Poster Presentation 43rd Lorne Genome Conference 2022

SLC35A2 and brain mosaicism in infantile spasms with focal brain malformations (#141)

Matthew Coleman 1 2 , Min Wang 2 , Sarah EM Stephenson 1 2 , Cas Simons 2 , Wei Shern Lee 1 2 , Colleen D'Arcy 3 , Saskia Freytag 4 , Wirginia J Maixner 3 , A. Simon Harvey 3 , Richard J Leventer 1 2 3 , Katherine B Howell 1 2 3 , Paul J Lockhart 1 2
  1. The University of Melbourne, Parkville, VIC, Australia
  2. Murdoch Children's Research Institute, Parkville, VIC, Australia
  3. Royal Children's Hospital, Parkville, VIC, Australia
  4. Harry Perkins Institute of Medical Research, Nedlands, WA, Australia

Background:

Focal brain malformations are a common cause of infantile spasms (IS). We aimed to investigate the genetic landscape of IS with focal brain malformations. 

Method:

We performed histopathologic review and genomic testing in 59 individuals with IS and a focal brain malformation following resective epilepsy neurosurgery for seizure control at the Royal Children’s Hospital, Melbourne, clinically classified as having tuberous sclerosis (n=23), focal cortical dysplasia type I (20) and II (11), dysembryoplastic neuroepithelial tumour (1), complex malformation of cortical development (1), and non-specific findings (3). Genomic testing was performed on blood or brain tissue using 200x (n=3) or 400x depth WES (n=32), or targeted panel sequencing (n=24). Variants were filtered using GATK & MuTect variant caller pipelines for germline and somatic candidate variants. Single nuclei RNA-seq analysis (snRNA-seq) was performed on resected brain to understand pathomechanism in a gene of interest, SLC35A2.

Results:

Germline putative pathogenic variants were identified in 23/59 (39%) individuals, in TSC2 (x16), TSC1 (x1), CDKL5 (x1), DEPDC5 (x1), PIK3CA (x1), COL4A1 (x1), SCN8A (x1) and NPRL3 (x1) genes. Putative pathogenic brain somatic variants were identified in 16/59 (27%) cases, in SLC35A2 (x9), AKT3 (x2), DEPDC5 (x1) MTOR (x1), OFD1 (x1) TSC1 (x1) and TSC2 (x1) genes. Somatic variants ranged in variant allele frequency between 0.95-41.0% in brain. mTOR pathway variants were identified in most individuals with TSC and FCD II. Histopathologic review led to reclassification of all 9 individuals with SLC35A2 variants to mild malformation of cortical development with oligodendroglial hypoplasia in epilepsy (MOGHE). Preliminary snRNA-seq data suggests oligodendrocyte progenitor cells and astrocytes exhibit abnormal expression profiles in lesional tissues from these individuals.

Conclusion:

The genetic landscape of IS with focal brain malformations other than tuberous sclerosis comprises predominantly brain somatic mutations. Somatic variants in SLC35A2 were a major cause of IS with focal malformations.