Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.

PURPOSE: The terminology used for gene-disease curation and variant annotation to describe inheritance, allelic requirement, and both sequence and functional consequences of a variant is currently not standardized. There is considerable discrepancy in the literature and across clinical variant reporting in the derivation and application of terms. Here, we standardize the terminology for the characterization of disease-gene relationships to facilitate harmonized global curation and to support variant classification within the ACMG/AMP framework. METHODS: Terminology for inheritance, allelic requirement, and both structural and functional consequences of a variant used by Gene Curation Coalition members and partner organizations was collated and reviewed. Harmonized terminology with definitions and use examples was created, reviewed, and validated. RESULTS: We present a standardized terminology to describe gene-disease relationships, and to support variant annotation. We demonstrate application of the terminology for classification of variation in the ACMG SF 2.0 genes recommended for reporting of secondary findings. Consensus terms were agreed and formalized in both Sequence Ontology (SO) and Human Phenotype Ontology (HPO) ontologies. Gene Curation Coalition member groups intend to use or map to these terms in their respective resources. CONCLUSION: The terminology standardization presented here will improve harmonization, facilitate the pooling of curation datasets across international curation efforts and, in turn, improve consistency in variant classification and genetic test interpretation.

Genomic Data Sharing for Novel Mendelian Disease Gene Discovery: The Matchmaker Exchange.

In the last decade, exome and/or genome sequencing has become a common test in the diagnosis of individuals with features of a rare Mendelian disorder. Despite its success, this test leaves the majority of tested individuals undiagnosed. This review describes the Matchmaker Exchange (MME), a federated network established to facilitate the solving of undiagnosed rare-disease cases through data sharing. MME supports genomic matchmaking, the act of connecting two or more parties looking for cases with similar phenotypes and variants in the same candidate genes. An application programming interface currently connects six matchmaker nodes-the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER), GeneMatcher, PhenomeCentral, seqr, MyGene2, and the Initiative on Rare and Undiagnosed Diseases (IRUD) Exchange-resulting in a collective data set spanning more than 150,000 cases from more than 11,000 contributors in 88 countries. Here, we describe the successes and challenges of MME, its individual matchmaking nodes, plans for growing the network, and considerations for future directions.

Seven years since the launch of the Matchmaker Exchange: The evolution of genomic matchmaking.

The Matchmaker Exchange (MME) was launched in 2015 to provide a robust mechanism to discover novel disease-gene relationships. It operates as a federated network connecting databases holding relevant data using a common application programming interface, where two or more users are looking for a match for the same gene (two-sided matchmaking). Seven years from its launch, it is clear that the MME is making outstanding contributions to understanding the morbid anatomy of the genome. The number of unique genes present across the MME has steadily increased over time; there are currently >13,520 unique genes (~68% of all protein-coding genes) connected across the MME's eight genomic matchmaking nodes, GeneMatcher, DECIPHER, PhenomeCentral, MyGene2, seqr, Initiative on Rare and Undiagnosed Disease, PatientMatcher, and the RD-Connect Genome-Phenome Analysis Platform. The collective data set accessible across the MME currently includes more than 120,000 cases from over 12,000 contributors in 98 countries. The discovery of potential new disease-gene relationships is happening daily and international collaborative teams are moving these advances forward to publication, now numbering well over 500. Expansion of data sharing into routine clinical practice by clinicians, genetic counselors, and clinical laboratories has ensured access to discovery for even more individuals with undiagnosed rare genetic diseases. Tens of thousands of patients and their family members have been directly or indirectly impacted by the discoveries facilitated by two-sided genomic matchmaking. MME supports further connections to the literature (PubCaseFinder) and to human and model organism resources (Monarch Initiative) and scientists (ModelMatcher). Efforts are now underway to explore additional approaches to matchmaking at the gene or variant level where there is only one querier (one-sided matchmaking). Genomic matchmaking has proven its utility over the past 7 years and will continue to facilitate discoveries in the years to come.

The impact of GeneMatcher on international data sharing and collaboration.

GeneMatcher (genematcher.org) is a tool designed to connect individuals with an interest in the same gene. Now used around the world to create collaborations and generate the evidence needed to support novel disease gene identification, GeneMatcher is a founding member of the Matchmaker Exchange (MME; matchmakerexchange.org) and strongest possible advocate for global data sharing including those in resource-limited environments. As of October 1, 2021, there are 12,531 submitters from 94 countries who have submitted 58,134 submissions with 13,498 unique genes in the database. Among these genes, 8970 (64%) have matched at least once and the total number of matches is 378,806, growing by about 10,000 per month. GeneMatcher submitters increase by 80-120 each month and submissions grow by >800 per month, while unique genes and gene matches continue to grow steadily at rate of about 80 per month. The number of genes without a match peaked at 4371 in February of 2019 and despite the increase in the number of new submissions, the number of unique genes without a match continues to slowly decline, currently standing at 4,016. All submissions in GeneMatcher are available for matching across the MME.

Variant-level matching for diagnosis and discovery: Challenges and opportunities.

Here we describe MyGene2, Geno2MP, VariantMatcher, and Franklin; databases that provide variant-level information and phenotypic features to researchers, clinicians, healthcare providers and patients. Following the footsteps of the Matchmaker Exchange project that connects exome, genome, and phenotype databases at the gene level, these databases have as one goal to facilitate connection to one another using Data Connect, a standard for discovery and search of biomedical data from the Global Alliance for Genomics and Health (GA4GH).

Pathogenic Variants in NUP214 Cause "Plugged" Nuclear Pore Channels and Acute Febrile Encephalopathy.

We report biallelic missense and frameshift pathogenic variants in the gene encoding human nucleoporin NUP214 causing acute febrile encephalopathy. Clinical symptoms include neurodevelopmental regression, seizures, myoclonic jerks, progressive microcephaly, and cerebellar atrophy. NUP214 and NUP88 protein levels were reduced in primary skin fibroblasts derived from affected individuals, while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays exhibited defects in the classical protein import and mRNA export pathways in affected cells. Direct surface imaging of fibroblast nuclei by scanning electron microscopy revealed a large increase in the presence of central particles (known as "plugs") in the nuclear pore channels of affected cells. This observation suggests that large transport cargoes may be delayed in passage through the nuclear pore channel, affecting its selective barrier function. Exposure of fibroblasts from affected individuals to heat shock resulted in a marked delay in their stress response, followed by a surge in apoptotic cell death. This suggests a mechanistic link between decreased cell survival in cell culture and severe fever-induced brain damage in affected individuals. Our study provides evidence by direct imaging at the single nuclear pore level of functional changes linked to a human disease.

Centers for Mendelian Genomics: A decade of facilitating gene discovery.

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources.

PURPOSE: Several groups and resources provide information that pertains to the validity of gene-disease relationships used in genomic medicine and research; however, universal standards and terminologies to define the evidence base for the role of a gene in disease and a single harmonized resource were lacking. To tackle this issue, the Gene Curation Coalition (GenCC) was formed. METHODS: The GenCC drafted harmonized definitions for differing levels of gene-disease validity on the basis of existing resources, and performed a modified Delphi survey with 3 rounds to narrow the list of terms. The GenCC also developed a unified database to display curated gene-disease validity assertions from its members. RESULTS: On the basis of 241 survey responses from the genetics community, a consensus term set was chosen for grading gene-disease validity and database submissions. As of December 2021, the database contained 15,241 gene-disease assertions on 4569 unique genes from 12 submitters. When comparing submissions to the database from distinct sources, conflicts in assertions of gene-disease validity ranged from 5.3% to 13.4%. CONCLUSION: Terminology standardization, sharing of gene-disease validity classifications, and resolution of curation conflicts will facilitate collaborations across international curation efforts and in turn, improve consistency in genetic testing and variant interpretation.

The Monarch Initiative in 2019: an integrative data and analytic platform connecting phenotypes to genotypes across species.

In biology and biomedicine, relating phenotypic outcomes with genetic variation and environmental factors remains a challenge: patient phenotypes may not match known diseases, candidate variants may be in genes that haven't been characterized, research organisms may not recapitulate human or veterinary diseases, environmental factors affecting disease outcomes are unknown or undocumented, and many resources must be queried to find potentially significant phenotypic associations. The Monarch Initiative (https://monarchinitiative.org) integrates information on genes, variants, genotypes, phenotypes and diseases in a variety of species, and allows powerful ontology-based search. We develop many widely adopted ontologies that together enable sophisticated computational analysis, mechanistic discovery and diagnostics of Mendelian diseases. Our algorithms and tools are widely used to identify animal models of human disease through phenotypic similarity, for differential diagnostics and to facilitate translational research. Launched in 2015, Monarch has grown with regards to data (new organisms, more sources, better modeling); new API and standards; ontologies (new Mondo unified disease ontology, improvements to ontologies such as HPO and uPheno); user interface (a redesigned website); and community development. Monarch data, algorithms and tools are being used and extended by resources such as GA4GH and NCATS Translator, among others, to aid mechanistic discovery and diagnostics.

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Next-generation sequencing and the evolution of data sharing.

Disease gene identification often relies on identifying multiple affected individuals with similar phenotypes and candidate variants in the same gene. Phenotypic and genomic data sharing tools have facilitated connections that led to novel disease gene discoveries and better characterization and recognition of rare diseases. Additionally, data sharing has evolved. From gene-based matches to variant-level information with increasing use of phenotypic information. We expect that these initiatives will continue to expand in the future affording clinicians, researchers, and most importantly, patients and their families faster and more comprehensive answers.

Three decades of the Human Genome Organization.

The Human Genome Organization (HUGO) was initially established in 1988 to help integrate international scientific genomic activity and to accelerate the diffusion of knowledge from the efforts of the human genome project. Its founding President was Victor McKusick. During the late 1980s and 1990s, HUGO organized lively gene mapping meetings to accurately place genes on the genome as chromosomes were being sequenced. With the completion of the Human Genome Project, HUGO went through some transitions and self-reflection. In 2020, HUGO (which hosts a large annual scientific meeting and comprises the renowned HUGO Gene Nomenclature Committee [HGNC], responsible for naming genes, and an outstanding Ethics Committee) was merged with the Human Genome Variation Society (HGVS; which defines the correct nomenclature for variation description) and the Human Variome Project (HVP; championed by the late Richard Cotton) into a single organization that is committed to assembling human genomic variation from all over the world. This consolidated effort, under a new Executive Board and seven focused committees, will facilitate efficient and effective communication and action to bring the benefits of increasing knowledge of genome diversity and biology to people all over the world.

Viewing Victor McKusick's legacy through the lens of his bibliography.

Victor McKusick's contributions to the field of medical genetics are legendary and include his contributions as a mentor, as creator of Mendelian Inheritance in Man (now Online Mendelian Inheritance in Man [OMIM®]), and as a leader in the field of medical genetics. McKusick's full bibliography includes 772 publications. Here we review the 453 papers authored by McKusick and indexed in PubMed, from his earliest paper published in the New England Journal of Medicine in 1949 to his last paper published in American Journal of Medical Genetics Part A in 2008. This review of his bibliography chronicles McKusick's evolution from an internist and cardiologist with an interest in genetics to an esteemed leader in the growing field of medical genetics. Review of his bibliography also provides a historical perspective of the development of the discipline of medical genetics. This field came into its own during his lifetime, transitioning from the study of interesting cases and families used to codify basic medical genetics principles to an accredited medical specialty that is expected to transform healthcare. Along the way, he helped to unite the fields of medical and human genetics to focus on mapping the human genome, culminating in completion of the Human Genome Project. This review confirms the critical role played by Victor McKusick as the founding father of medical genetics.

Online Mendelian Inheritance in Man (OMIM®): Victor McKusick's magnum opus.

Victor McKusick's many contributions to medicine are legendary, but his magnum opus is Mendelian Inheritance in Man (MIM), his catalog of Mendelian phenotypes and their associated genes. The catalog, originally published in 1966 in book form, became available on the internet as Online Mendelian Inheritance in Man (OMIM®) in 1987. The first of 12 editions of MIM included 1486 entries; this number has increased to over 25,000 entries in OMIM as of April 2021, which demonstrates the growth of knowledge about Mendelian phenotypes and their genes through the years. OMIM now has over 20,000 unique users a day, including users from every country in the world. Many of the early decisions made by McKusick, such as to maintain MIM data in a computer-readable format, to separate phenotype entries from those for genes, and to give phenotypes and genes MIM numbers, have proved essential to the long-term utility and flexibility of his catalog. Based on his extensive knowledge of genetics and vision of its future in the field of medicine, he developed a framework for the capture and summary of information from the published literature on phenotypes and their associated genes; this catalog continues to serve as an indispensable resource to the genetics community.

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

OMIM.org: leveraging knowledge across phenotype-gene relationships.

For over 50 years Mendelian Inheritance in Man has chronicled the collective knowledge of the field of medical genetics. It initially cataloged the known X-linked, autosomal recessive and autosomal dominant inherited disorders, but grew to be the primary repository of curated information on both genes and genetic phenotypes and the relationships between them. Each phenotype and gene is given a separate entry assigned a stable, unique identifier. The entries contain structured summaries of new and important information based on expert review of the biomedical literature. OMIM.org provides interactive access to the knowledge repository, including genomic coordinate searches of the gene map, views of genetic heterogeneity of phenotypes in Phenotypic Series, and side-by-side comparisons of clinical synopses. OMIM.org also supports computational queries via a robust API. All entries have extensive targeted links to other genomic resources and additional references. Updates to OMIM can be found on the update list or followed through the MIMmatch service. Updated user guides and tutorials are available on the website. As of September 2018, OMIM had over 24,600 entries, and the OMIM Morbid Map Scorecard had 6,259 molecularized phenotypes connected to 3,961 genes.

Orthopaedic Problems in 35 Patients With Organic Acid Disorders.

INTRODUCTION: Organic acid disorders (OADs) are a subset of inborn errors of metabolism that result in a toxic accumulation of organic acids in the body, which can lead to metabolic derangements and encephalopathy. Patients with these disorders are managed by a team of biochemical geneticists and metabolic nutritionists. However, subspecialists such as neurologists and orthopaedic surgeons are often needed to help manage the sequelae of the metabolic derangements. The breadth of orthopaedic sequelae of these disease states is poorly understood. Herein, we describe orthopaedic problems associated with 5 types of OAD most commonly seen at our institution: maple syrup urine disease, methylmalonic aciduria, propionic aciduria, pyruvate dehydrogenase deficiency, and glutaric aciduria type 1. METHODS: We retrospectively reviewed medical records of 35 patients with an OAD who were seen at our academic tertiary care center from May 1999 to May 2020. Patients were grouped into cohorts according to OAD type and analyzed for orthopaedic presentations of hip, knee, or foot disorders, presence and severity of scoliosis, history of fracture, movement disorders, and osteopenia/osteoporosis. RESULTS: Of the 35 patients, 13 had maple syrup urine disease, 12 had methylmalonic aciduria, 4 had propionic aciduria, 4 had pyruvate dehydrogenase deficiency, and 2 had glutaric aciduria type 1. Associated orthopaedic problems included spasticity causing neuromuscular scoliosis and/or hip subluxation or dislocation (10 patients), fractures (7 patients), and osteopenia/osteoporosis (7 patients). Overall, 22 of 35 patients had some orthopaedic condition. CONCLUSIONS: Most in this cohort of patients with OAD also had an orthopaedic abnormality. It is important for physicians treating these patients to understand their propensity for musculoskeletal problems. When treating patients with OAD, it is important to initiate and maintain communication with specialists in several disciplines and to develop collaborative treatments for this unique population. LEVEL OF EVIDENCE: Level IV-prognostic study.

International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases.

Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

The utility of exome sequencing for fetal pleural effusions.

OBJECTIVE: We sought to evaluate the performance of exome sequencing (ES) in determining an underlying genetic etiology for cases of fetal pleural effusions. STUDY DESIGN: We examined a prospective cohort series of fetal pleural effusions visualized sonographically between 1 April 2016 and 31 August 2017. Fetal pleural effusions attributed to twin sharing, anemia, or structural anomalies were excluded, as were all cases with a genetic diagnosis established by karyotype or chromosomal microarray analysis. The remaining cases with pleural effusions of unclear etiology were offered ES. ES was performed by clinical sequencing and/or sequencing under the Baylor-Hopkins Center for Mendelian Genomics' (BHCMG) research platform. All cases were evaluated for novel genes or phenotypic expansion of disease-causing genes. RESULTS: ES was performed on six probands affected by pleural effusions. A pathogenic variant was identified in one case (16.7%). Four additional cases had variants of uncertain significance (VUS) in candidate genes of pathological interest. Neither clinical nor candidate genes were evident in the final case. CONCLUSION: ES should be considered in the evaluation of prenatally detected idiopathic pleural effusions when other diagnostic workup for a genetic etiology has failed.