Haskell GT, Adams MC, Fan Z, Amin K, Guzman Badillo RJ, Zhou
L, Bizon C, Chahin N, Greenwood RS, Milko LV, Shiloh-Malawsky Y, Crooks
KR, Strande N, Tennison M, Tilley CR, Brandt A, Wilhelmsen KC, Weck K,
Evans JP, Berg JS. Diagnostic utility of exome sequencing in the evaluation of
neuromuscular disorders. Neurol Genet. 2018 Feb 1;4(1):e212.
Abstract
OBJECTIVE:
To evaluate the diagnostic yield and workflow of
genome-scale sequencing in patients with neuromuscular disorders (NMDs).
METHODS:
We performed exome sequencing in 93 undiagnosed patients
with various NMDs for whom a molecular diagnosis was not yet established.
Variants on both targeted and broad diagnostic gene lists were identified.
Prior diagnostic tests were extracted from the patient's medical record to
evaluate the use of exome sequencing in the context of their prior diagnostic
workup.
RESULTS:
The overall diagnostic yield of exome sequencing in our
cohort was 12.9%, with one or more pathogenic or likely pathogenic variants
identified in a causative gene associated with the patient's disorder. Targeted
gene lists had the same diagnostic yield as a broad NMD gene list in patients
with clear neuropathy or myopathy phenotypes, but evaluation of a broader set
of disease genes was needed for patients with complex NMD phenotypes. Most
patients with NMD had undergone prior testing, but only 10/16 (63%) of these
procedures, such as muscle biopsy, were informative in pointing to a final
molecular diagnosis.
CONCLUSIONS:
Genome-scale sequencing or analysis of a panel of relevant
genes used early in the evaluation of patients with NMDs can provide or clarify
a diagnosis and minimize invasive testing in many cases.
Retrospective analysis of the NMD patient cohort revealed
that most individuals had undergone an extensive prior workup, often over a
period of many years. Almost half (43%) of patients had undergone a muscle
biopsy before enrollment in this study, and almost 10% had undergone a nerve
biopsy. A majority (86%) had prior electrodiagnostic testing. Furthermore, most
patients (67.7%) had previously had negative single gene testing, with an
average of roughly 2 genes tested per patient, and 20.4% of patients had prior
multigene panel testing, all with negative results (since not having received a
molecular diagnosis was necessary for participation in the study). All prior
diagnostic workup is summarized in figure 1, illustrating the challenging
nature of obtaining an accurate diagnosis in such patients…
In at least 2 cases, WES identified molecular diagnoses that
directly impacted medical treatment. In case H this patient was thought to have
a chronic inflammatory demyelinating polyneuropathy; WES identified 2
frameshifting indels in SACS, consistent with Spastic Ataxia of
Charlevoix-Saguenay, and consequently, this individual was not started on
immunotherapy. In 1 patient previously thought to have hereditary spastic
paraplegia, WES identified a nonsense variant in GCH1, indicating dopa-responsive
dystonia (MIM 128230). This patient demonstrates the dramatic utility that can
stem from making a correct diagnosis, as she was started on dopa therapy and
regained the ability to walk without assistance…
Only 62.5% of prior muscle biopsy or electrodiagnostic
testing suggested the type of NMD in patients later found to have a pathogenic
mutation in an NMD gene. Often, the prior testing could identify no specific
myopathy/neuropathy or did not identify the same type of myopathy/neuropathy
indicated by the genetic testing result. Uninformative muscle biopsies were
often apparently normal, or consisting mainly of fat tissue, which while
possibly consistent with mild myopathies, or later stage myopathy or muscular
dystrophy, are not informative toward a specific diagnosis. Nerve conduction
studies that were informative often delineated the affected region (proximal vs
distal) and those that were uninformative often were due to being normal or
limited due to the patient being uncomfortable with the procedure. One
limitation of our analysis is that patients in this study were often enrolled
on the basis of being undiagnosed, despite extensive prior testing, potentially
biasing the present analysis in a way that makes invasive or prior testing
appear to be less informative than in an unselected cohort. Nevertheless, we
propose the use of sequencing early in the diagnostic workup of patients with
NMD, particularly in complex cases in which additional testing may be likely to
be uninformative in pointing to a specific diagnosis.
The decreasing cost of massively parallel sequencing,
coupled with clear diagnostic utility, raises the question of the precise role
that genomic analysis should have in a diagnostic workup for NMDs. A thorough
physical examination, clinical history, and common laboratory test results
should always be obtained first to identify more common, nonheritable causes of
NMD. WES cannot reliably detect some major causes of several more common NMDs,
including large deletions, duplications, and repeat expansions such as those
causative of Duchenne muscular dystrophy, type 2 myotonic dystrophy
facioscapulohumeral muscular dystrophy, or CMT1A. If a heritable condition
amenable to sequencing is considered most likely, it is reasonable to consider
a “sequence-early” approach, consisting of a dedicated gene panel or exome
sequencing with targeted analysis.
Given the potential costs, invasiveness and incomplete yield
from muscle biopsy, as well as the cost of testing for a broad array of
hereditary conditions using traditional Sanger single gene testing, we suggest
that genome-scale sequencing or multigene panel testing be considered early in
the diagnostic process in patients likely to have a monogenic neuromuscular
disorder, particularly in complex or challenging cases. Early genome-scale
sequencing may shorten the diagnostic odyssey, minimize invasive testing, and
provide potential opportunities for clinical and investigational therapeutics
for patients with NMD.
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