The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of ...genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals.
Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada.
Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.
Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum ...levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization.
Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of 125ITH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.
The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells.
We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction.
Deep learning algorithms have demonstrated remarkable potential in clinical diagnostics, particularly in the field of medical imaging. In this study, we investigated the application of deep learning ...models in early detection of fetal kidney anomalies. To provide an enhanced interpretation of those models' predictions, we proposed an adapted two-class representation and developed a multi-class model interpretation approach for problems with more than two labels and variable hierarchical grouping of labels. Additionally, we employed the explainable AI (XAI) visualization tools Grad-CAM and HiResCAM, to gain insights into model predictions and identify reasons for misclassifications. The study dataset consisted of 969 ultrasound images from unique patients; 646 control images and 323 cases of kidney anomalies, including 259 cases of unilateral urinary tract dilation and 64 cases of unilateral multicystic dysplastic kidney. The best performing model achieved a cross-validated area under the ROC curve of 91.28% ± 0.52%, with an overall accuracy of 84.03% ± 0.76%, sensitivity of 77.39% ± 1.99%, and specificity of 87.35% ± 1.28%. Our findings emphasize the potential of deep learning models in predicting kidney anomalies from limited prenatal ultrasound imagery. The proposed adaptations in model representation and interpretation represent a novel solution to multi-class prediction problems.
Genetic diagnosis provides important information for prenatal decision-making and management. Promising results from exome sequencing (ES) for genetic diagnosis in fetuses with structural anomalies ...are emerging. The objective of this scoping review was to identify what is known about the use of ES for genetic testing in prenatal cases with known or suspected genetic disease. A rapid scoping review was conducted over a six-week timeframe of English-language peer-reviewed studies. Search strategies for major databases (e.g., Medline) and gray literature were developed, and peer reviewed by information specialists. Identified studies were categorized and charted using tables and diagrams. Twenty-four publications were included from seven countries published between 2014 and 2019. Most commonly reported outcomes were diagnostic yields, which varied widely from 5% to 57%, and prenatal phenotype. Few studies reported clinical outcomes related to impact, decision-making, and clinical utility. Qualitative studies (n = 6) provided useful insights into patient and health-care provider experiences with ES. Findings suggest prenatal ES is beneficial, but more research is needed to better understand the clinical utility, circumstances for ideal use, feasibility, and costs of offering rapid ES as a routine option for prenatal genetic testing.
The purpose of the current study was to assess the penetrance of NRXN1 deletions.
We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to ...that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions.
We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91–22.72; P < 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3ʹ end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5ʹ NRXN1 deletion (OR = 7.47; 95% CI: 2.36–23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035).
The results support the importance of exons near the 5ʹ end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.
Cell-free fetal DNA screening is routinely offered to pregnant individuals to screen for aneuploidies. Although cell-free DNA screening is consistently more accurate than multiple-marker screening, ...it sometimes fails to yield a result. These test failures and their clinical implications are poorly described in the literature. Some studies suggest that a failed cell-free DNA screening result is associated with increased likelihood of cytogenetic abnormalities.
This study aimed to assess the association between a failed cell-free DNA test and common aneuploidies. The objectives were to determine: (1) the proportion of test failures on first and subsequent attempts, and (2) whether a failed cell-free DNA screen on first attempt is associated with increased likelihood of common aneuploidies (trisomies 21, 18, and 13, and sex chromosome aneuploidies).
This was a population-based retrospective cohort study using data from Ontario’s prescribed maternal and child registry, Better Outcomes Registry and Network Ontario. The study included all singleton pregnancies in Ontario with an estimated date of delivery from September 1, 2016 to March 31, 2019 that had a cell-free DNA screening record in the registry. Specific outcomes (trisomies 21, 18, and 13, and sex chromosome aneuploidies) of pregnancies with a failed cell-free DNA screen on first attempt were compared with those of pregnancies with low-risk cell-free DNA-screening results using modified Poisson regression adjusted for funding status (publicly funded vs self-paid), gestational age at screening, method of conception, and maternal age for autosomal aneuploidies.
Our cohort included 35,146 pregnancies that had cell-free DNA screening during the study period. The overall cell-free DNA screening failure rate was 4.8% on first attempt and 2.2% after multiple attempts. An abnormal cytogenetic result for trisomies 21, 18, and 13, or sex chromosome aneuploidies was identified in 19.4% of pregnancies with a failed cell-free DNA screening for which cytogenetic testing was performed. Pregnancies with a failed cell-free DNA screen on first attempt had a relative risk of 130.3 (95% confidence interval, 64.7–262.6) for trisomy 21, trisomy 18, or trisomy 13, and a risk difference of 5.4% (95% confidence interval, 2.6–8.3), compared with pregnancies with a low-risk result. The risk of sex chromosome aneuploidies was not significantly greater in pregnancies with a failed result compared with pregnancies with a low-risk result (relative risk, 2.7; 95% confidence interval, 0.9–7.9; relative difference, 1.2%; 95% confidence interval, −0.9 to 3.2).
Cell-free DNA screening test failures are relatively common. Although repeated testing improves the likelihood of an informative result, pregnancies with a failed cell-free DNA screen upon first attempt remain at increased risk for common autosomal aneuploidies, but not sex chromosome aneuploidies.
Nontruncating sequence variants represent a major challenge in variant interpretation and classification. Here, we report a patient with features of Kabuki syndrome who carries two rare heterozygous ...variants in KMT2D: c.12935C>T, p.(Ser4312Phe) and c.15785‐10T>G. The clinical significance of these variants were discordantly interpreted by different diagnostic laboratories. Parental testing showed that the missense variant was inherited from the father with a mild Kabuki phenotype and the intronic variant from the mother with mosaic status. Through genome‐wide DNA methylation analysis of peripheral blood, we confirmed that the proband exhibited a previously described episignature of Kabuki syndrome. Parental samples had normal DNA methylation profiles, thus ruling out the involvement of the paternally inherited missense variant. RNA analysis revealed that the intronic change resulted in exon 49 skipping and frameshift, thereby providing a molecular diagnosis of Kabuki syndrome. This study demonstrates the utility of epigenomic and RNA analyses in resolving ambiguous clinical cases.
The transformative power of artificial intelligence (AI) is reshaping diverse domains of medicine. Recent progress, catalyzed by computing advancements, has seen commensurate adoption of AI ...technologies within obstetrics and gynaecology. We explore the use and potential of AI in three focus areas: predictive modelling for pregnancy complications, Deep learning-based image interpretation for precise diagnoses, and large language models enabling intelligent health care assistants. We also provide recommendations for the ethical implementation, governance of AI, and promote research into AI explainability, which are crucial for responsible AI integration and deployment. AI promises a revolutionary era of personalized health care in obstetrics and gynaecology.
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