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Review
. 2023 Nov 22;12(12):1459.
doi: 10.3390/biology12121459.

The Diagnostic Landscape of Adult Neurogenetic Disorders

Maggie W Waung  1 , Fion Ma  2 , Allison G Wheeler  2   3 , Clement C Zai  4   5 , Joyce So  6
Affiliations
Review

The Diagnostic Landscape of Adult Neurogenetic Disorders

Maggie W Waung et al. Biology (Basel). .

Abstract

Neurogenetic diseases affect individuals across the lifespan, but accurate diagnosis remains elusive for many patients. Adults with neurogenetic disorders often undergo a long diagnostic odyssey, with multiple specialist evaluations and countless investigations without a satisfactory diagnostic outcome. Reasons for these diagnostic challenges include: (1) clinical features of neurogenetic syndromes are diverse and under-recognized, particularly those of adult-onset, (2) neurogenetic syndromes may manifest with symptoms that span multiple neurological and medical subspecialties, and (3) a positive family history may not be present or readily apparent. Furthermore, there is a large gap in the understanding of how to apply genetic diagnostic tools in adult patients, as most of the published literature focuses on the pediatric population. Despite these challenges, accurate genetic diagnosis is imperative to provide affected individuals and their families guidance on prognosis, recurrence risk, and, for an increasing number of disorders, offer targeted treatment. Here, we provide a framework for recognizing adult neurogenetic syndromes, describe the current diagnostic approach, and highlight studies using next-generation sequencing in different neurological disease cohorts. We also discuss diagnostic pitfalls, barriers to achieving a definitive diagnosis, and emerging technology that may increase the diagnostic yield of testing.

Keywords: adult-onset; complex neurological disease; genetic analysis; neurogenetic disease; next generation sequencing; personalized medicine; whole exome sequencing; whole genome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Example of the current state of genetic testing for each phenotype in an adult with complex neurological phenotypes (case based on [12]). The typical diagnostic odyssey entails multiple genetic tests before a neurogenetic disorder can be identified and molecularly confirmed. Access to whole-exome sequencing can often be restricted by insurance/payor coverage policies, limiting testing to gene panels (dotted line) instead of or prior to WES, as illustrated for ASD. Priority should always be to identify treatable genetic disorders, as illustrated by pursuing biochemical and gene panel testing for neurometabolic disorders before other testing for treatment-resistant SSD. Note that WES, in addition to covering only coding regions in the genome, is unable to capture variant types such as repeat expansions and large copy number variants, whereas WGS is able to capture all variant types and be analyzed for all phenotypes. WGS could present a “one-stop shop” test for adult neurogenetic disorders as cost and feasibility improve. Abbreviations: ASD, autism spectrum disorder; EE, epileptic encephalopathy; NDD, neurodevelopmental disorder; SCA, spinocerebellar ataxia; SSD, schizophrenia spectrum disorder; WES, whole-exome sequencing; WGS, whole-genome sequencing.
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