First description of an unusual novel double mutation in MECP2 co-occurring with the m.827A > G mutation in the MT-RNR1 gene associated with angelman-like syndrome

Mutations in Methyl-CpG-Binding protein 2 (MECP2), located on Xq28 and encoding a methyl CpG binding protein, are commonly related to Rett syndrome. However, MECP2 mutations have already been reported in patients with neurodevelopmental abnormalities such as X-linked mental retardation, severe neonatal encephalopathy and Angelman-like syndrome (AS-like). Accordingly, we report the clinical, molecular and bioinformatic analyses in a Tunisian patient with AS-like phenotype. In fact, the direct sequencing of MECP2 and cloning essay reveals the emergence of an unusual novel double mutation, including a de novo mutation c.397C > T (p.R133C) and an inherited one c.608C > T (p.T203 M) co-occurring in Trans. We also provide the molecular evidence of the c.608C > T transmission to the patient which was present in her father at somatic mosaicism state. To gain insight into the molecular basis of this disorder, we undertook, for the first time, a whole mitochondrial genome mutational analysis. Thus, the results showed the presence of several variations and a homoplasmic mutation m.827A > G in the MT-RNRI gene, leading to the disruption of the 12S rRNA secondary structure. Our report is considered as the first to describe an unusual novel double mutation (c.397C > T in trans with c.608C > T) in MECP2 co-occurring with the mitochondrial m.827A > G mutation in the MT-RNR1 gene in a Tunisian patient with AS-like. Besides, our results highlight the importance of studying MECP2 and the significance of mDNA screening in AS-like disorder for a better understanding of its etiopathogenesis.