5600
Sherif Abdel Ghafar Fawzy Abdel Ghafar
Mutational Analysis of RAB3GAP1 Gene in Patients with Micro and Martsolf Syndromes
RAB3GAP1, Micro syndrome , Martsolf, mutations
Micro syndrome is an autosomal recessive disorder characterized by multiple organ abnormalities involving the eye, nervous, and endocrine systems. It is caused by mutations in RAB3GAP1, RAB3GAP2, RAB18 or TBC1D20. Of them, mutations in RAB3GAP1 are more frequent and have been described in patients from diverse ethnicities. On the other hand, Martsolf is a clinically overlapping syndrome but with milder phenotypic presentation and results mainly from mutations in RAB3GAP2 and less commonly RAB3GAP1. The current study included 25 patients from 20 unrelated Egyptian families, 20 patients with Micro and 5 with Martsolf syndrome. Patients presented with the characteristic clinical manifestations of the two syndromes including postnatal microcephaly, congenital cataracts, microphthalmia, optic atrophy, spasticity and intellectual disability. In addition, brain MRI showed polymicrogyra, thin corpus callosum, cortical atrophy, and white matter dysmyelination. Genital anomalies were also prominent in majority of patients. Unusual additional clinical findings found included congenital heart disease (3 patients), pectus carinatum (3 patients) and pectus excavatum (2 patients). Mutational analysis of the entire coding region of the RAB3GAP1 gene was performed for all patients and pathogenic mutations were detected in 13 patients from 11 families (Frequency= 55%) with Micro syndrome. No RAB3GAP1 mutations were detected in Martsolf patients. Eleven distinct mutations (5 nonsense, 4 frameshift and 2 splice site) were identified including 6 novel ones, c.151-15_155del (p.Gly51Ilefs*12), c.726T>A (p.Tyr242*), c.1026delT (p.Asp342Glufs*19), c.1407_1417delinsCCAT (p.Tyr470Hisfs*3), c.1555-1G>A and c.2218delT (p.Trp740Glyfs*45). Two mutations were recurrent and found in more than one family including the c.1335delC (p.Tyr445*) that was found in two unrelated families from the same government (Sohag) which might suggest that it has arisen from a common ancestor there. No clear genotype-phenotype correlations were observed among the studied patients and there was phenotypic variability among patients carrying the same mutation indicating that other gene modifiers, epigenetic or environmental factors may play role in the scenario. In conclusion, the present study described the detailed clinical and neuro-radiological findings of a relatively large cohort of patients with Micro and Martsolf syndromes. Furthermore, the molecular results obtained enlarged the available mutational data of Micro syndrome, offering new insights into the types and frequencies of the RAB3GAP1 mutations and enabled us to provide accurate genetic counseling, carrier detection of at risk family relatives and prenatal diagnosis.
2019
M.Sc
Alexandria
Medicine