First Clinical Report of Two RAB3GAP1 Pathogenic Variant in Warburg Micro Syndrome

Area of Science:

• Genetics
• Developmental Biology
• Ophthalmology

Background:

• Warburg micro syndrome (WARBM) is a rare autosomal recessive disorder.
• It is characterized by severe microcephaly, microphthalmia, intellectual disability, and hypotonia.
• Loss-of-function mutations in genes including RAB18, RAB3GAP2, RAB3GAP1, and TBC1D20 are known causes.

Purpose of the Study:

• To report two novel homozygous mutations in the RAB3GAP1 gene.
• To describe the clinical presentation of two unrelated patients with these mutations.
• To contribute to the understanding of genotype-phenotype correlations in WARBM.

Main Methods:

• Next-generation sequencing and Sanger sequencing were employed.
• Genetic analysis focused on identifying mutations in genes associated with WARBM.
• Clinical data including physical examinations and developmental assessments were collected.

Main Results:

• Two unrelated patients presented with homozygous nonsense variations in RAB3GAP1: c.559 C>T (p.Arg187Ter) and c.520 C>T (p.Arg174Ter).
• Both patients exhibited classic WARBM features: microcephaly, microphthalmia, microcornea, bilateral congenital cataracts, severe intellectual disability, and congenital hypotonia.
• These novel splice site mutations are predicted to cause premature stop codons, leading to the WARBM1 phenotype.

Conclusions:

• This study presents the first clinical report of two distinct, previously unreported RAB3GAP1 variants associated with Warburg micro syndrome.
• The findings expand the spectrum of known mutations causing WARBM.
• Genetic identification of these variants aids in diagnosis and understanding the molecular basis of the syndrome.