الفهرس 
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Abstract
Micro and Martsolf syndromes are rare autosomal recessive neurological disorders characterized by intellectual disability, ocular defects, brain anomalies, progressive spasticity and genital abnormalities. Both syndromes are clinically overlapping but Martsolf is usually associated with a milder phenotypic presentation. Micro syndrome is genetically heterogeneous and is caused by mutations in four different genes, RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20. On the other hand, Martsolf syndrome results mainly from mutationsin RAB3GAP2 with very few families reported with mutations inRAB3GAP1gene. Meanwhile, many families described in the literature did not harbor mutations in any of the four genes suggesting further genetic heterogeneity and the involvement of other genes that are not discovered yet.
The current study included 25 patients from 20 unrelated families from different provinces of Egypt. Patients were classified into 20 with Micro syndrome and only 5 patients clinically diagnosed with Martsolf syndrome. Consanguinity was evident in 17 families (85%) while 3 families (15%) were non-consanguineous. Patients shared the main clinical features of the two syndromes including postnatal microcephaly, congenital cataracts, spasticity and variable degrees of intellectual disability. Other eye manifestations included microcornea (6 Micro/ 3 Martsolf), microphthalmia (8 Micro/3 Martsolf) and optic atrophy (11 Micro/0 Martsolf). Brain imaging revealed thin corpus callosum (20 Micro/5 Martsolf), polymicrogyria (16 Micro/3 Martsolf), cortical atrophy (14 Micro/ 2 Martsolf),white matter dysmyelination (19 Micro/ 3 Martsolf), cerebellar hypoplasia/atrophy (3 Micro/ 3 Martsolf) and cerebellar vermis hypoplasia (8 Micro/0 Martsolf). Moreover, genital anomalies were present in 60% of patients. Unusual findings included congenital heart disease (3 Micro), pectus carinatum (2 Micro/ 1 Martsolf) and pectus excavatum (2 Micro).
Screening of RAB3GAP1gene was carried out by direct sequencing of whole coding exons of the gene in all patients. Sequence analyses identified pathogenic RAB3GAP1 mutations in 11 families with a mutation detection rate of 55%. Eleven distinct disease-causing mutations were identified including 5 nonsense, 4 frameshift, and 2 splice site. Of them, 6 mutations were novel [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 andc.2218delT(p.Trp740Glyfs*45)].On the other hand, five mutations werepreviously described: c.899+1G>A, c.1039C>T (p.Arg347*), c.1335delC (p.Tyr445*), c.1725G>A (p.Trp575*) and c.1471C>T (p.Arg491*).
Mutations were scattered all over the gene with no hot-spot exons. However, three and two mutations were located in exon 15 and 12, respectively. In addition, two different mutations were recurrent in this study;c.899+1G>Aandc.1335delC, both were found in two unrelated families. Interestingly, the c.1335delC mutation was found in the homozygous form in two unrelated families from Sohag which might suggest that it has arisen from a common ancestor there. In addition, c.899+1G>A mutation was previously reported in another Egyptian family.
Generally, no significant phenotype-genotype correlation was observed among the studied patients and those described in the literature. This may be due to rarity of cases and the fact that a limited number of mutations were recurrent in more than one family.In addition, there was a notable difference in the phenotypic severity among sibs and patients carrying the same mutations. This may be attributed to the presence of an unknown role played by other gene modifiers or epigenetic factors which needs further studies and investigations in the future.
6.2. Conclusion
• The present study enlarged the available mutational data of Micro syndrome, offering new insights into the types and frequencies of the RAB3GAP1 mutations in a cohort of Egyptian patients.
• This study significantly extends the range of the reported clinical manifestations associated with RAB3GAP1 mutations.
• The studyalso highlighted the clinical and neuroimaging variability observed in patients with the same mutations.
• Finally, the molecular data obtained in this study can be used to provide proper genetic counseling, carrier detection of at risk family relatives and prenatal diagnosis for families with RAB3GAP1 mutations.