Spondyloepimetaphyseal dysplasia with joint laxity type 2: Aggregating the literature and reporting on the life of a 66-year-old man.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22. Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the progression of SEMDJL2 throughout the life of the oldest individual reported in the literature-a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.

Diagnostic yield of clinical exome sequencing in adulthood in medical genetics clinics.

Clinical exome sequencing (ES) is the most comprehensive genomic test to identify underlying genetic diseases in Canada. We performed this retrospective cohort study to investigate the diagnostic yield of clinical ES in adulthood. Inclusion criteria were: (1) Adult patients ≥18 years old; (2) Patients underwent clinical ES between January 1 and December 31, 2021; (3) Patients were seen in the Department of Medical Genetics. We reviewed patient charts. We applied American College of Medical Genetics and Genomics and the Association for Molecular Pathology variant classification guidelines for interpretation of variants. Non-parametric Fisher's exact statistical test was used. Seventy-seven patients underwent clinical ES. Fourteen different genetic diseases were confirmed in 15 patients: FBXO11, MYH7, MED13L, NSD2, ANKRD11 (n = 2), SHANK3, RHOBTB2, CDKL5, TRIO, TCF4, SCN1, SMAD3, POGZ, and EIF2B3 diseases. The diagnostic yield of clinical ES was 19.5%. Patients with a genetic diagnosis had a significantly higher frequency of neurodevelopmental disorders than those with no genetic diagnosis (p = 0.00339). The diagnostic yield of clinical ES was the highest in patients with seizures (35.7%), and with progressive neurodegenerative diseases (33.3%). Clinical ES is a helpful genomic test to provide genetic diagnoses to the patients who are referred to medical genetic clinics due to suspected genetic diseases in adulthood to end their diagnostic odyssey. Targeted next generation sequencing panels for specific phenotypes may decrease the cost of genomic test in adulthood.

VLF: An R package for the analysis of very low frequency variants in DNA sequences.

Here, we introduce VLF, an R package to determine the distribution of very low frequency variants (VLFs) in nucleotide and amino acid sequences for the analysis of errors in DNA sequence records. The package allows users to assess VLFs in aligned and trimmed protein-coding sequences by automatically calculating the frequency of nucleotides or amino acids in each sequence position and outputting those that occur under a user-specified frequency (default of p = 0.001). These results can then be used to explore fundamental population genetic and phylogeographic patterns, mechanisms and processes at the microevolutionary level, such as nucleotide and amino acid sequence conservation. Our package extends earlier work pertaining to an implementation of VLF analysis in Microsoft Excel, which was found to be both computationally slow and error prone. We compare those results to our own herein. Results between the two implementations are found to be highly consistent for a large DNA barcode dataset of bird species. Differences in results are readily explained by both manual human error and inadequate Linnean taxonomy (specifically, species synonymy). Here, VLF is also applied to a subset of avian barcodes to assess the extent of biological artifacts at the species level for Canada goose (Branta canadensis), as well as within a large dataset of DNA barcodes for fishes of forensic and regulatory importance. The novelty of VLF and its benefit over the previous implementation include its high level of automation, speed, scalability and ease-of-use, each desirable characteristics which will be extremely valuable as more sequence data are rapidly accumulated in popular reference databases, such as BOLD and GenBank.

Outcomes of mitochondrial long chain fatty acid oxidation and carnitine defects from a single center metabolic genetics clinic.

BACKGROUND: Mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects are a group of inherited metabolic diseases. We performed a retrospective cohort study to report on the phenotypic and genotypic spectrum of mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects as well as their treatment outcomes. METHODS: All patients with mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects were included. We divided patients into two groups to compare outcomes of those treated symptomatically (SymX) and asymptomatically (AsymX). We reviewed patient charts for clinical features, biochemical investigations, molecular genetic investigations, cardiac assessments, neuroimaging, treatments, and outcomes. RESULTS: There were 38 patients including VLCAD (n = 5), LCHAD (n = 4), CACT (n = 3), MAD (n = 1), CPT-I (n = 13), CPT-II (n = 3) deficiencies and CTD (n = 9). Fourteen patients were diagnosed symptomatically (SymX), and 24 patients were diagnosed asymptomatically (AsymX). Twenty-eight variants in seven genes were identified in 36 patients (pathogenic/likely pathogenic n = 25; variant of unknown significance n = 3). Four of those variants were novel. All patients with LCHAD deficiency had the common variant (p.Glu474Gln) in HADHA and their phenotype was similar to the patients reported in the literature for this genotype. Only one patient with VLCAD deficiency had the common p.Val283Ala in ACADVL. The different genotypes in the SymX and AsymX groups for VLCAD deficiency presented with similar phenotypes. Eight patients were treated with carnitine supplementation [CTD (n = 6), CPT-II (n = 1), and MAD (n = 1) deficiencies]. Thirteen patients were treated with a long-chain fat restricted diet and MCT supplementation. A statistically significant association was found between rhabdomyolysis, and hypoglycemia in the SymX group compared to the AsymX group. A higher number of hospital admissions, longer duration of hospital admissions and higher CK levels were observed in the SymX group, even though the symptomatic group was only 37% of the study cohort. CONCLUSION: Seven different mitochondrial long-chain fatty acid oxidation and carnitine metabolism defects were present in our study cohort. In our clinic, the prevalence of mitochondrial long-chain fatty acid oxidation and carnitine defects was 4.75%.

Prevalence of Congenital Disorders of Glycosylation in Childhood Epilepsy and Effects of Anti-Epileptic Drugs on the Transferrin Isoelectric Focusing Test.

INTRODUCTION: Childhood epilepsy is one of the most common neurological problems. The transferrin isoelectric focusing (TIEF) test is a screening test for congenital disorders of glycosylation (CDG). We identified abnormal TIEF test in children with epilepsy in our epilepsy genetics clinic. To determine if an abnormal TIEF test is associated with anti-epileptic medications or abnormal liver functions, we performed a retrospective cohort study. METHODS: This study was performed between January 2012 and March 2020. Electronic patient charts were reviewed. Standard non-parametric statistical tests were applied using R statistical software. Fischer's exact test was used for comparisons. RESULTS: There were 206 patients. The TIEF test was abnormal in 11% (23 out of 206) of the patients. Nine patients were diagnosed with CDG: PMM2-CDG (n = 5), ALG3-CDG (n = 1), ALG11-CDG (n = 2), SLC35A2-CDG (n = 1). We report 51 different genetic diseases in 84 patients. Two groups, (1) abnormal TIEF test; (2) normal TIEF test, showed statistically significant differences for abnormal liver functions and for valproic acid treatment. CONCLUSION: The TIEF test guided CDG diagnosis in 2.9% of the patients. Due to the high prevalence of CDG (4.4%) in childhood epilepsy, the TIEF test might be included into the diagnostic investigations to allow earlier and cost-effective diagnosis.

Canada-Wide Epidemic of emm74 Group A Streptococcus Invasive Disease.

BACKGROUND: The number of invasive group A Streptococcus (iGAS) infections due to hitherto extremely rare type emm74 strains has increased in several Canadian provinces since late 2015. We hypothesized that the cases recorded in the different provinces are linked and caused by strains of an emm74 clone that recently emerged and expanded explosively. METHODS: We analyzed both active and passive surveillance data for iGAS infections and used whole-genome sequencing to investigate the phylogenetic relationships of the emm74 strains responsible for these invasive infections country-wide. RESULTS: Genome analysis showed that highly clonal emm74 strains, genetically different from emm74 organisms previously circulating in Canada, were responsible for a country-wide epidemic of >160 invasive disease cases. The emerging clone belonged to multilocus sequence typing ST120. The analysis also revealed dissemination patterns of emm74 subclonal lineages across Canadian provinces. Clinical data analysis indicated that the emm74 epidemic disproportionally affected middle-aged or older male individuals. Homelessness, alcohol abuse, and intravenous drug usage were significantly associated with invasive emm74 infections. CONCLUSIONS: In a period of 20 months, an emm74 GAS clone emerged and rapidly spread across several Canadian provinces located more than 4500 km apart, causing invasive infections primarily among disadvantaged persons.

Use of Genome Sequencing to Define Institutional Influenza Outbreaks, Toronto, Ontario, Canada, 2014-15.

Adequacy of the current clinical definition of institutional influenza outbreaks is unclear. We performed a retrospective genome sequencing and epidemiologic analysis of institutional influenza outbreaks that occurred during the 2014-15 influenza season in Toronto, Canada. We sequenced the 2 earliest submitted samples positive for influenza A(H3N2) from each of 38 reported institutional outbreaks in long-term care facilities. Genome sequencing showed most outbreak pairs identified by using the current clinical definition were highly related. Inclusion of surveillance samples demonstrated that outbreak sources were likely introductions from broader circulating lineages. Pairwise distance analysis using majority genome and hemagglutinin-specific genes enabled identification of thresholds for discrimination of within and between outbreak pairs; the area under the curve ranged 0.93-0.95. Routine genome sequencing for defining influenza outbreaks in long-term care facilities is unlikely to add significantly to the current clinical definition. Sequencing may prove most useful for investigating sources of outbreak introductions.

Genetic evidence for a novel variant of the pilus island 1 backbone protein in group B Streptococcus.

PURPOSE: Pili contribute significantly to the pathogenesis of infection of group B Streptococcus (GBS) by facilitating adhesion and invasion of host cells. GBS pilin subunits (the backbone pilin protein, BP, and the ancillary pilin proteins, AP) as well as the specific enzymes required for pilus assembly are encoded by genes located in two separate genomic regions, known as pilus island 1 (PI-1) and PI-2. Our aim was to characterize the pilus profile of a collection of GBS isolates from metropolitan Toronto, Canada. METHODOLOGY: The pilus profile of 1332 invasive and colonizing GBS isolates was determined by PCR and, in selected cases, by whole genome sequencing. RESULTS: While investigating the pilus profile of a collection of GBS organisms, we discovered that 51 isolates possessed a novel variant of the PI-1 BP, which we named BP-1b. The predicted translated sequences of archetypical GBS BP-1 and novel BP-1b variants shared only 63 % amino acid sequence homology. The novel BP-1b variant was most common among strains of serotype Ib and VI, but was also found among strains of serotypes Ia, II, III and VIII. CONCLUSION: We describe a relatively frequent occurrence of a novel PI-1 BP that cannot be detected by a commonly used multiplex PCR scheme, which could lead to strains being mistyped as PI-1 negative. We present PCR primers that can easily be incorporated into the multiplex PCR assay to identify strains with novel BP-1b variant.

A single amino acid polymorphism in the glycosyltransferase CpsK defines four Streptococcus suis serotypes.

The capsular polysaccharide (CPS) is the major virulence factor of the emerging zoonotic pathogen Streptococcus suis. CPS differences are also the basis for serological differentiation of the species into 29 serotypes. Serotypes 2 and 1/2, which possess identical gene content in their cps loci, express CPSs that differ only by substitution of galactose (Gal) by N-acetylgalactosamine (GalNAc) in the CPS side chain. The same sugar substitution differentiates the CPS of serotypes 14 and 1, whose cps loci are also identical in gene content. Here, using mutagenesis, CPS structural analysis, and protein structure modeling, we report that a single amino acid polymorphism in the glycosyltransferase CpsK defines the enzyme substrate predilection for Gal or GalNAc and therefore determines CPS composition, structure, and strain serotype. We also show that the different CPS structures have similar antiphagocytic properties and that serotype switching has limited impact on the virulence of S. suis.

Rapid Emergence of a New Clone Impacts the Population at Risk and Increases the Incidence of Type emm89 Group A Streptococcus Invasive Disease.

BACKGROUND: Invasive group A Streptococcus (iGAS) disease caused by type emm89 strains has been increasing worldwide, driven by the emergence of an epidemic clonal variant (clade 3 emm89). The clinical characteristics of patients with emm89 iGAS disease, and in particular with clade 3 emm89 iGAS disease, are poorly described. METHODS: We used population-based iGAS surveillance data collected in metropolitan Toronto, Ontario, Canada during the period 2000-2014. We sequenced the genomes of 105 emm89 isolates representing all emm89 iGAS disease cases in the area during the period and 138 temporally matched emm89 iGAS isolates collected elsewhere in Ontario. RESULTS: Clades 1 and 2 and clade O, a newly discovered emm89 genetic variant, caused most cases of emm89 iGAS disease in metropolitan Toronto before 2008. After rapid emergence of new clade 3, previously circulating clades were purged from the population and the incidence of emm89 iGAS disease significantly increased from 0.14 per 100000 in 2000-2007 to 0.22 per 100000 in 2008-2014. Overall, emm89 organisms caused significantly more arthritis but less necrotizing fasciitis than strains of the more common type emm1. Other clinical presentations were soft tissue and severe respiratory tract infections. Clinical outcomes did not differ significantly between emm89 clades overall. However, clade 3 emm89 iGAS disease was more common in youth and middle-aged individuals. CONCLUSIONS: The rapid shift in emm89 iGAS strain genetics in metropolitan Toronto has resulted in a significant increase in the incidence of emm89 iGAS disease, with noticeably higher rates of clade 3 disease in younger patients.

Whole-Genome Sequencing Applied to the Molecular Epidemiology of Shiga Toxin-Producing Escherichia coli O157:H7 in Argentina.

Shiga toxin-producing Escherichia coli strains are worldwide associated with sporadic human infections and outbreaks. In this work, we report the availability of high-quality draft whole-genome sequences for 19 O157:H7 strains isolated in Argentina.

Capsular Switching and Other Large-Scale Recombination Events in Invasive Sequence Type 1 Group B Streptococcus.

We report several cases of recombination events leading to capsular switching among sequence type (ST) 1 group B Streptococcus strains. These strains otherwise shared a common genome backbone with serotype V ST1 strains. However, the genomes of ST1 serotype V strains and those of serotypes VI, VII, and VIII strains differed substantially.

Genomic Recombination Leading to Decreased Virulence of Group B Streptococcus in a Mouse Model of Adult Invasive Disease.

Adult invasive disease caused by Group B Streptococcus (GBS) is increasing worldwide. Whole-genome sequencing (WGS) now permits rapid identification of recombination events, a phenomenon that occurs frequently in GBS. Using WGS, we described that strain NGBS375, a capsular serotype V GBS isolate of sequence type (ST)297, has an ST1 genomic background but has acquired approximately 300 kbp of genetic material likely from an ST17 strain. Here, we examined the virulence of this strain in an in vivo model of GBS adult invasive infection. The mosaic ST297 strain showed intermediate virulence, causing significantly less systemic infection and reduced mortality than a more virulent, serotype V ST1 isolate. Bacteremia induced by the ST297 strain was similar to that induced by a serotype III ST17 strain, which was the least virulent under the conditions tested. Yet, under normalized bacteremia levels, the in vivo intrinsic capacity to induce the production of pro-inflammatory cytokines was similar between the ST297 strain and the virulent ST1 strain. Thus, the diminished virulence of the mosaic strain may be due to reduced capacity to disseminate or multiply in blood during a systemic infection which could be mediated by regulatory factors contained in the recombined region.

Determining Streptococcus suis serotype from short-read whole-genome sequencing data.

BACKGROUND: Streptococcus suis is divided into 29 serotypes based on a serological reaction against the capsular polysaccharide (CPS). Multiplex PCR tests targeting the cps locus are also used to determine S. suis serotypes, but they cannot differentiate between serotypes 1 and 14, and between serotypes 2 and 1/2. Here, we developed a pipeline permitting in silico serotype determination from whole-genome sequencing (WGS) short-read data that can readily identify all 29 S. suis serotypes. RESULTS: We sequenced the genomes of 121 strains representing all 29 known S. suis serotypes. We next combined available software into an automated pipeline permitting in silico serotyping of strains by differential alignment of short-read sequencing data to a custom S. suis cps loci database. Strains of serotype pairs 1 and 14, and 2 and 1/2 could be differentiated by a missense mutation in the cpsK gene. We report a 99 % match between coagglutination- and pipeline-determined serotypes for strains in our collection. We used 375 additional S. suis genomes downloaded from the NCBI's Sequence Read Archive (SRA) to validate the pipeline. Validation with SRA WGS data resulted in a 92 % match. Included pipeline subroutines permitted us to assess strain virulence marker content and obtain multilocus sequence typing directly from WGS data. CONCLUSIONS: Our pipeline permits rapid and accurate determination of S. suis serotype, and other lineage information, directly from WGS data. By discriminating between serotypes 1 and 14, and between serotypes 2 and 1/2, our approach solves a three-decade longstanding S. suis typing issue.

Comparative Genome Analyses of Streptococcus suis Isolates from Endocarditis Demonstrate Persistence of Dual Phenotypic Clones.

Many bacterial species coexist in the same niche as heterogeneous clones with different phenotypes; however, understanding of infectious diseases by polyphenotypic bacteria is still limited. In the present study, encapsulation in isolates of the porcine pathogen Streptococcus suis from persistent endocarditis lesions was examined. Coexistence of both encapsulated and unencapsulated S. suis isolates was found in 26 out of 59 endocarditis samples. The isolates were serotype 2, and belonged to two different sequence types (STs), ST1 and ST28. The genomes of each of the 26 pairs of encapsulated and unencapsulated isolates from the 26 samples were sequenced. The data showed that each pair of isolates had one or more unique nonsynonymous mutations in the cps gene, and the encapsulated and unencapsulated isolates from the same samples were closest to each other. Pairwise comparisons of the sequences of cps genes in 7 pairs of encapsulated and unencapsulated isolates identified insertion/deletions (indels) ranging from one to 104 bp in different cps genes of unencapsulated isolates. Capsule expression was restored in a subset of unencapsulated isolates by complementation in trans with cps expression vectors. Examination of gene content common to isolates indicated that mutation frequency was higher in ST28 pairs than in ST1 pairs. Genes within mobile genetic elements were mutation hot spots among ST28 isolates. Taken all together, our results demonstrate the coexistence of dual phenotype (encapsulated and unencapsulated) bacterial clones and suggest that the dual phenotypes arose independently in each farm by means of spontaneous mutations in cps genes.

Population structure and drug resistance patterns of emerging non-PCV-13 Streptococcus pneumoniae serotypes 22F, 15A, and 8 isolated from adults in Ontario, Canada.

The introduction of pneumococcal conjugate vaccines has led to the emergence of non-vaccine serotypes, which contributed to invasive pneumococcal disease in Canada and worldwide. A significant increase in the prevalence of non-13-valent pneumococcal conjugate vaccine (PCV-13)-included serotypes 22F, 15A, and 8 was observed from 2009 to 2013 in Ontario (all p values<0.01). In this study, whole genome sequencing was conducted on the 25 isolates of serotype 22F, seven of 15A and 10 of 8 to investigate the population structure and antibiotic resistance. All seven serotype 15A isolates were found to be multidrug resistant. From whole genome analysis, we observed recombination events among serotypes 22F, 15A and 8 populations. Serotype 22F (ST433) has emerged into two sub-populations, with 28% (7/25) exhibiting recombination events, and five also acquiring macrolide resistance as a result of recombination. This study enhances the knowledge on the molecular evolution of emerging non-PCV-13 vaccine serotype 22F, including acquisition of resistance genes through recombination events. It underpins the importance of whole genome sequencing in studying Streptococcus pneumoniae population structures and dynamics, and its utility in molecular surveillance.

Population Structure and Antimicrobial Resistance Profiles of Streptococcus suis Serotype 2 Sequence Type 25 Strains.

Strains of serotype 2 Streptococcus suis are responsible for swine and human infections. Different serotype 2 genetic backgrounds have been defined using multilocus sequence typing (MLST). However, little is known about the genetic diversity within each MLST sequence type (ST). Here, we used whole-genome sequencing to test the hypothesis that S. suis serotype 2 strains of the ST25 lineage are genetically heterogeneous. We evaluated 51 serotype 2 ST25 S. suis strains isolated from diseased pigs and humans in Canada, the United States of America, and Thailand. Whole-genome sequencing revealed numerous large-scale rearrangements in the ST25 genome, compared to the genomes of ST1 and ST28 S. suis strains, which result, among other changes, in disruption of a pilus island locus. We report that recombination and lateral gene transfer contribute to ST25 genetic diversity. Phylogenetic analysis identified two main and distinct Thai and North American clades grouping most strains investigated. These clades also possessed distinct patterns of antimicrobial resistance genes, which correlated with acquisition of different integrative and conjugative elements (ICEs). Some of these ICEs were found to be integrated at a recombination hot spot, previously identified as the site of integration of the 89K pathogenicity island in serotype 2 ST7 S. suis strains. Our results highlight the limitations of MLST for phylogenetic analysis of S. suis, and the importance of lateral gene transfer and recombination as drivers of diversity in this swine pathogen and zoonotic agent.

Distribution of Suicin Gene Clusters in Streptococcus suis Serotype 2 Belonging to Sequence Types 25 and 28.

Recently, we reported the purification and characterization of three distinct lantibiotics (named suicin 90-1330, suicin 3908, and suicin 65) produced by Streptococcus suis. In this study, we investigated the distribution of the three suicin lantibiotic gene clusters among serotype 2 S. suis strains belonging to sequence type (ST) 25 and ST28, the two dominant STs identified in North America. The genomes of 102 strains were interrogated for the presence of suicin gene clusters encoding suicins 90-1330, 3908, and 65. The gene cluster encoding suicin 65 was the most prevalent and mainly found among ST25 strains. In contrast, none of the genes related to suicin 90-1330 production were identified in 51 ST25 strains nor in 35/51 ST28 strains. However, the complete suicin 90-1330 gene cluster was found in ten ST28 strains, although some genes in the cluster were truncated in three of these isolates. The vast majority (101/102) of S. suis strains did not possess any of the genes encoding suicin 3908. In conclusion, this study indicates heterogeneous distribution of suicin genes in S. suis.

Whole-genome Sequencing for Surveillance of Invasive Pneumococcal Diseases in Ontario, Canada: Rapid Prediction of Genotype, Antibiotic Resistance and Characterization of Emerging Serotype 22F.

Background: Molecular typing is essential for inferring genetic relatedness between bacterial pathogens. In this study, we applied whole genome sequencing (WGS) for rapid prediction of sequence type and antibiotic resistance for invasive pneumococcal isolates. Methods: 240 isolates from adults (≥50 years old) in Ontario, Canada during 2009 to 2013 were subjected to WGS. Sequence type, antibiotic susceptibility and resistance were predicted directly from short reads. Emerging non-vaccine serotype 22F was further characterized by WGS. Results: Sequence type was successfully determined for 98.3% of isolates. The overall sensitivity and specificity for antibiotic resistance prediction were 95 and 100% respectively, compared to standard susceptibility testing methods. WGS-based phylogeny divided emerging 22F (ST433) strains into two distinct clades: clade A harboring a 23 kb-prophage and anti-phage PhD/Doc system and clade B with virulence-related proteases. Five isolates in clade A developed macrolide resistance via 5.1 kb mega element recombination (encoding mefE and msrD), while one isolate in clade B displayed quinolone resistance via a gyrA mutation. Conclusions: WGS is valuable for routine surveillance of pneumococcal clinical isolates and facilitates prediction of genotype and antibiotic resistance. The emergence of 22F in Ontario in the post-vaccine era and evidence of evolution and divergence of the 22F population warrants heightened pneumococcal molecular surveillance.

High Incidence of Invasive Group A Streptococcus Disease Caused by Strains of Uncommon emm Types in Thunder Bay, Ontario, Canada.

An outbreak of type emm59 invasive group A Streptococcus (iGAS) disease was declared in 2008 in Thunder Bay District, Northwestern Ontario, 2 years after a countrywide emm59 epidemic was recognized in Canada. Despite a declining number of emm59 infections since 2010, numerous cases of iGAS disease continue to be reported in the area. We collected clinical information on all iGAS cases recorded in Thunder Bay District from 2008 to 2013. We also emm typed and sequenced the genomes of all available strains isolated from 2011 to 2013 from iGAS infections and from severe cases of soft tissue infections. We used whole-genome sequencing data to investigate the population structure of GAS strains of the most frequently isolated emm types. We report an increased incidence of iGAS in Thunder Bay compared to the metropolitan area of Toronto/Peel and the province of Ontario. Illicit drug use, alcohol abuse, homelessness, and hepatitis C infection were underlying diseases or conditions that might have predisposed patients to iGAS disease. Most cases were caused by clonal strains of skin or generalist emm types (i.e., emm82, emm87, emm101, emm4, emm83, and emm114) uncommonly seen in other areas of the province. We observed rapid waxing and waning of emm types causing disease and their replacement by other emm types associated with the same tissue tropisms. Thus, iGAS disease in Thunder Bay District predominantly affects a select population of disadvantaged persons and is caused by clonally related strains of a few skin and generalist emm types less commonly associated with iGAS in other areas of Ontario.