From cataract to syndrome diagnosis: Revaluation of Warburg‐Micro syndrome Type 1 patients

Abstract

Warburg-Micro syndrome (WARBM) is a rare autosomal recessively inherited neuro-ophthalmologic syndrome. Although WARBM shows genetic heterogeneity, the pathogenic variants in RAB3GAP1 were the most common cause of WARBM. In this study, we aimed to evaluate the detailed clinical and dysmorphic features of seven WARBM1 patients and overview the variant spectrum of RAB3GAP1 in comparison with the literature who were referred due to congenital cataracts. A previously reported homozygous variant (c.2187_2188delGAinsCT) was identified in three of these patients, while the other four had three novel variants (c.251_258delAGAA, c.2606+1G>A, and c.2861_2862dupGC). Congenital cataract and corpus callosum hypo/agenesia are pathognomonic for WARBM, which could be distinguished from other similar syndromes with additional typical dysmorphic facial features. Although there is no known phenotype and genotype correlation in any type of WARBM, RAB3GAP1 gene analysis should be previously requested as the first step of genetic diagnosis in clinically suspicious patients when it is not possible to request a multi-gene panel.

Novel, homozygous RAB3GAP1 c.2606 + 1G>A, p.Glu830ValfsTer9 variant and chromosome 3q29 duplication in a Turkish individual with Warburg micro syndrome

“…In family 3, we found a homozygous c.2606 + 1G>A splice site variant in intron 22 (Geckinli et al , 2020; Albayrak et al ., 2021). cDNA analysis of this patient showed that this variant causes skipping of exon 22 and fusion of exon 21 to exon 23 leading to a PSC in exon 23.…”

Whole-Exome Sequencing and Copy Number Analysis in a Patient with Warburg Micro Syndrome

“…Combining the above genotypic and phenotypic information, the patient was diagnosed with WARBM. According to previous reports [ 1 , 3 , 22 , 23 , 24 , 25 ], most WARBM patients originated from consanguineous families (mostly in Egypt, Pakistan, Turkey, India, Iran, and Tunisia). The disease is rare in the Chinese population because of uncommon consanguineous marriages in China.…”

Phenotypic comparison of a novel variant (p.P164R) and A founder mutation (c.748+1G>A) in Warburg Micro syndrome

“…6 To date, about 100 families from various ethnic groups who have been confirmed as WARBM in which mutations in RAB3GAP1 were the most common cause (frequency 75%). 5,7 RAB3GAP1/2 encodes the catalytic subunit of a GTPase activator protein and activates Rab18 by forming a heterodimeric complex and acting as a guanosine nucleotide exchange factor. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy, and synaptic transmission.…”