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

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.