A systematic review of the assessment of the clinical utility of genomic sequencing: Implications of the lack of standard definitions and measures of clinical utility.

PURPOSE: Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility is defined and measured in studies evaluating the impacts of ES/GS results for pediatric patients. METHODS: Relevant articles were identified in PubMed, Medline, Embase, and Web of Science. Eligible studies assessed clinical utility of ES/GS for pediatric patients published before 2021. Other relevant articles were added based on articles' references. Articles were coded to assess definitions and measures of clinical utility. RESULTS: Of 1346 articles, 83 articles met eligibility criteria. Clinical utility was not clearly defined in 19% of studies and 92% did not use an explicit measure of clinical utility. When present, definitions of clinical utility diverged from recommended definitions and varied greatly, from narrow (diagnostic yield of ES/GS) to broad (including decisions about withdrawal of care/palliative care and/or impacts on other family members). CONCLUSION: Clinical utility is used to guide policy and practice decisions about test use. The lack of a standard definition of clinical utility of ES/GS may lead to under- or overestimations of clinical utility, complicating policymaking and raising ethical issues.

The Need to Consider Context: A Systematic Review of Factors Involved in the Consent Process for Genetic Tests from the Perspective of Patients.

Background: Informed consent for genetic tests is a well-established practice. It should be based on good quality information and in keeping with the patient's values. Existing informed consent assessment tools assess knowledge and values. Nevertheless, there is no consensus on what specific elements need to be discussed or considered in the consent process for genetic tests.Methods: We performed a systematic review to identify all factors involved in the decision-making and consent process about genetic testing, from the perspective of patients. Through public databases, we identified studies reporting factors that influence the decision to accept or decline genetic testing. Studies were included if they reported the perspective of patients or at-risk individuals. All articles were thematically coded.Results: 1989 articles were reviewed: 70 met inclusion criteria and 12 additional articles were identified through the references of included studies. Coding of the 82 articles led to the identification of 45 factors involved in decision-making and consent, which were initially divided into three domains: in favor of, against or with an undetermined influence on genetic testing. Each factor was also divided into three subdomains relating to the informed choice concept: knowledge, values or other. The factors in the "other" subdomain were all related to the context of testing (e.g. timing, cost, influence of family members, etc), and were present in all three domains.Conclusions: We describe the network of factors contributing to decision-making and consent process and identify the context of genetic testing as a third component to influence this process. Future studies should consider the evaluation of contextual factors as an important and relevant component of the consent and decision-making process about genetic tests. Based on these results, we plan to develop and test a more comprehensive tool to assess informed consent for genetic testing.

Harvey and Gurvir's Law: Ontario Bill for Quality Prenatal Information about Down Syndrome: Terminology, Feasibility, and Ethical Issues.

Harvey and Gurvir's Law is a bill proposed to the Legislative Assembly of Ontario (Canada) to reduce stigma and bias associated with Down syndrome, by developing and disseminating quality information about Down syndrome in the context of prenatal testing.

The Experience of Parents of Children With Genetically Determined Leukoencephalopathies With the Health Care System: A Qualitative Study.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents. Data was analyzed thematically. Five themes were identified: challenges of the diagnostic odyssey, limited access to services, excessive parental responsibilities, positive relationships with health care professionals as a facilitator of care, and benefits of a specialized leukodystrophy clinic. Parents felt like waiting for the diagnosis was extremely stressful, and they expressed their need for transparency during this period. They identified multiple gaps and barriers in the health care system, which burdened them with many responsibilities. Parents emphasized the importance of a positive relationship with their child's health care professionals. They also felt grateful for being followed at a specialized clinic as it improved the quality of care received.

Views of Canadian healthcare professionals on the future uses of non-invasive prenatal testing: a mixed method study.

Non-invasive prenatal testing's (NIPT) potential to screen for a wide range of conditions is receiving growing attention. This study explores Canadian healthcare professionals' perceptions towards NIPT's current and possible future uses, including paternity testing, sex determination, and fetal whole genome sequencing. Semi-structured interviews were conducted with ten healthcare professionals, and another 184 participated in a survey. The triangulation of our findings shows that there is considerable agreement among healthcare professionals on expanding NIPT use for medical conditions including fetal aneuploidies and monogenic diseases, but not for non-medical conditions (sex determination for non-medical reasons and paternity testing), nor for risk predisposition information (late onset diseases and Fetal Whole Genome Sequencing). Healthcare professionals raise concerns related to eugenics, the future child's privacy, and psychological and emotional burdens to prospective parents. Professional societies need to take these concerns into account when educating healthcare professionals on the uses of NIPT to ensure prospective parents' reproductive decisions are optimal for them and their families.

Experience of Parents of Children with Genetically Determined Leukoencephalopathies Regarding the Adapted Health Care Services During the COVID-19 Pandemic.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.

Family Experiences with Care for Children with Inherited Metabolic Diseases in Canada: A Cross-Sectional Survey.

BACKGROUND AND OBJECTIVE: Children with inherited metabolic diseases often require complex and highly specialized care. Patient and family-centered care can improve health outcomes that are important to families. This study aimed to examine experiences of family caregivers (parents/guardians) of children diagnosed with inherited metabolic diseases with healthcare to inform strategies to improve those experiences. METHODS: A cross-sectional mailed survey was conducted of family caregivers recruited from an ongoing cohort study. Participants rated their healthcare experiences during their child's visits to five types of healthcare settings common for inherited metabolic diseases: the metabolic clinic, the emergency department, hospital inpatient units, the blood laboratory, and the pharmacy. Participants provided narrative descriptions of any memorable negative or positive experiences. RESULTS: There were 248 respondents (response rate 49%). Caregivers were generally very or somewhat satisfied with the care provided at each care setting. Appropriate treatment, provider knowledge, provider communication, and care coordination were deemed essential aspects of satisfaction with care by the majority of participants across many settings. Memorable negative experiences were reported by 8-22% of participants, varying by setting. Among participants who reported memorable negative experiences, contributing factors included providers' demeanor, lack of communication, lack of involvement of the family, and disregard of an emergency protocol letter provided by the family. CONCLUSIONS: While caregivers' satisfaction with care for children with inherited metabolic diseases was high, we identified gaps in family-centered care and factors contributing to negative experiences that are important to consider in the future development of strategies to improve pediatric care for inherited metabolic diseases.

Individual and family characteristics associated with health indicators at entry into multidisciplinary pediatric weight management: findings from the CANadian Pediatric Weight management Registry (CANPWR).

OBJECTIVES: (1) To explore individual and family characteristics related to anthropometric and cardiometabolic health indicators and (2) examine whether characteristics that correlate with cardiometabolic health indicators differ across severity of obesity at time of entry to Canadian pediatric weight management clinics. METHODS: We conducted a cross-sectional analysis of 2-17 year olds with overweight or obesity who registered in the CANadian Pediatric Weight Management Registry (CANPWR) between May 2013 and October 2017 prior to their first clinic visit. Individual modifiable health behaviors included dietary intake, physical activity, screen time, and sleep. Family characteristics included parental BMI, family medical history, socioeconomic status and family structure. Linear mixed effects stepwise regression analysis was performed to determine which characteristics were related to each health indicator: BMI z-score; waist circumference; waist to height ratio; blood pressure; glycemia; HDL cholesterol; non-HDL cholesterol; triglycerides. RESULTS: This study included 1296 children (mean age ± standard deviation: 12.1 ± 3.5 years; BMI z-score: 3.55 ± 1.29; 95.3% with obesity). Hours spent sleeping (estimated ß = -0.10; 95% CI [-0.15, -0.05], p = 0.0001), hours per week of organized physical activity (estimated ß = -0.32; 95% CI [-0.53, -0.11], p = 0.0026), daily sugared drink intake (estimated ß = 0.06; 95% CI [0.01, 0.10], p = 0.0136) and maternal BMI (estimated ß = 0.03; 95% CI [0.02, 0.04], p < 0.0001) were associated with BMI z-score (adj. R2 = 0.2084), independent of other individual and family characteristics. Physical activity, total sugared drink intake and sleep duration were associated with glycemia and non-HDL cholesterol, independent of child BMI z-score. However, irrespective of obesity severity, little of the variance (0.86-11.1%) in cardiometabolic health indicators was explained by individual modifiable health behaviors. CONCLUSIONS: Physical activity, total sugared drink intake and hours spent sleeping were related to anthropometric and some cardiometabolic health indicators in children entering pediatric weight management programs. This highlights the importance of these modifiable health behaviors on multiple health indicators in children with obesity.

Metabolically healthy obesity in children enrolled in the CANadian Pediatric Weight management Registry (CANPWR): An exploratory secondary analysis of baseline data.

Our study purpose was to determine the prevalence of metabolically healthy obesity (MHO) and examine factors associated with MHO in children with obesity. This cross-sectional study was a secondary, exploratory analysis of data that included 2-17 years old with a body mass index (BMI) ≥85th percentile from the CANadian Pediatric Weight management Registry. Children were classified as having MHO or metabolically unhealthy obesity (MUO) using consensus-based criteria. Those with MHO had normal triglycerides, high-density lipoprotein cholesterol, blood pressure, and fasting glucose. Logistic regression was used to examine factors associated with MHO, which included calculating odds ratios (ORs) and 95% confidence intervals (CIs). In total, 945 children were included (mean age: 12.3 years; 51% female). The prevalence of MHO was 31% (n = 297), with lower levels across increasing age categories (2-5 years [n = 18; 43%], 6-11 years [n = 127; 35%], 12-17 years [n = 152; 28%]). Children with MHO were younger, weighed less, and had lower BMI z-scores than their peers with MUO (all p < 0.01). MHO status was positively associated with physical activity (OR: 1.18; 95% CI: 1.01-1.38), skim milk intake (OR: 1.10; 95% CI: 1.01-1.19), and fruit intake (OR: 1.12; 95% CI: 1.01-1.24) and negatively associated with BMI z-score (OR: 0.69; 95% CI: 0.60-0.79), total screen time in hours (OR: 0.79; 96% CI: 0.68-0.92), and intake of fruit flavoured drinks (OR: 0.91; 95% CI: 0.84-0.99). These findings may help guide clinical decision-making regarding obesity management by focusing on children with MUO who are at relatively high cardiometabolic risk.

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists.

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems. METHODS OF STATEMENT DEVELOPMENT: A multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context. The statement was circulated for comments to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors on 19 February 2021. RESULTS AND CONCLUSIONS: The use of prenatal GWS is indicated for the investigation of multiple fetal anomalies. Its use in the context of isolated fetal anomaly should be guided by available resources and current evidence, which is continually changing. During pregnancy, GWS should be ordered by, or in collaboration with, a medical geneticist. It should be used following detailed phenotyping to interrogate known disease genes, preferably using a trio approach, following detailed fetal phenotyping. Testing should be done with an overall aim to help in the management of the pregnancy, delivery and postnatal care. It should be guided by personal utility of the test for the pregnant person and clinical utility for pregnancy and birth management, as outlined herein. Genetic counselling is crucial in making the parental decision an informed decision. Chromosomal microarray analysis should be completed in parallel or prior to GWS and should be preceded by Quantitative Fluorescent PCR (QF-PCR) for detection of common aneuploidies. In normal circumstances, only pathogenic and likely pathogenic variants with a high likelihood of being associated with the identified fetal anomalies should be reported. Reporting of secondary findings, defined as purposeful analysis of variants in a set of medically actionable genes, should not, by default, be performed in the prenatal context. Laboratories should only report incidental findings that reveal risk of a significant Mendelian condition during infancy and childhood. Should a laboratory have a policy for reporting incidental findings in medically actionable adult-onset conditions, they should only be reported with explicit opt-in consent signed by the tested individuals. Genetic counselling is crucial in disclosing the test results and the implications the results may have for the fetus. It should be emphasised that negative results do not rule out a genetic diagnosis nor guarantee a good prognosis. Postnatal phenotyping and reanalysis of existing data should be considered. Families should be given the opportunity to participate in research studies as appropriate. These recommendations will be routinely re-evaluated as knowledge of the diagnostic and clinical utility of fetal GWS during pregnancy improves.

Variability in How Canadian Pediatric Weight Management Clinics Deliver Care: Evidence from the CANadian Pediatric Weight Management Registry.

Background: Clinical practice guidelines for pediatric weight management highlight the importance of family-based behavioral strategies to enhance health behaviors. Little is known, however, of how clinics implement these programs. The study objectives were to (1) describe how Canadian pediatric weight management clinics deliver care and (2) evaluate change in services over time. Methods: The CANadian Pediatric Weight management Registry (CANPWR) is a multisite prospective cohort study of participants enrolled in a Canadian pediatric weight management clinic. Clinical program characteristics (e.g., referral process, inclusion criteria, funding, program characteristics, patient interaction methods, and follow-up) were collected at the start and end of the CANPWR recruitment period (2015-2019). Results: Entrance into the nine clinics varied with limiting criteria based on geographic proximity, age, weight status, and presence of health conditions. The clinics varied in size (50-220 new patients/year). The planned length of intervention varied widely, from 10 weeks to open-ended (median 2 years). Behavior modification strategies were delivered with a mix of individual and group-based sessions and most were delivered in person, complemented by use of virtual care. Over time, more clinics saw patients under the age of 5 years and all clinics defined a program length. Conclusion: Although all clinics offered family-based behavioral weight management services, these varied considerably, especially in program entrance criteria, size of clinic, and the length of intervention. The influence of the variability in delivery of services on health outcomes will be addressed in future studies.

Genetic burden linked to founder effects in Saguenay-Lac-Saint-Jean illustrates the importance of genetic screening test availability.

The Saguenay-Lac-Saint-Jean (SLSJ) region located in the province of Quebec was settled in the 19th century by pioneers issued from successive migration waves starting in France in the 17th century and continuing within Quebec until the beginning of the 20th century. The genetic structure of the SLSJ population is considered to be the product of a triple founder effect and is characterised by a higher prevalence of some rare genetic diseases. Several studies were performed to elucidate the historical, demographic and genetic background of current SLSJ inhabitants to assess the origins of these rare disorders and their distribution in the population. Thanks to the development of new sequencing technologies, the genes and the variants responsible for the most prevalent conditions were identified. Combined with other resources such as the BALSAC population database, identifying the causal genes and the pathogenic variants allowed to assess the impacts of some of these founder mutations on the population health and to design precision medicine public health strategies based on carrier testing. Furthermore, it stimulated the establishment of many public programmes.We report here a review and an update of a subset of inherited disorders and founder mutations in the SLSJ region. Data were collected from published scientific sources. This work expands the knowledge about the current frequencies of these rare disorders, the frequencies of other rare genetic diseases in this population, the relevance of the carrier tests offered to the population, as well as the current available treatments and research about future therapeutic avenues for these inherited disorders.

When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort.

PURPOSE: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype-phenotype correlations. METHODS: Three hundred fifty-two chromosomal microarray-negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons. RESULTS: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM. CONCLUSION: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.

A qualitative study of women and partners from Lebanon and Quebec regarding an expanded scope of noninvasive prenatal testing.

BACKGROUND: In the near future, developments in non-invasive prenatal testing (NIPT) may offer couples the opportunity to expand the range of genetic conditions tested with this technology. This possibility raises a host of ethical and social concerns, such as the type of information (medical vs. non-medical information) that couples might be exposed to and how this might complicate their informed decision-making. Currently, only limited research, mainly carried out in western countries, was conducted on women's and partners' views regarding the potential expansion of NIPT. METHODS: This study used semi-structured interviews with pregnant women and their partners to explore their views on future potential NIPT applications such as non-medical sex selection and non-medical traits, paternity testing, and NIPT use for fetal whole genome sequencing (FWGS). It was conducted in Lebanon and Quebec, as case studies to explore the impact of cultural differences on these views. RESULTS: We found no differences and many similarities when comparing the perceptions of participants in both contexts. While couples in both settings disapproved of the use of NIPT for non-medical sex selection and non-medical traits such as physical characteristics, they were near-unanimous about their support for its use for paternity testing in specific cases, such as legal doubts or conflicts related to the identity of the father. Participants were more ambivalent about NIPT for Fetal Whole Genome Sequencing. They supported this use to detect conditions that would express at birth or early childhood, while objecting to testing for adult-onset conditions. CONCLUSIONS: These results can further inform the debate on the future uses of NIPT and future policy related its implementation.

Noninvasive Prenatal Testing: Views of Canadian Pregnant Women and Their Partners Regarding Pressure and Societal Concerns.

BACKGROUND: Noninvasive prenatal testing (NIPT) provides important benefits yet raises ethical concerns. We surveyed Canadian pregnant women and their partners to explore their views regarding pressure to test and terminate a pregnancy, as well as other societal impacts that may result from the routinization of NIPT. METHODS: A questionnaire was offered (March 2015 to July 2016) to pregnant women and their partners at five healthcare facilities in four Canadian provinces. RESULTS: 882 pregnant women and 395 partners completed the survey. 64% of women anticipated feeling no pressure to take the test if it were offered routinely, and 39% were not concerned about routinization leading to increased pressure to terminate a pregnancy of a fetus with Down Syndrome. Regarding other social concerns possibly resulting from routinization, pregnant women were most concerned regarding a reduction in resources available for people with Down Syndrome and their families and least concerned regarding a decrease in the population of people with Down Syndrome. CONCLUSIONS: Our findings reflect the concerns expressed by pregnant women and their partners, both personal (pressure to test, pressure to terminate) and societal (e.g., regarding potential negative impact on people with disabilities and their families). Even if most women were not concerned about feeling pressured to test due to NIPT routinization, a large minority express concerns that should not be taken lightly. Moreover, a majority of respondents were concerned regarding pressure to terminate pregnancies due to NIPT routinization as well as regarding most societal impacts they were queried on, especially the possible future reduction in resources available for people with DS and their families. Canadian policy-makers should consider these potential negative ramifications of NIPT and ensure that appropriate social policies accompany its implementation.

Variants in LSM7 impair LSM complexes assembly, neurodevelopment in zebrafish and may be associated with an ultra-rare neurological disease.

Leukodystrophies, genetic neurodevelopmental and/or neurodegenerative disorders of cerebral white matter, result from impaired myelin homeostasis and metabolism. Numerous genes have been implicated in these heterogeneous disorders; however, many individuals remain without a molecular diagnosis. Using whole-exome sequencing, biallelic variants in LSM7 were uncovered in two unrelated individuals, one with a leukodystrophy and the other who died in utero. LSM7 is part of the two principle LSM protein complexes in eukaryotes, namely LSM1-7 and LSM2-8. Here, we investigate the molecular and functional outcomes of these LSM7 biallelic variants in vitro and in vivo. Affinity purification-mass spectrometry of the LSM7 variants showed defects in the assembly of both LSM complexes. Lsm7 knockdown in zebrafish led to central nervous system defects, including impaired oligodendrocyte development and motor behavior. Our findings demonstrate that variants in LSM7 cause misassembly of the LSM complexes, impair neurodevelopment of the zebrafish, and may be implicated in human disease. The identification of more affected individuals is needed before the molecular mechanisms of mRNA decay and splicing regulation are added to the categories of biological dysfunctions implicated in leukodystrophies, neurodevelopmental and/or neurodegenerative diseases.