ABSTRACT: Bilateral frontoparietal polymicrogyria (BFPP, MIM 606854) is a heterogeneous autosomal recessive disorder of abnormal cortical lamination, leading to moderate-to-severe intellectual disability (ID), seizure disorder, and motor difficulties, and caused by mutations in the G protein-coupled receptor 56 ( GPR56 ) gene. Twenty-eight mutations in 40 different families have been reported in the literature. The clinical and neuroimaging phenotype is consistent in these cases. The BFPP cortex consists of numerous small gyral cells, with scalloping of the cortical-white matter junction. There are also associated white matter, brain stem, and cerebellar changes. GPR56 is a member of an adhesion G protein-coupled receptor family with a very long N-terminal stalk and seven transmembrane domains. In this study, we identified three families from Pakistan, ascertained primarily for ID, with overlapping approximately 1 Mb region (chr16:56,973,335-57,942,866) of homozygosity by descent, including 24 RefSeq genes. We found three GPR56 homozygous mutations, using next-generation sequencing. These mutations include a substitutional variant, c.1460T?>?C; p.L487P, (chr16:57693480 T?>?C), a 13-bp insertion causing the frameshift and truncating mutation, p.Leu269Hisfs*21 (NM_005682.6:c.803_804insCCATGGAGGTGCT; Chr16: 57689345_57689346insCCATGGAGGTGCT), and a truncating mutation c.1426C?>?T; p.Arg476* (Chr16:57693446C?>?T). These mutations fully segregated with ID in these families and were absent in the Exome Aggregation Consortium database that has approximately 8,000 control samples of South Asian origin. Two of these mutations have been reported in ClinVar database, and the third one has not been reported before. Three families from Pakistan with GPR56 mutations have been reported before. With the addition of our findings, the total number of mutations reported in Pakistani patients now is six. These results increase our knowledge regarding the mutational spectrum of the GPR56 gene causing BFPP/ID.
