MUTATION ANALYSIS OF INDONESIAN MENTALLY RETARDED INDIVIDUALS WITH MICROCEPHALY AND MACROCEPHALY

Abstract

Background Among the mentally retarded individuals, associated features are often found that may lead to specific diagnosis, such as microcephaly or macrocephaly. Mutations in the autosomal recessive primary hereditary microcephaly (MCPH) genes are known to cause mental retardation (MR) and microcephaly, while mutations in the PTEN gene cause MR and macrocephaly. This study aims to analyse the presence of mutations in the Indonesian individuals with MR and microcephaly or macrocephaly. Methods From a previous study of 527 mentally retarded individuals, 48 microcephalic and 10 macrocephalic individuals underwent DNA sequencing. Secondary data from a previous study was used to determine the head circumference based on the Nellhaus head charts. The DNA of the microcephalic subjects was analysed for mutations of the MCPH genes while PTEN DNA sequencing were performed on macrocephalic subjects. The likelihood of pathogenicity of the variants found was determined by comparing them to mutation database and analysis of protein prediction programs of SIFT, Align-GVGD and Polyphen-2. Results From 48 individuals with MR and microcephaly, 23 variants on the MCPH genes were found as likely to be pathogenic, while no pathogenic mutation was found. One subject was found to have 2 variants which were predicted as likely to be pathogenic and underwent follow up, in which a monozygotic twin with the same 2 variants was discovered to be unaffected, revealing twin discordance result. None of the 10 subjects with macrocephaly and MR had any mutations in the PTEN gene. Conclusion Microcephaly was present in 9.1% of 527 individuals with MR, while macrocephaly occured in 1.9%. This study did not find any pathogenic causative mutation in the MCPH genes as well as PTEN gene that underwent DNA sequencing. This might be due to the non-genetic cause of microcephaly or macrocephaly and MR or mutations that were not yet discovered in this study. Interestingly, one twins discordance result was found. The findings of MR associated with microcephaly and macrocephaly may aid in providing genetic counseling in the Indonesian setting. Keywords : Mental retardation, microcephaly, macrocephaly, PTEN, MCPH