EP05.14: Fetal cortical malformation: the role of the brain biopsy in etiological diagnosis

It is postulated that most of the malformations of cortical development (MCD) are caused by genetic mutations that alter proteins and associated molecular pathways involved in the development of the cerebral cortex. Some MCDs are associated with postzygotic mutations that produce somatic mosaicism. All cases described of somatic mutations have been identified in cortical tissue resected to treat disease-related epilepsy. We present a prenatal case of megalencephaly caused by a postzygotic mutation in PIK3R2 that was diagnosed by fetal brain biopsy. A 31-week pregnant woman came to our neurosonography unit for a second opinion due to a progressive fetal macrocephaly. The neurosonography showed a head circumference of +4DS, triangular cavum morphology, decreased subarachnoid space and perisylvian polymicrogyria, all suggestive of megalencephaly. Fetal MRI confirmed extensive cortical malformation consistent with an oversulcation pattern. Array and trio exome in amniotic fluid were normal. Due to the associated poor prognosis of this condition the family decided to terminate the pregnancy at 33 weeks. It was proposed to the family to study the exome in brain tissue by brain biopsy after delivery. The results showed the variant c.1117G>A, p.(G1y373Arg) in the gen PIK3R2, described as pathogenic and associated to megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus syndrome (MPPH). Necropsy confirmed prenatal findings. MPPH presents autosomic dominant inheritance pattern and in most cases, it is described as a sporadic syndrome caused by germline or postdizygotic mutations. The present case would be a postzygotic mutation, which would explain why the pathogenic variant was not identified in the amniotic fluid study but in the brain tissue. The risk of recurrence in these cases is negligible. This case illustrates for the first time the utility of the brain biopsy after TOP in MCDs, highlighting the importance for future genetic counselling.