GFAP canonical transcript may not be suitable for the diagnosis of adult-onset Alexander disease
Acta Neuropathologica Communications volume 6, Article number: 112 (2018)
To the editor,
Alexander disease (AD) is an autosomal dominant progressive leukoencephalopathy caused by heterozygous mutations in the glial fibrillary acidic protein (GFAP) gene. Onset of symptoms can range from infancy to adulthood, with the infantile form being most common and the adult onset form accounting for one third of cases . A clinical diagnosis is typically confirmed via sequencing of the GFAP gene, as 98% of the individuals have detectable single nucleotide or small indels pathogenic variants. Here we highlight the emerging importance of testing an exon only expressed in an alternative GFAP transcript, which has recently been shown to harbor pathogenic variation found in later-onset patient presentations. A brief survey of clinical testing laboratories reveals that not all include this exon in the reportable range of GFAP testing and consequently fail to reveal the correct genetic diagnosis. This point is highlighted in a 43-year-old male patient was referred to Clinical Genomics for evaluation of hereditary hemorrhagic telangiectasia (HTT) based on positive family history and a variant of uncertain significance (VUS) in ACVRL1 (c.106T > C; p.Cys36Arg). In addition, he presented with a family history of an unidentified leukodystrophy in mother and maternal uncle, and a potential AD diagnosis based on the characteristic distribution of Rosenthal fibers in uncle’s autopsy and mother’s neurological symptoms. His mother was 67 years old and had history for about four years of progressive worsening gait, spasticity, and slurred speech. MRI revealed leukodystrophy. The patient was asymptomatic with a normal neurological examination (no gait abnormality, abnormal posture, dysarthria, or other symptoms related to AD) but a brain MRI demonstrated findings previously described in adult-onset AD (Fig. 1) . GFAP sequencing (NM_002055.3 transcript) done at a CLIA laboratory revealed no pathogenic variants. Additional genetic evaluation for adult-onset leukoencephalopathies was also negative. Subsequent research whole exome sequencing (WES) detected a pathogenic variant in a deep intronic region of the canonical transcript (c.1171 + 472G > A) as well as in exon 7 of an alternative transcript (NM_001131019.2(GFAP):c.1289G > A; p.(Arg430His)). This variant has been previously reported in two affected individuals with clinical and MRI findings of AD and a variant in HDAC6, a possible modifier gene . Noteworthy, we did not find variants in HDAC6 or other known modifiers in our patient. The GFAP variant is present in 2 of 245,904 alleles in gnomAD . Since the disease is thought to be fully penetrant, there may be two other presently asymptomatic/oligosymptomatic individuals who remain undiagnosed. Therefore, when the diagnosis is clinically suspected, alternative molecular analysis may be warranted to detect changes in all relevant transcripts. Moreover, our patient is the third reported case with the same causative variant in an alternative GFAP exon, making this variant a recurrent cause of adult-onset AD. We believe that the available clinical genetic testing for AD should be revisited and include this alternate exon.
Let et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91. https://doi.org/10.1038/nature19057.
Melchionda L, Fang M, Wang H et al (2013) Adult-onset Alexander disease, associated with a mutation in an alternative GFAP transcript, may be phenotypically modulated by a non-neutral HDAC6 variant. Orphanet J Rare Dis 8:66
Schmidt S, Wattjes MP, Gerding WM, van der Knaap M (2011) Late onset Alexander's disease presenting as cerebellar ataxia associated with a novel mutation in the GFAP gene. J Neurol 258:938–940
Srivastava S, Naidu S. Alexander Disease. In: Adam MP, Ardinger HH, Pagon RA, et al. editors. GeneReviews((R)). Seattle 1993.
The authors are grateful to the patient reported here for giving them permission to share his data.
This work was supported by the Mayo Clinic Center for Individualized Medicine (CIM), the Investigative and Functional Genomics Program, and the William O. Lund, Jr. and Natalie C. Lund Charitable Foundation.
Availability of data and materials
Ethics approval and consent to participate
This study was performed in accordance with the guidelines of Mayo Clinic Institutional Review Board (12–009346) and ethical standards laid down in the 1964 Declaration of Helsinki.
Consent for publication
The patient has consented for publication.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Pinto e Vairo, F., Bertsch, N., Klee, E.W. et al. GFAP canonical transcript may not be suitable for the diagnosis of adult-onset Alexander disease. acta neuropathol commun 6, 112 (2018). https://doi.org/10.1186/s40478-018-0616-z