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Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation. Plasma cells then produce SARS-CoV-2-specific antibodies. Here, we review published data linking HLA genetic variation or polymorphisms with differences in SARS-CoV-2-specific antibody responses. While there is evidence that heterogeneity in antibody response might be related to HLA variation, there are conflicting findings due in part to differences in study designs. We provide insight into why more research is needed in this area. Elucidating the genetic basis of variability in the SARS-CoV-2 immune response will help to optimize diagnostic tools and lead to the development of new vaccines and therapeutics against SARS-CoV-2 and other infectious diseases.

Background Knowledge of pathogenic variants in cancer‐predisposing genes is important when making breast cancer treatment decisions, but genetic testing is not universal and criteria must be met to qualify for genetic testing. The objective of this study was to evaluate the pathogenic variant yield for nine cancer predisposition genes by testing criteria, singly and in combination. Methods Women diagnosed with breast cancer between June 2013 and May 2018 were recruited from four centers in Toronto, Canada. Participants completed a demographics and family history questionnaire and clinical characteristics were collected from medical charts. Genetic testing was done for BRCA1, BRCA2, PALB2, ATM, CHEK2, BRIP1, RAD51D, RECQL, and TP53. Pathogenic variant frequencies were calculated according to five criteria (age ≤ 50, triple‐negative breast cancer, family history, bilateral breast cancer, or Jewish ethnicity). Results Of the 1006 women studied, 100 women (9.9%) were found to have a pathogenic variant in one of the nine genes tested. The highest prevalence of pathogenic variants was found in women with triple‐negative breast cancer (23%). Of the 100 pathogenic variants detected, 78 were detected in women diagnosed at age 50 or less. A total of 96% of the mutations were identified with three criteria (age of diagnosis, family history, and triple‐negative status). Conclusions Genetic testing criteria for women with breast cancer should include women with triple‐negative breast cancer, regardless of age. All women aged 50 years or below at time of breast cancer diagnosis should be offered genetic testing. All genetic testing criteria evaluated resulted in at least a 10% pathogenic variant positive rate, with the highest being in women with triple negative breast cancer (23.2%). For women who only met one of the identified criteria, positivity rates ranged between 2.0% (Jewish ethnicity) to 14.3% (synchronous bilateral breast cancer).

Methylmalonic aciduria and homocystinuria, cblC type (OMIM 277400), is the most common inborn error of vitamin B 12 (cobalamin) metabolism, with about 250 known cases. Affected individuals have developmental, hematological, neurological, metabolic, ophthalmologic and dermatologic clinical findings 1 . Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood 2 . The cblC locus was mapped to chromosome region 1p by linkage analysis 3 . We refined the chromosomal interval using homozygosity mapping and haplotype analyses and identified the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA, accounted for 40% of all disease alleles. Transduction of wild-type MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype. Molecular modeling predicts that the C-terminal region of the gene product folds similarly to TonB, a bacterial protein involved in energy transduction for cobalamin uptake.

This commentary is based on the key note address given by Jordan Lerner-Ellis at the annual symposium of the Society for the Study of Inborn Errors of Metabolism, held in Geneva, Switzerland in August 2011. The content of the address was developed from a series of discussions with seven clinicians and medical geneticists, all having a long-time interest in genetic testing and genomic medicine (the interviews were not intended to be a forum for the introduction of new data). All participants were asked to offer their views on five questions: the benefits of using whole genome sequencing (WGS) in the clinic; the corresponding risks; the limitations on its wider use; the interviewees’ particular interests in using WGS in their practice; and projected timelines for successful adoption in clinical medicine.

Succinyl‐CoA synthetase or succinate‐CoA ligase deficiency can result from biallelic mutations in SUCLG1 gene that encodes for the alpha subunit of the succinyl‐CoA synthetase. Mutations in this gene were initially associated with fatal infantile lactic acidosis. We describe an individual with a novel biallelic pathogenic mutation in SUCLG1 with a less severe phenotype dominated by behavioral problems. The mutation was identified to be c.512A>G corresponding to a p.Asn171Ser change in the protein. The liquid chromatography tandem mass spectrometry‐based enzyme activity assay on cultured fibroblasts revealed a markedly reduced activity of succinyl‐CoA synthetase enzyme when both ATP and GTP were substrates, affecting both ADP‐forming and GDP‐forming functions of the enzyme.

The genetic basis of a defect in the metabolism of vitamin B 12 (the cblD defect) was studied in cultured skin fibroblasts from seven patients with the defect. The defect was localized to chromosome 2q23.2, and a candidate gene (designated MMADHC ) was identified in this region. Mutations in MMADHC were found in all seven patients. Transfection of the gene into fibroblasts from patients rescued the affected metabolic pathways. 12 The genetic basis of a defect in the metabolism of vitamin B 12 (the cblD defect) was studied in seven patients with the defect. The defect was localized to chromosome 2q23.2, and a candidate gene was identified. Vitamin B 12 (cobalamin) is essential for normal development and survival in humans and must be obtained from animal products or supplements. Inside the cell, it is converted to two active cofactors, adenosylcobalamin and methylcobalamin (Figure 1). 1 Adenosylcobalamin is the coenzyme for mitochondrial methylmalonyl–coenzyme A mutase, which converts L-methylmalonyl–coenzyme A to succinyl–coenzyme A and is involved in catabolism of odd-chain fatty acids and some amino acids. Methylcobalamin is the coenzyme for cytosolic methionine synthase, which converts homocysteine to methionine and is essential for normal one-carbon metabolism, which is in turn involved in vital cellular processes such as methylation and DNA . . .

IntroductionThe high demand for genetic tests and limited supply of genetics professionals has created a need for alternative service delivery models. Digital tools are increasingly being used to support multiple points in the genetic testing journey; however, none are transferable across multiple clinical specialties and settings nor do they encompass the entire trajectory of the journey. We aim to evaluate the effectiveness of the Genetics Adviser, an interactive, patient-facing, online digital health tool that delivers pre-test counselling, provides support during the waiting period for results, and returns results with post-test counselling, encompassing the entire patient genetic testing journey.Methods and analysisWe will compare the Genetics Adviser paired with a brief genetic counselling session to genetic counselling alone in a randomised controlled trial. One hundred and forty patients who previously received uninformative genetic test results for their personal and family history of cancer will be recruited from familial cancer clinics in Toronto and offered all clinically significant results from genomic sequencing. Participants randomised into the intervention arm will use the Genetics Adviser to learn about genomic sequencing, receive pre-test counselling, support during the waiting period and results, supplemented with brief counselling from a genetic counsellor. Participants in the control arm will receive standard pre-test and post-test counselling for genomic sequencing from a genetic counsellor. Our primary outcome is decisional conflict following pre-test counselling from the Genetics Adviser+genetic counsellor or counsellor alone. Secondary outcomes include: knowledge, satisfaction with decision-making, anxiety, quality of life, psychological impact of results, empowerment, acceptability and economic impact for patients and the health system. A subset of patients will be interviewed to assess user experience.Ethics and disseminationThis study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System (REB#20–035). Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals.Trial registration number NCT04725565.

We aimed to describe patient preferences for a broad range of secondary findings (SF) from genomic sequencing (GS) and factors driving preferences. We assessed preference data within a trial of the Genomics ADvISER, (SF decision aid) among adult cancer patients. Participants could choose from five categories of SF: (1) medically actionable; (2) polygenic risks; (3) rare diseases; (4) early-onset neurological diseases; and (5) carrier status. We analyzed preferences using descriptive statistics and drivers of preferences using multivariable logistic regression models. The 133 participants were predominantly European (74%) or East Asian or mixed ancestry (13%), female (90%), and aged > 50 years old (60%). The majority chose to receive SF. 97% (129/133) chose actionable findings with 36% (48/133) choosing all 5 categories. Despite the lack of medical actionability, participants were interested in receiving SF of polygenic risks (74%), carrier status (75%), rare diseases (59%), and early-onset neurologic diseases (53%). Older participants were more likely to be interested in receiving results for early-onset neurological diseases, while those exhibiting lower decisional conflict were more likely to select all categories. Our results highlight a disconnect between cancer patient preferences and professional guidelines on SF, such as ACMG’s recommendations to only return medically actionable secondary findings. In addition to clinical evidence, future guidelines should incorporate patient preferences.

Mutations in the MMAA gene on human chromosome 4q31.21 result in vitamin B12‐responsive methylmalonic aciduria (cblA complementation group) due to deficiency in the synthesis of adenosylcobalamin. Genomic DNA from 37 cblA patients, diagnosed on the basis of cellular adenosylcobalamin synthesis, methylmalonyl–coenzyme A (CoA) mutase function, and complementation analysis, was analyzed for deleterious mutations in the MMAA gene by DNA sequencing of exons and flanking sequences. A total of 18 novel mutations were identified, bringing the total number of mutations identified in 37 cblA patients to 22. A total of 13 mutations result in premature stop codons; three are splice site defects; and six are missense mutations that occur at highly conserved residues. Eight of these mutations were common to two or more individuals. One mutation, c.433C>T (R145X), represents 43% of pathogenic alleles and a common haplotype was identified. Restriction endonuclease or heteroduplex diagnostic tests were designed to confirm mutations. None of the sequence changes identified in cblA patients were found in 100 alleles from unrelated control individuals. Hum Mutat 24:509–516, 2004. © 2004 Wiley‐Liss, Inc.

The GENCOV study aims to identify patient factors which affect COVID-19 severity and outcomes. Here, we aimed to evaluate patient characteristics, acute symptoms and their persistence, and associations with hospitalization. Participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada. Patient-reported demographics, medical history, and COVID-19 symptoms and complications were collected through an intake survey. Regression analyses were performed to identify associations with outcomes including hospitalization and COVID-19 symptoms. In total, 966 responses were obtained from 1106 eligible participants (87% response rate) between November 2020 and May 2022. Increasing continuous age (aOR: 1.05 [95%CI: 1.01–1.08]) and BMI (aOR: 1.17 [95%CI: 1.10–1.24]), non-White/European ethnicity (aOR: 2.72 [95%CI: 1.22–6.05]), hypertension (aOR: 2.78 [95%CI: 1.22–6.34]), and infection by viral variants (aOR: 5.43 [95%CI: 1.45–20.34]) were identified as risk factors for hospitalization. Several symptoms including shortness of breath and fever were found to be more common among inpatients and tended to persist for longer durations following acute illness. Sex, age, ethnicity, BMI, vaccination status, viral strain, and underlying health conditions were associated with developing and having persistent symptoms. By improving our understanding of risk factors for severe COVID-19, our findings may guide COVID-19 patient management strategies by enabling more efficient clinical decision making.