Clinical and molecular genetic study on 21 children with lissencephaly / 中华实用儿科临床杂志

ABSTRACT

Objective:To study the clinical features and molecular genetic mechanisms of children with lissencephaly (LIS), as well as to analyze the relationship between genotypes and phenotypes of the disease.Methods:From October 2016 to December 2017, the clinical data and follow-ups of 21 LIS children were collected in the Department of Neurology, Shenzhen Children′s Hospital.Whole genome sequencing (WGS) was performed for genetic testing.Results:Among these 21 cases, 18 cases developed epilepsy (86%), and 3 cases were seizure free (14%). The onset age of children with epilepsy was relatively young, and 16 cases occurred within 1 year old (89%). Among these cases, 16 were pachygyria (76%), 3 cases were agyria combined with pachygyria (14%) and 2 cases were agyria (10%). Epileptic syndromes included 12 cases of West syndrome (67%), 2 cases of Ohtahara syndrome (11%), 2 cases of other epileptic encephalopathy (11%), and 2 cases of focal epilepsy (11%). Brain magnetic resonance imaging(MRI) demonstrated that most cases were pachygyria, among which diffuse pachygyria was more common (56%, 9/16 cases). The results of WGS 13 pathogenic or likely pathogenic single nucleotide variants (SNV) and copy number variants (CNV) were detected.The total detection rate was 62%, of which 2 cases were frameshift, 1 case was nonsense and 1 case was missense variants of PAFAH1B1, 6 cases were chromosome 17p13.3 deletion syndrome, thus lea-ding to the whole gene deletion of PAFAH1B1, and 1 case was missense variant of DCX, frameshift variant of KIF2A, and missense variant of PIK3R2, respectively.Totally, 48% (10/21 cases) of the cases were variants or deletions of PAFAH1B1, which resulted in lissencephaly in the parietal-occipital region of the brain.Novel variants were PAFAH1B1 c.1067G>A, PAFAH1B1 c.897delT and KIF2A c.2225delG. Conclusions:Most cases of LIS accompanied with epilepsy, in which West syndrome was relatively more common.Brain MRI showed that most cases were diffuse pachygyria.The variants and deletions of PAFAH1B1 was the main genetic cause of LIS.The identification of the novel variants expanded the genotypical spectrum of LIS.