Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease

Abstract

Alexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white-gray junction. Initial mutation screening of the gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the gene. Mutations in the gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

NovelDLX3variants in amelogenesis imperfecta with attenuated tricho‐dento‐osseous syndrome

“…For individual II:1, family 3, a heterozygous deletion of the entire coding region of DLX3 was detected by comparative NGS read‐depth analysis (Green et al, ). After correcting for sample‐to‐sample variation in each of the samples in the same sequencing lane ( n = 8), read depths across DLX3 exons for individual II:1 were compared to the median value for the dataset, effectively using the other seven sequenced samples in the lane as a control data set for the patient sample.…”

Psychiatric Onset Alexander Disease: An Important Challenge in Neuropsychiatric Diagnosis: A Case Report

“…(Quinlan, Brenner, Goldman, & Messing, 2007;Yasuda et al, 2019) Alexander disease is considered a gain-of function disorder in the sense that the GFAP mutations produce consequences that differ dramatically from those caused by the absence of GFAP (like that case in this study).Although the main cause of sever and lethal AxD is accumulation of toxic defective proteins in astrocytes as a consequence of point mutation in GFAP gene; but, in this case with deletion of 1-9 exons, GFAP protein is produced from intact allele with less than 50% performance-This phenomenon is called haploinsufficiencybesides, previous studies demonstrated that deletion of some exons like exon 5. (Green, 2018) After a pathogenic mutation is discovered, it is preferred to assess mutation in other family members, whom could be asymptomatic or minimally affected.…”

Novel Dlx3 Variants in Amelogenesis Imperfecta With Attenuated Tricho-Dento-Osseous Syndrome

“…For individual II:1, family 3, a heterozygous deletion of the entire coding region of DLX3 was detected by comparative NGS read-depth analysis (Green et al, 2017). After correcting for sample-to-sample variation in each of the samples in the same sequencing lane (n = 8), read depths across DLX3 exons for individual II:1 were compared to the median value for the dataset, effectively using the other seven sequenced samples in the lane as a control data set for the patient sample.…”