Identification of a novel PAFAH1B1 missense mutation as a cause of mild lissencephaly with basal ganglia calcification

Abstract Purpose To investigate the genetic and clinical features of a Chinese family exhibiting an autosomal dominant inheritance pattern of lissencephaly. Methods Clinical examinations and cranial imaging studies were performed for all members of the family (two unaffected members and three surviving members from a total of four affected members). In addition, whole-exome sequencing analysis was performed for DNA from an affected patient to scan for candidate mutations, followed by Sanger sequencing to verify these candidate mutations in the entire family. A total of 200 ethnicity-matched healthy controls without neuropsychiatric disorder were also included and analyzed. Results We identified a novel missense mutation, c.412G > A, p.(E138K), that cosegregated with the disease in exon 6 of the platelet activating factor acetylhydrolase 1b regulatory subunit 1 ( PAFAH1B1 ) gene in the affected members; this mutation was not found in the 200 controls. Multiple sequence alignments showed that codon 138, where the mutation (c.G412A) occurred, was located within a phylogenetically conserved region. Brain magnetic resonance imaging revealed calcification within the bilateral globus pallidus in all three affected members. Conclusions We identified a novel missense mutation, c.412G > A, p.(E138K), in the PAFAH1B1 gene of a Chinese family with lissencephaly. In addition, our findings suggest that basal ganglia calcification is a novel clinical feature of PAFAH1B1- related lissencephaly.