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Exome sequencing identifies a novel pathogenic variant in RAB3GAP1 causing Warburg Micro syndrome in a Pakistani family

Ullah, Wahid; Ilyas, Muhammad; Tariq, Muhammad; Imdad, Maria; Ullah, Ikram; Efthymiou, Stephanie; Faheem, Muhammad; ... SYNAPS Study Group; + view all (2023) Exome sequencing identifies a novel pathogenic variant in RAB3GAP1 causing Warburg Micro syndrome in a Pakistani family. International Journal of Developmental Neuroscience , 83 (4) pp. 368-373. 10.1002/jdn.10264. Green open access

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Abstract

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.

Type: Article
Title: Exome sequencing identifies a novel pathogenic variant in RAB3GAP1 causing Warburg Micro syndrome in a Pakistani family
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/jdn.10264
Publisher version: https://doi.org/10.1002/jdn.10264
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Micro syndrome, Rab18, RAB3GAP1, spastic diplegia, WARBM
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10169617
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