Abstract
Polymicrogyria (PMG) is the most common malformation of cortical development (MCD) and presents as an irregularly patterned cortical surface with numerous small gyri and shallow sulci leading to various neurological deficits including developmental delays, intellectual disability, epilepsy, and language and motor issues. The presentation of PMG varies and is often found in conjunction with other congenital anomalies. Histologically, PMG features an abnormal cortical structure and dyslamination, resulting in its classification as a defect of neuronal migration and organization. Due in part to a variety of etiologies, little is known about the molecular mechanism(s) underlining PMG. To address this gap in knowledge, a case study is presented where an elderly individual with a medical history of unspecified PMG was examined postmortem by using a combination of anatomical, magnetic resonance imaging (MRI), histopathological, and genetic techniques. The results of the study allowed the classification of this case as bifrontal PMG. The genetic screening by whole exome sequencing (WES) on the Illumina Next Generation Sequencing (NGS) platform yielded 83 rare (minor allele frequency, MAF ≤ 0.01) pathological/deleterious variants where none of the respective genes has been previously linked to PMG. However, a subsequent analysis of those variants revealed that a significant number of affected genes were associated with most of the biological processes known to be impaired in PMG thereby pointing toward a polygenic nature in the present case. One of the notable features of the WES dataset was the presence of rare pathological/deleterious variants of genes (ADGRA2, PCDHA1, PCDHA12, PTK7, TPGS1, and USP4) involved in the regulation of Wnt signaling potentially highlighting the latter as an important PMG contributor in the present case. Notably, ADGRA2 warrants a closer look as a candidate gene for PMG because it not only regulates cortical patterning but has also been recently linked to two cases of bifrontal PMG with multiple congenital anomalies through its compound heterozygous mutations.