Clinical validity of phenotype-driven analysis software PhenoVar as a diagnostic aid for clinical geneticists in the interpretation of whole-exome sequencing data.

PURPOSE: We sought to determine the diagnostic yield of whole-exome sequencing (WES) combined with phenotype-driven analysis of variants in patients with suspected genetic disorders. METHODS: WES was performed on a cohort of 51 patients presenting dysmorphisms with or without neurodevelopmental disorders of undetermined etiology. For each patient, a clinical geneticist reviewed the phenotypes and used the phenotype-driven analysis software PhenoVar (http://phenovar.med.usherbrooke.ca/) to analyze WES variants. The prioritized list of potential diagnoses returned was reviewed by the clinical geneticist, who selected candidate variants to be confirmed by segregation analysis. Conventional analysis of the individual variants was performed in parallel. The resulting candidate variants were subsequently reviewed by the same geneticist, to identify any additional potential diagnoses. RESULTS: A molecular diagnosis was identified in 35% of the patients using the conventional analysis, and 17 of these 18 diagnoses were independently identified using PhenoVar. The only diagnosis initially missed by PhenoVar was rescued when the optional "minimal phenotypic cutoff" filter was omitted. PhenoVar reduced by half the number of potential diagnoses per patient compared with the conventional analysis. CONCLUSION: Phenotype-driven software prioritizes WES variants, provides an efficient diagnostic aid to clinical geneticists and laboratories, and should be incorporated in clinical practice.

No. 363-Investigation and Management of Non-immune Fetal Hydrops.

OBJECTIVE: To describe the current investigation and management of non-immune fetal hydrops with a focus on treatable or recurring etiologies. OUTCOMES: To provide better counselling and management in cases of prenatally diagnosed non-immune hydrops. EVIDENCE: Published literature was retrieved through searches of PubMed or MEDLINE, CINAHL, and The Cochrane Library in 2017 using key words (non-immune hydrops fetalis, fetal hydrops, fetal therapy, fetal metabolism). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, observational studies, and significant case reports. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Searches were updated on a regular basis and incorporated in the guideline to September 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinicalpractice guideline collections, clinical trial registries, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: These guidelines educate readers about the causes of non-immune fetal hydrops and its prenatal counselling and management. It also provides a standardized approach to non-immune fetal hydrops, emphasizing the search for prenatally treatable conditions and recurrent genetic etiologies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care.

N° 363 - Évaluation et prise en charge de l'anasarque fœtoplacentaire non immune.

OBJECTIF: Décrire les méthodes actuelles d'évaluation et de prise en charge de l'anasarque fœtoplacentaire non immune en mettant l'accent sur les étiologies traitables ou récurrentes. RéSULTATS: Offrir de meilleurs services de conseil et de prise en charge en cas d'anasarque fœtoplacentaire non immune diagnostiquée en période prénatale. DONNéES: La littérature publiée a été récupérée au moyen de recherches menées dans PubMed, MEDLINE, CINAHL, et la Bibliothèque Cochrane en 2017 à l'aide de mots-clés (« non-immune hydrops fetalis ¼, « fetal hydrops ¼, « fetal therapy ¼, « fetal metabolism ¼). Les articles retenus portaient sur des revues systématiques, des essais cliniques contrôlés, randomisés ou non, des études observationnelles et des études de cas importantes. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Les recherches ont été mis à jour régulièrement, et les résultats ont été incorporés à la directive clinique jusqu'en septembre 2017. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, INCONVéNIENTS ET COûTS: La présente directive clinique renseigne les lecteurs sur les causes de l'anasarque fœtoplacentaire non immune ainsi que sur son évaluation et sa prise en charge. Elle propose également une approche standardisée d'évaluation et de prise en charge, et met l'accent sur la recherche des conditions traitables en période prénatale et des étiologies génétiques récurrentes. VALEURS: La qualité des données probantes a été évaluée en fonction des critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. RECOMMANDATIONS.

No. 365-Fetal and Perinatal Autopsy in Prenatally Diagnosed Fetal Abnormalities with Normal Chromosome Analysis.

OBJECTIVE: To review the information on fetal and perinatal autopsies, the process of obtaining consent, and the alternative information-gathering options following a prenatal diagnosis of non-chromosomal anomalies in order to assist health care providers in providing postnatal counselling regarding diagnosis and potential recurrence risks. OUTCOMES: To provide better counselling about fetal and perinatal autopsies for women and families who are dealing with a prenatally diagnosed non-chromosomal fetal anomaly. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2010, 2011, and 2017, using appropriate key words (fetal autopsy postmortem, autopsy, perinatal postmortem examination, autopsy protocol, postmortem magnetic resonance imaging, autopsy consent, tissue retention, autopsy evaluation). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: This update educates readers about (1) the benefits of a fetal perinatal autopsy, (2) the consent process, and (3) the alternatives when the family declines autopsy. It also highlights the need for a standardized approach to fetal and perinatal autopsies, emphasizing pertinent additional sampling when indicated. The authors recognize that there is variability across Canada in access to the cited services and resources. As such, these recommendations were developed in an attempt to promote access and to provide a minimum standard for all provinces and territories across the country. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table).

N° 365 -Autopsies fœtales et périnatales en cas d'anomalies fœtales diagnostiquées avant la naissance avec une analyse chromosomique normale.

OBJECTIF: Examiner les données sur les autopsies fœtales et périnatales, le processus de consentement et les options de collecte de renseignements à la suite d'un diagnostic prénatal d'anomalies non chromosomiques afin d'aider les fournisseurs de soins à offrir du conseil postnatal au sujet du diagnostic et des éventuels risques de récurrence. RéSULTATS: Offrir de meilleurs conseils sur les autopsies fœtales et périnatales aux femmes et aux familles qui ont reçu un diagnostic prénatal d'anomalie fœtale non chromosomique. ÉVIDENCE: Nous avons examiné des études publiées récupérées au moyen de recherches dans PubMed, Medline, CINAHL et la Bibliothèque Cochrane en 2010, en 2011 et en 2017 à l'aide de mots-clés appropriés (« fetal autopsy postmortem ¼, « autopsy ¼, « perinatal postmortem examination ¼, « autopsy protocol ¼, « postmortem magnetic resonance imaging ¼, « autopsy consent ¼, « tissue retention ¼ et « autopsy evaluation ¼). Nous n'avons tenu compte que des résultats provenant de revues systématiques, d'essais cliniques, randomisés ou non, et d'études observationnelles. D'autres publications ont été repérées dans les bibliographies de ces articles. Aucune restriction de date ou de langue n'a été employée. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et dans des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. AVANTAGES, DéSAVANTAGES ET COUTS: La présente mise à jour renseigne les lecteurs sur : 1) les avantages de l'autopsie fœtale ou périnatale; 2) le processus de consentement; et 3) les autres options offertes aux familles qui refusent l'autopsie. Elle met également en évidence la nécessité d'adopter une démarche normalisée pour la réalisation des autopsies fœtales et périnatales, et met l'accent sur les prélèvements additionnels qui peuvent être pertinents. Les auteurs sont conscients que l'accès aux ressources et aux services mentionnés varie d'un endroit l'autre au Canada; les recommandations formulées ont donc pour but de promouvoir l'accès et de fournir une norme minimale aux provinces et aux territoires du pays. VALEURS: La qualité des données a été évaluée au moyen des critères énoncés dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs (tableau). RECOMMANDATIONS.

Loss-of-function de novo mutations play an important role in severe human neural tube defects.

BACKGROUND: Neural tube defects (NTDs) are very common and severe birth defects that are caused by failure of neural tube closure and that have a complex aetiology. Anencephaly and spina bifida are severe NTDs that affect reproductive fitness and suggest a role for de novo mutations (DNMs) in their aetiology. METHODS: We used whole-exome sequencing in 43 sporadic cases affected with myelomeningocele or anencephaly and their unaffected parents to identify DNMs in their exomes. RESULTS: We identified 42 coding DNMs in 25 cases, of which 6 were loss of function (LoF) showing a higher rate of LoF DNM in our cohort compared with control cohorts. Notably, we identified two protein-truncating DNMs in two independent cases in SHROOM3, previously associated with NTDs only in animal models. We have demonstrated a significant enrichment of LoF DNMs in this gene in NTDs compared with the gene specific DNM rate and to the DNM rate estimated from control cohorts. We also identified one nonsense DNM in PAX3 and two potentially causative missense DNMs in GRHL3 and PTPRS. CONCLUSIONS: Our study demonstrates an important role of LoF DNMs in the development of NTDs and strongly implicates SHROOM3 in its aetiology.

Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population.

Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.

Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome.

Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole-exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.

Mutations in TMEM231 cause Joubert syndrome in French Canadians.

BACKGROUND: Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French-Canadian (FC) individuals. METHODS AND RESULTS: Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c.12T>A[p.Tyr4*]; c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors. CONCLUSIONS: Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.

RETIRED: Investigation and management of non-immune fetal hydrops.

This document has been archived because it contains outdated information. It should not be consulted for clinical use, but for historical research only. Please visit the journal website for the most recent guidelines.

Ce document a été archivé, car il contient des informations périmées. Il ne devrait pas être consulté pour un usage clinique, mais uniquement pour des recherches historiques. Veuillez consulter le site web du journal pour les directives les plus récentes.

Quality of Narratives in Assessment: Piloting a List of Evidence-Based Quality Indicators.

Background & Need for Innovation: Appraising the quality of narratives used in assessment is challenging for educators and administrators. Although some quality indicators for writing narratives exist in the literature, they remain context specific and not always sufficiently operational to be easily used. Creating a tool that gathers applicable quality indicators and ensuring its standardized use would equip assessors to appraise the quality of narratives. Steps taken for Development and Implementation of innovation: We used DeVellis' framework to develop a checklist of evidence-informed indicators for quality narratives. Two team members independently piloted the checklist using four series of narratives coming from three different sources. After each series, team members documented their agreement and achieved a consensus. We calculated frequencies of occurrence for each quality indicator as well as the interrater agreement to assess the standardized application of the checklist. Outcomes of Innovation: We identified seven quality indicators and applied them on narratives. Frequencies of quality indicators ranged from 0% to 100%. Interrater agreement ranged from 88.7% to 100% for the four series. Critical Reflection: Although we were able to achieve a standardized application of a list of quality indicators for narratives used in health sciences education, it does not exclude the fact that users would need training to be able to write good quality narratives. We also noted that some quality indicators were less frequent than others and we suggested a few reflections on this.

Assessing commitment to reflection: perceptions of medical students.

Background: While developing reflection skills is considered important by educators, the assessment of these skills is often associated with unintended negative consequences. In the context of a mandatory longitudinal course that aims to promote the development of reflection on professional identity, we assessed students' commitment to reflection. This study explores students' perception of this assessment by their mentor. Methods: We conducted a qualitative descriptive study using semi-structured interviews with twenty-one 1st and six 2nd year medical students. Thematic analysis was informed by Braun and Clarke's six-step approach. Results: We identified four main themes: 1- assessment as a motivator, 2- consequences on authenticity, 3- perception of inherent subjectivity, and 4 - relationship with the mentor. Conclusions: In the context of assessing reflection skills in future physicians, we observed that students -when assessed on the process of reflection- experienced high motivation but were ambivalent on the question of authenticity. The subjectivity of the assessment as well as the relationship with their mentor also raises questions. Nevertheless, this assessment approach for reflective skills appears to be promising in terms of limiting the negative consequences of assessment.

Contexte: Malgré l'importance que les éducateurs attribuent à l'acquisition de compétences de réflexion, l'évaluation de ces compétences entraîne souvent des conséquences négatives involontaires. Dans le cadre d'un cours longitudinal obligatoire visant à promouvoir le développement de la réflexion sur l'identité professionnelle, nous avons évalué l'engagement des étudiants à cultiver leurs compétences de réflexion. Cette étude explore leur perception de cette évaluation menée par leur mentor. Méthodes: Nous avons réalisé une étude qualitative descriptive à l'aide d'entretiens semi-structurés avec vingt-et-un étudiants en médecine de première année et six étudiants en médecine de deuxième année. Notre analyse thématique repose sur l'approche en six étapes de Braun et Clarke. Résultats: Nous avons identifié quatre thèmes principaux : 1 ­ l'évaluation comme facteur de motivation, 2 ­ les conséquences sur l'authenticité, 3 ­ la perception de la subjectivité inhérente, et 4 ­ la relation avec le mentor. Conclusions: Dans le contexte de l'évaluation des compétences de réflexion des futurs médecins, focalisée plus particulièrement sur le processus de réflexion, les étudiants se sont montrés très motivés, mais incertains quant à son authenticité. La subjectivité de l'évaluation et la relation avec leur mentor soulèvent également des interrogations. Néanmoins, cette approche d'évaluation des compétences réflexives semble prometteuse dans la mesure où elle permet de limiter les conséquences négatives de l'évaluation.

Reflecting on professional identity in undergraduate medical education: implementation of a novel longitudinal course.

BACKGROUND: Today's healthcare professionals face numerous challenges. Improving reflection skills has the potential to contribute to the better management of complex patients and healthcare systems, as well as to improve professional practice. However, the question of how reflection skills can inform professional identity development at the undergraduate medical education level remains unanswered. APPROACH: The authors developed and implemented a 4-year course that aims to engage students in a reflective process to increase their awareness of their professional identity development. The course is structured around three types of pedagogical activities: workshops, reflections deposited in an electronic portfolio, and individual discussions with mentors. EVALUATION: Sixty-four 1st year students (33%) and 17 mentors (50%) from the 2017-2018 cohort completed evaluation questionnaires. For the 2018-2019 academic year, 73 1st year students (34%) and 27 2nd year students (14%), as well as 20 1st year (59%) and 19 2nd year mentors (57%) replied. Students and mentors considered that the pedagogical activities contributed to the development of students' professional identity through the acquisition of reflection skills, but some elements were perceived as challenging, notably, completing the portfolio, finding a subject to reflect about and the timing of the proposed activities. REFLECTION: An important preoccupation when wanting to foster the development of professional identity through the acquisition of reflection skills is the authenticity of students' reflection. We tried to favor authentic reflection, by having a mentee-mentor pair throughout the entire 4­year course. A rigorous evaluation process helped us identify and promptly correct issues as they surfaced.

Narrative Assessments in Higher Education: A Scoping Review to Identify Evidence-Based Quality Indicators.

PURPOSE: Narrative comments are increasingly used in assessment to document trainees' performance and to make important decisions about academic progress. However, little is known about how to document the quality of narrative comments, since traditional psychometric analysis cannot be applied. The authors aimed to generate a list of quality indicators for narrative comments, to identify recommendations for writing high-quality narrative comments, and to document factors that influence the quality of narrative comments used in assessments in higher education. METHOD: The authors conducted a scoping review according to Arksey & O'Malley's framework. The search strategy yielded 690 articles from 6 databases. Team members screened abstracts for inclusion and exclusion, then extracted numerical and qualitative data based on predetermined categories. Numerical data were used for descriptive analysis. The authors completed the thematic analysis of qualitative data with iterative discussions until they achieved consensus for the interpretation of the results. RESULTS: After the full-text review of 213 selected articles, 47 were included. Through the thematic analysis, the authors identified 7 quality indicators, 12 recommendations for writing quality narratives, and 3 factors that influence the quality of narrative comments used in assessment. The 7 quality indicators are (1) describes performance with a focus on particular elements (attitudes, knowledge, skills); (2) provides a balanced message between positive elements and elements needing improvement; (3) provides recommendations to learners on how to improve their performance; (4) compares the observed performance with an expected standard of performance; (5) provides justification for the mark/score given; (6) uses language that is clear and easily understood; and (7) uses a nonjudgmental style. CONCLUSIONS: Assessors can use these quality indicators and recommendations to write high-quality narrative comments, thus reinforcing the appropriate documentation of trainees' performance, facilitating solid decision making about trainees' progression, and enhancing the impact of narrative feedback for both learners and programs.

Archivée: Exploration et prise en charge de l'anasarque fœtoplacentaire non immune.

Ce document a été archivé, car il contient des informations périmées. Il ne devrait pas être consulté pour un usage clinique, mais uniquement pour des recherches historiques. Veuillez consulter le site web du journal pour les directives les plus récentes.

Fetal and perinatal autopsy in prenatally diagnosed fetal abnormalities with normal karyotype.

OBJECTIVE: To review the information on fetal and perinatal autopsies, the process of obtaining consent, and the alternative information-gathering options following a prenatal diagnosis of non-chromosomal malformations, and to assist clinicians in providing postnatal counselling regarding fetal diagnosis and recurrence risks. OUTCOMES: To provide better counselling about fetal and perinatal autopsies for women and families who are dealing with a prenatally diagnosed non-chromosomal fetal anomaly. EVIDENCE: Published literature was retrieved through searches of PubMed or Medline, CINAHL, and The Cochrane Library in 2009 and 2010, using appropriate key words (fetal autopsy, postmortem, autopsy, perinatal postmortem examination, autopsy protocol, postmortem magnetic resonance imaging, autopsy consent, tissue retention, autopsy evaluation). Results were restricted to systematic reviews, randomized controlled trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. There were no date or language restrictions. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. BENEFITS, HARMS, AND COSTS: This update educates readers about (1) the benefits of a fetal perinatal autopsy, (2) the consent process, and (3) the alternatives when the family declines autopsy. It also provides a standardized approach to fetal and perinatal autopsies, emphasizing pertinent additional sampling when indicated. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). Recommendations 1. Standard autopsy should ideally be an essential part of fully investigating fetal loss, stillbirths, and neonatal deaths associated with non-chromosomal fetal malformations. (II-3A) 2. Clinicians and health care providers approaching parents for autopsy consent should discuss the options for a full, limited, or step-wise postmortem examination; the issue of retained fetal tissues; and the value of autopsy and the possibility that the information gained may not benefit them but may be of benefit to others. This information should be provided while respecting the personal and cultural values of the families. (III-A) 3. If parents are unwilling to give consent for a full autopsy, alternatives to full autopsy that provide additional clinical information must be presented in a manner that includes disclosure of limitations. (III-A) 4. External physical examination, medical photographs, and standard radiographic or computed tomography should be offered in all cases of fetal anomaly(ies) of non-chromosomal etiology. (II-2A) 5. Well-designed, large prospective studies are needed to evaluate the accuracy of postmortem magnetic resonance imaging. It cannot function as a substitute for standard full autopsy. (III-A) 6. The fetal and perinatal autopsies should be performed by trained perinatal or pediatric pathologists. (II-2A) 7. The need for additional sampling is guided by the results of previous prenatal and/or genetic investigations, as well as the type of anomalies identified in the fetus. Fibroblast cultures may allow future laboratory studies, particularly in the absence of previous karyotyping or if a biochemical disorder is suspected, and DNA analysis. (II-3A) 8. In cases requiring special evaluation, the most responsible health care provider should have direct communication with the fetopathologist to ensure that all necessary sampling is performed in a timely manner. (II-3A) 9. The most responsible health care providers must see the families in follow-up to share autopsy findings, plan for the management of future pregnancies, obtain consent for additional testing, and offer genetic counselling to other family members when appropriate. (III-A).

Preimplantation genetic testing.

OBJECTIVE: To review the techniques and indications of preimplantation genetic testing, including preimplantation genetic diagnosis and screening. OPTIONS: Limited to an introductory discussion about the genetic aspects of preimplantation reproductive techniques. OUTCOMES: This update does not discuss in detail the adverse outcomes that have been recorded in association with assisted reproductive technologies. EVIDENCE: The Cochrane Library and Medline were searched for articles relating to preimplantation testing that were published from 1990 to February 2008, using the following terms: preimplantation genetic diagnosis, preimplantation genetic screening, and in vitro fertilization. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies. VALUES: This update is a consensus of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: This update educates readers about new genetic concepts, directions, and technology. The major harms and costs identified are those of assisted reproductive technologies. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. CONCLUSIONS: Preimplantation genetic diagnosis is an alternative to prenatal diagnosis for the detection of genetic disorders in couples at risk of transmitting a genetic condition to their offspring. Preimplantation genetic screening has been proposed to improve the effectiveness of in vitro fertilization in women of advanced maternal age or in couples with recurrent miscarriage or implantation failure, but the benefits of this approach are debated. RECOMMENDATIONS: The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. 1. Before preimplantation genetic diagnosis is performed, genetic counselling must be provided to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis. (III-A) 2. Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell. (II-2B) 3. Invasive prenatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false negative result. (II-2B) 4. Before preimplantation genetic screening is performed, thorough education and counselling must be provided to ensure that patients fully understand the limitations of the technique, the risk of error, and the lack of evidence that preimplantation genetic screening improves live-birth rates. (III-A) 5. Available evidence does not support the use of preimplantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss. (I-D).

Caudal dysgenesis, sirenomelia, and situs inversus totalis: a primitive defect in blastogenesis.

Caudal dysgenesis (CD) constitutes a heterogeneous spectrum of congenital caudal anomalies, including varying degrees of agenesis of the vertebral column, as well as anorectal and genitourinary anomalies. Sirenomelia, characterized by a fusion of the lower limbs, could represent the most severe end of this spectrum. The two main debated pathogenic hypotheses are an aberrant vascular supply versus a primary axial mesoderm defect. We present the autopsy findings of two fetuses of non-diabetic mothers, with normal karyotype. Both fetuses presented situs inversus associated with a CD, in one case consisting of sirenomelia, establishing a very rare association profile that might be random. This association also suggests the occurrence of a common pathogenic mechanism, in accordance to recent genetic data, such as displayed in the Kif3A murine mutation phenotype. Some cases of sirenomelia and CD could represent developmental field defects of blastogenesis involving the caudal mesoderm, rather than being related to vascular insufficiency.

New molecular techniques for the prenatal detection of chromosomal aneuploidy.

OBJECTIVE: To review the molecular genetic techniques currently available for rapid prenatal diagnosis of fetal aneuploidy, as well as those still under investigation. OPTIONS: Limited to introductory discussion of rapid aneuploidy detection methods. EVIDENCE: Medline was searched for articles related to the topic that were published after 1992. This document represents an abstraction of the information. VALUES: This update was prepared by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada approved by the Executive and Council of the Society of Obstetricians and Gynaecologists of Canada. BENEFITS, HARMS, AND COSTS: This update provides information about methods of rapid aneuploidy detection using molecular techniques and the evidence supporting their use in prenatal diagnosis. These methods are reliable and cost-effective for detecting the targeted fetal aneuploidies, but are limited in their ability to detect non-aneuploid chromosome abnormalities, some of which are clinically significant.