The current study investigated the mutation spectrum of MECP2 in Vietnamese patients. The patients had been enrolled and pediatricians and neurologists carried out clinical evaluation. Therefore, the cohort is well defined and well suited for molecular study. Prior to availability of MECP2 mutation test, criteria for Rett syndrome diagnosis are based on a collection of clinical features organized into age-related stages [23]. Classic Rett syndrome was classified for girls meeting all main criteria while variants of this disorder were marked for patients with a less severe clinical presentation, including preserved speech or hand use, normal head circumference, or delayed symptom onset.
Mutations of MECP2 gene are highly correlated with RTT and have been found in other neurological disorder such as autism, Angelman syndrome, and other behavioral and intellectual disorders. Therefor molecular diagnosis for MECP2 mutations is an important step in diagnosis of neurodevelopmental disorders. Routine diagnostic protocol for MECP2 mutations is often carried out by DNA sequencing because of the gene’s broad spectrum of mutation.
We identified MECP2 mutation in 74% of the cases, the mutation detection rate is comparable with other study in which MECP2 mutations were identified in approximately 75% of RTT patients [24,25,26] . The result suggest that MECP2 mutation is not the only cause of RTT, as there are also FOXG1 gene (locus 14q13) which causes the congenital variant of Rett syndrome and others mutations which could also lead to RTT [27]. Furthermore, we did not take into account intronic sequence change (i.e. splice site mutation) which could lead to changes in the protein structure and function. Therefore, the absent of MECP2 alone is not enough to rule out the possibility of RTT in cases where the child does not have typical symptoms or not old enough to conclude with the diagnosis of classic RTT.
The study identified 14 pathogenic mutations, including 2 missenses, 4 nonsenses, 6 frame shifts and 2 deletions. The more frequently detected mutations in our cohort (c.473 C > T; c.808 C > T, c.763 C > T and c.502C > T) are also the most common mutations reported worldwide as listed on RettBASE [18]. The mutation profile suggested that the similarity of the mutation spectrum in MECP2 is not the product of heredity, but the susceptibility of the mutation sites. We noted that most of the point mutations in our cohort are C > T in CpG sites. The CpG sites are often mutation hotspot because the cytosine in these sites is often methylated (mCpG) and 5-methylcytosine is genetically unstable [28]. In disorder like RTT, which is strictly due to de novo mutations, these CpG sites mutations became more frequent.
In our cohort, we detected a novel mutation not listed previously in any mutation databases: c.1384-1385delGT. The patient had clear clinical presentations of classic RTT. The patients had a relatively normal neurodevelopmental phase in the first 8 months, and then the child’s development regressed. At 12 months of age, she experienced a seizure and was taken to the hospital. At 3 years of age, she was unable to walk independently, and stereotypic hand movements hindered hand usage. She exhibited poor interaction to her surrounding and to other people, and show no communication ability. In silico analysis confirmed the mutation as a disease causing variant.
Before the availability of MECP2 mutation test in Vietnam, criteria for the diagnosis of Rett were solely based on clinical findings. This could lead to the under-diagnosis of Rett thus, overlooking the milder form of the disease. In order to better manage and reduce the incident of Rett we need to develop a framework to provide counseling, prenatal diagnosis for the patients and families.
