, microphthalmia, microcornea, congenital cataracts, optic atrophy, and hypogonadism.
Methods:
Magnetic resonance imaging (MRI) analysis revealed pronounced cerebral atrophy including corpus callosum hypoplasia and polymicrogyria. Exome sequencing and subsequent filtering identified a novel homozygous missense variant NM_001172435: c.2891A>G, p.Gln964Arg in the RAB3GAP1 gene. The variant was validated, and its segregation confirmed, by Sanger sequencing.
Results:
Multiple prediction tools assess this variant to be damaging, and structural analysis of the protein shows that the mutant amino acid residue affects polar contact with the neighboring atoms. It is extremely rare and is absent in all the public databases. Taken together, these observations suggest that this variant underlies Micro syndrome in our family and is extremely important for management and family planning.
Conclusions:
Identification of this extremely rare variant extends the mutations spectrum of Micro syndrome. Screening more families, especially in underrepresented populations, will help unveil the mutation spectrum underlying this syndrome.
Insights
A novel RAB3GAP1 gene variant was identified in a Pakistani family with Warburg Micro (WARBM) syndrome, expanding the known genetic causes of this rare disorder.
Area of Science:
- Genetics
- Rare diseases
- Molecular biology
Background:
- Warburg Micro (WARBM) syndrome is a rare, heterogeneous genetic disorder.
- It presents with ocular, neurological, and endocrine abnormalities.
- RAB3GAP1 gene variants are the most frequent cause of WARBM syndrome.
Purpose of the Study:
- Investigate the genetic basis of WARBM syndrome in a Pashtun family from Pakistan.
- Identify causative variants in patients with spastic diplegia, intellectual disability, and other symptoms.
- Contribute to understanding WARBM syndrome in underrepresented populations.
Main Methods:
- Magnetic resonance imaging (MRI) to assess brain structure.
- Exome sequencing to identify genetic variants.
- Sanger sequencing to validate the identified variant and its segregation.
Main Results:
- MRI revealed cerebral atrophy, corpus callosum hypoplasia, and polymicrogyria.
- A novel homozygous missense variant (c.2891A>G, p.Gln964Arg) in the RAB3GAP1 gene was identified.
- Prediction tools and structural analysis indicated the variant is damaging and extremely rare.
Conclusions:
- The identified RAB3GAP1 variant is likely causative of WARBM syndrome in this family.
- This finding expands the known mutation spectrum for Micro syndrome.
- Further screening in underrepresented populations is crucial for a comprehensive understanding of WARBM syndrome genetics.
Related Concept Videos
02:38The Ras Gene
Ras is a...
01:14Rab Proteins
Rab proteins switch between a cytosolic, GDP-bound inactive state and a membrane-anchored, GTP-bound active state. By themselves, Rabs show slow rates of GDP/GTP exchange and GTP hydrolysis. Thus, Rab proteins are considered...
01:11Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...
01:25Rab Cascades
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...