A clinical laboratory’s experience using GeneMatcher – building
stronger gene-disease relationships.
Julie P. Taylor, Alka Malhotra, Nicole J. Burns, Amanda R. Clause,
Carolyn M. Brown, Brendan T. Burns, Anjana Chandrasekhar, Zina
Schlachetzki, Maren Bennett, Erin Thorpe, Ryan J. Taft, Denise L. Perry,
Alison J. Coffey.
Medical Genomics Research, Illumina Inc., 5200 Illumina Way, San Diego,
CA 92122, USA
Abstract:
The use of whole-genome sequencing (WGS) has accelerated the pace of
gene discovery and highlighted the need for open and collaborative data
sharing in the search for novel disease genes and variants. GeneMatcher
(GM) is designed to facilitate connections between researchers,
clinicians, health-care providers and others to help in the
identification of additional patients with variants in the same
candidate disease genes. The Illumina Clinical Services Laboratory
offers a WGS test for patients with suspected rare and undiagnosed
genetic disease and regularly submits potential candidate genes to GM to
strengthen gene-disease relationships. We describe our experience with
GM, including criteria for evaluation of candidate genes, and our
workflow for the submission and review process. We have made 69
submissions, 36 of which are currently active. Ten per cent of
submissions have resulted in publications, with an additional 14
submissions part of ongoing collaborations and expected to result in a
publication.
Keywords: whole-genome sequencing; data sharing; rare disease;
gene-disease relationship; GeneMatcher; gene discovery
Whole-genome sequencing (WGS) is a comprehensive genetic test that is
emerging as a first-tier diagnostic test for patients with rare and
undiagnosed genetic disease (RUGD) (Bertoli-Avella et al., 2021; Lionel
et al., 2018; NICUSeq Study Group et al., 2021; Scocchia et al., 2019;
Turro et al., 2020). Diagnostic rates are estimated at between 20% and
68% depending on the study population, inclusion criteria, and
comprehensiveness of the test (Dimmock et al., 2021; French et al.,
2019; NICUSeq Study Group et al., 2021; Scocchia et al., 2019), meaning
that even after WGS testing, some cases remain unsolved.
While the use of genome sequencing
has accelerated the pace of gene discovery (Bamshad et al., 2019), for
many rare genetic diseases, the scientific literature is restricted to
only one or maybe a handful of families with affected individuals,
making clinical interpretation and reporting of potentially relevant
variant data difficult due to the limited evidence of the relationship
between the gene and the disease. For clinicians and researchers, it can
be time- and resource-intensive to gather sufficient evidence to publish
individual families as case reports, and therefore these cases may go
unreported. Open and collaborative data sharing is thus essential in the
search for, and confirmation of, novel disease genes and variants.
The Illumina Clinical Services Laboratory is a Clinical Laboratory
Improvement Amendments (CLIA)-certified, College of American
Pathologists (CAP)-approved clinical laboratory offering WGS for
patients with a suspected rare and undiagnosed genetic disease. The WGS
test includes an assessment of single nucleotide variants, indels, copy
number variants, mitochondrial single nucleotide variants, select repeat
expansions, and spinal muscular atrophy status. The majority of cases
have a trio family structure (parents and affected child), with other
family structures supported including duos (parent and child),
higher-order family structures (e.g., quad) and proband-only. Cases
analyzed in the laboratory are primarily from a pediatric population but
also include adults with an indication for testing for RUGD (NICUSeq
Study Group et al., 2021; Scocchia et al., 2019; Vanderver et al.,
2020). During the course of case analysis, all variants meeting specific
variant filtering criteria are reviewed across all genes in the genome
that meet coverage and mapping quality metrics. Genes that lack
sufficient evidence of a relationship to human genetic disease but have
some evidence to suggest a potential association or relevance to the
patient being tested are identified through this analysis. Here, we
describe our clinical laboratory’s process and experience to date in
submitting candidate genes to GeneMatcher (GM) (Sobreira et al., 2015),
a node of the Matchmaker Exchange (MME) (Azzariti & Hamosh, 2020).
The laboratory considers
submitting a gene to GM if no diagnostic variant was identified in the
patient tested or if the variants identified do not fully explain the
patient’s phenotype. Before a candidate gene is submitted to GM,
evidence supporting a potential gene-disease relationship (GDR) is
gathered from the literature or publicly available variant or gene
databases (e.g., ClinVar; Landrum et al., (2018); DECIPHER (Firth et
al., 2009); The Clinical Genome Resource (ClinGen;
https://clinicalgenome.org/curation-activities/gene-disease-validity/);
The Gene Curation Coalition (GenCC; https://thegencc.org/); Mouse Genome
Informatics (MGI; Blake et al., (2021) and evaluated using the ClinGen
gene disease validity curation process (Strande et al., 2017). This
gene-level evidence, and the characteristics of the identified variant
in the context of the patient being tested, are evaluated against a set
of internally developed minimum criteria created to ensure consistency
across laboratory analysts in the identification of strong candidates
likely to result in successful matches (Figure 1). Variants are checked
for call quality, allele frequency in the Genome Aggregation Database
(gnomAD) (Karczewski et al., 2020), potential to be disease-causing in
the patient based on phenotype information, variant consequence and
inheritance, and occurrence in a gene without an established GDR.
Candidate genes with a well-established GDR may be submitted if the
proband’s phenotypic presentation differs from that reported in the
literature to explore a potential expansion of phenotype or a new GDR.
Genes may also be submitted if the inheritance pattern in the proband
differs from that described in the literature.
Our clinical laboratory’s internal workflow, from identification of
candidate genes through submission, follow-up, and review of ongoing
submissions is illustrated in Figure 2. Ordering physicians are notified
of any possible collaborations to prevent duplicate submissions that
could result in self-matches and to ensure any necessary additional
patient consent is obtained. In this workflow, laboratory personnel
facilitate collaborations and initiate the connection between
researchers and clinicians with ongoing support as required. Submissions
are reviewed on a quarterly basis to determine if any actions are
required. In this review, a literature search for the gene is performed
to identify any new clinical or experimental evidence supporting the
GDR. Evidence in publicly available databases is also reviewed.
Following review, next steps may include prioritization of matches for
more proactive follow up, recuration of the GDR (if new literature has
been identified), and/or suspension of a submission. Submissions may be
suspended for a variety of reasons (see below) and are excluded from
matching with other submissions but may be reactivated at any time.
Table 1 provides a summary of our submissions to GM from 2016 to date.
In total we have made 69 submissions over the six year time period. From
September 2020 through September 2021, since implementation of the
minimum criteria, 508 RUGD cases were sequenced through our laboratory.
Of these, variants were reported in 325 cases (64%), with 183 cases
(36%) having no variants identified that are of likely relevance to the
clinical indications for the test. During this time period, 13
submissions were made to GM.
At the time of this publication, we have 36 active submissions in GM,
corresponding to 36 unique genes from 36 unrelated families. The
majority of submissions involve genes in which missense variants, with
nearly half of these variants occurring in a de novo state.
Twenty-five submissions predate our minimum criteria but were reviewed
upon implementation of the criteria to ensure they were still considered
strong submissions. Fourteen of the 36 submissions are part of active
ongoing collaborations at different stages of clinical and functional
evidence gathering; all of these are expected to result in a
publication. The earliest submission that is part of an ongoing
collaboration is from August 2018, and the most recent from July 2021.
At least nine of the genes involved in collaborations have 10 or more
matches in either GM or MME, with a range from two to 69.
Twenty-two of our submissions are not currently part of an active
collaboration. However, 19 of the 22 have matches, ranging in number
from four to 33 (with an average of 14), all with potential for
follow-up. For 10 of the 22 submissions, the patient’s phenotype matched
that of cases in the literature, and submissions were made to GM with
the aim of identifying additional individuals with a similar phenotype
or to explore a possible expansion of phenotype. In one example, ade novo heterozygous missense variant was identified in a patient
whose phenotype did not overlap the typical presentation for single
nucleotide variants reported in the literature. However, the patient’s
phenotype did overlap the phenotype seen in a mouse model which defined
a critical region for a deletion syndrome, and one other affected
individual in the literature. In another example, missense variants were
reported in the literature in either a homozygous or compound
heterozygous state in individuals whose phenotype overlapped our
patient’s phenotype, in whom we had also identified a compound
heterozygous pair of variants. However, no evidence of gene impact was
provided for any of the reported variants resulting in a limited
classification for the GDR. Experimental support was available at the
gene level, but additional clinical data were needed to strengthen the
GDR and potentially upgrade the variant classification from a variant of
uncertain significance (VUS).
For 12 of the 22 submissions, there was no phenotypic overlap between
the patient and previously published cases, but the gene met our
criteria for submission based on the characteristics of the case, the
GDR, and the variant identified in the patient. In one instance, no
clinical data had been reported in the literature but both expression
data and two strong mouse models were consistent with the patient’s
phenotype. The GDR was classified as “no known disease relationship –
animal model only”, and the gene submitted to GM with the goal of
identifying probands with a similar phenotype. In another instance, a
homozygous missense variant classified as VUS, was identified in a
patient who presented with a severe, atypical phenotype which was not
yet well described in the literature. There was sufficient support for
the GDR to be classified as definitive. In this instance, the submission
was made to explore whether additional cases with a similar phenotype
exist and could indicate the expansion of the phenotypic spectrum of
this disease.
For six of the 22 GM submissions, variants were reported to the ordering
clinician as variants of uncertain significance in genes of uncertain
significance based on the limited available evidence for the GDR. For
the remaining 15 submissions, variants were not considered to meet our
current reporting criteria.
We have suspended 33 submissions: seven were suspended due to the
matches resulting in a publication; twelve were suspended as a result of
publication of new evidence potentially impacting the classification of
the GDR; two were suspended based on updated frequency data from gnomAD
suggesting the variant in the candidate gene was unlikely to be
disease-causing; and twelve were suspended due to being legacy
submissions and no longer considered strong candidates.
To date, seven submissions involving cases analyzed by the Illumina
Clinical Services Laboratory led to collaborations that resulted in
publications (see Table 2). In three instances, (USP7, SPEN, andAMMECR1 ), the evidence published through the GM collaboration
established a new disease gene and resulted in recuration of, and
subsequent upgrade in the classification of the GDR. This in turn led to
recuration of the associated variants and a change in variant
classification from a variant of uncertain significance (previously
reported as a research candidate) to a classification of likely
pathogenic, thereby allowing reporting as a potential diagnostic finding
in an amended report.
In the instance of USP7 , Hao et al.,(2015) previously reported
six cases with heterozygous chromosomal microdeletions, and one case
with a heterozygous nonsense variant in individuals with a
neurodevelopmental phenotype, suggesting haploinsufficiency ofUSP7 as a disease mechanism. The microdeletions could not be
scored using the ClinGen framework (Strande et al., 2017), hence the GDR
was classified as limited. As a result of the collaboration established
through GM, Fountain et al., (2019) reported 15 newly identified
unrelated cases with a similar phenotype carrying heterozygous de
novo USP7 variants, including partial and full gene deletions,
missense, frameshift, nonsense and canonical splice site variants. These
data allowed an upgrade in classification of the GDR from limited to
definitive, as well as an upgrade in classification of the variant
identified in our patient.
The SPEN gene was identified as a strong candidate for GM because
if its location within the critical region for the well-described 1p36
deletion syndrome and phenotypic overlap of the patient with the
deletion syndrome. At the point of submission to GM, no cases had been
identified in the literature with causal variants in SPEN , hence
the GDR was classified as no known disease relationship. Based on the
collaboration established through GM, Radio et al., (2021) reported 32
unrelated individuals, all with truncating loss of function variants,
most of which were de novo . The GDR was reclassified as strong,
pending replication of the association over time.
The AMMECR1 gene is located within the Alport syndrome, mental
retardation, midface hypoplasia, and elliptocytosis complex interval,
which is associated with an Xq22.3 contiguous gene deletion syndrome
encompassing about 20 genes. Prior to the GM publication, only two
single nucleotide variants had been reported in the AMMECR1 gene,
(one nonsense and one missense). A submission was made to GM based on
phenotypic overlap between our patient and the deletion syndrome, and
variant type. Subsequently through a GM collaboration, Moysés-Oliveira
et al., (2018) described five individuals with predicted loss of
function variants in the AMMECR1 gene presenting with short
stature, cardiac and skeletal abnormalities, and hearing loss, with a
similar presentation to the patient. These data supported the
involvement of AMMECR1 in a new syndrome with an expanded
phenotype.
In the case of GRIA3 (located on the X chromosome), the
publication arising from the GM collaboration resulted in additional
evidence allowing an upgrade in variant classification and resulting in
issuing of an amended report. A notable aspect of this case is its
contribution to the understanding of potential phenotypic manifestation
and mechanism of disease in females, where previously variants had only
been reported in association with a neurodevelopmental phenotype in
males. Functional studies in cell culture models provided evidence that
a gain of function and increased synaptic transmission may cause the
epileptic encephalopathy and developmental delay seen in the affected
female patient (Sun et al., 2021).
For three GDRs, AGMO with AGMO -related neurodevelopmental
disorder (Okur et al., 2019), LMBRD2 with LMBRD2 -related
neurodevelopmental disorder (Malhotra et al., 2021), and CAMK4with CAMK4 -related neurodevelopmental disorder with dystonia and
chorea (Zech et al., 2021), the additional evidence in the GM
publication was insufficient to result in an upgrade to the
classification of the GDR or variant at this time. For CAMK4 andAGMO, the publications contained only one or two case reports,
respectively. For LMBRD2, while ten de novo missense
variants including at least three recurrent variants were reported,
functional studies were not performed so these were without experimental
support of gene impact and so did not score highly in the ClinGen
framework for gene curation (Strande et al., 2017).
Overall, submission to GM has been invaluable in our clinical laboratory
for the discovery of new GDRs and in the confirmation of diagnostic
variants in patients tested through WGS. In total we have made over 69
submissions from 2016 to 2021, 10% of which have resulted in
publications of new disease genes, with a further 20% in ongoing
collaborations.
As a clinical laboratory, a number of challenges apply to all aspects of
data sharing, including through GM. These include the time required to
prepare the data for sharing, updating data shared in external sources,
and time for follow-up of queries and collaborations. To help address
these challenges, we have developed an internal workflow and tracking
system which restricts submissions to strong candidates and allows for
easy review of submissions to maximize efforts. Our review process has
proved valuable to keep submissions, and hence the content of GM,
relevant by removing submissions that have been published or are in a
firmly established collaboration, and to serve as a flag for reanalysis
of GDRs when new data are available.
The time taken from GM submission to publication can be lengthy and
varied considerably, from eight months to almost four years, with an
average of just under 26 months. Factors that contribute to variability
in GM submission to publication time include: the maturity of an ongoing
collaboration (data gathering vs. manuscript already in preparation),
difficulty in finding collaborations with the ability to perform
functional studies, resource limitations, and challenges in case
follow-up including the impracticality of obtaining additional consent
from families who may not have already consented for research, who may
be located in remote areas, or who may be lost to follow-up. Resources
for functional studies can also be problematic, hence the importance of
centralized functional data sets including those for model organisms. To
facilitate data sharing in a more timely fashion, researchers and
publishers could consider moving towards publication of aggregated case
data without the requirement of experimental support to allow more rapid
publication of a new GDR. Alternatively, ways of sharing data publically
within GM could be explored to allow clinical laboratories visualization
of new potential GDRs to aid in clinical reporting and maximizing return
to the patients.
Taking all challenges into account, the value of data sharing via GM
cannot be overstated, as demonstrated by the number of citations of GM
(over 504) and novel gene-disease discoveries facilitated by GM to date
(over 209) (Azzariti & Hamosh, 2020). Acceleration of gene discovery
only serves to help deliver the full promise of WGS, particularly for
individuals with rare disease, whose chance of receiving a potentially
informative finding should not be constrained by the absence of large
numbers of previously described cases.
Acknowledgements: We would like to acknowledge the ICSL Interpretation
and Reporting Team and the Illumina Clinical Services Laboratory team
for sequencing and bioinformatics support.
Conflicts of Interest Disclosure: All authors are employees and
shareholders of Illumina Inc.
Data Availability Statement: Some of the data supporting this study are
published and therefore publicly available. Other data that support the
findings of this study are available from the corresponding author upon
reasonable request.
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Table 1. Summary of submissions to GeneMatcher (submitted as a separate
file)
Table 2. Summary of publications arising from GeneMatcher collaborations
to date (submitted as a separate file).
Figure legends
Figure 1: Minimum criteria for candidate genes for submission to
GeneMatcher.
Figure 2: Workflow for submission of candidate genes to GeneMatcher.