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Objectives To determine etiologies and outcomes of fetal hyperechogenic kidneys (HEK). Methods We conducted a retrospective chart review of HEK in British Columbia (January 2013-December 2019) and literature review. Results We identified 20 cases of HEK without other anomalies (isolated) in our provincial cohort, one was lost to follow-up. Eight had testable genetic etiologies (autosomal dominant polycystic kidney disease [ADPKD], autosomal recessive polycystic kidney disease [ARPKD], Bardet-Biedl syndrome [BBS], and HNF1B-related disorder). The remaining seven did not have an identifiable genetic etiology. Of cases without a genetic etiology with postnatal follow-up (n = 6) there were no abnormalities of blood pressure, creatinine/estimated glomerular filtration rate or urinalysis identified with follow-up from 2-71 months. We report 11 cases with extrarenal anomalies (nonisolated), with outcomes and etiologies. We identified 224 reported cases of isolated HEK in the literature. A potentially testable genetic etiology was found in 128/224 (57.1%). The neonatal death rate in those with testable etiologies was 17/128 (13.3%) compared to 2/96 (2.1%) when testable etiologies were excluded. Conclusions Genetic etiologies (ARPKD, ADPKD, BBS, HNF1B-related disorder, Beckwith-Wiedemann syndrome, tubular dysgenesis, familial nephroblastoma, and cytogenetic abnormalities) account for approximately half of prenatally isolated HEK; once excluded there are few neonatal deaths and short-term renal outcomes may be normal. There remains a paucity of knowledge about long-term renal outcomes.

Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.

White matter lesions have been described in patients with PTEN hamartoma tumor syndrome (PHTS). How these lesions correlate with the neurocognitive features associated with PTEN mutations, such as autism spectrum disorder (ASD) or developmental delay, has not been well established. We report nine patients with PTEN mutations and white matter changes on brain magnetic resonance imaging (MRI), eight of whom were referred for reasons other than developmental delay or ASD. Their clinical presentations ranged from asymptomatic macrocephaly with normal development/intellect, to obsessive compulsive disorder, and debilitating neurological disease. To our knowledge, this report constitutes the first detailed description of PTEN-related white matter changes in adult patients and in children with normal development and intelligence. We present a detailed assessment of the neuropsychological phenotype of our patients and discuss the relationship between the wide array of neuropsychiatric features and observed white matter findings in the context of these individuals.

Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad.

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

This review highlights how skeletal dysplasias are diagnosed and how our understanding of some of these conditions has now translated to treatment options. The use of multigene panels, using next-generation sequence technology, has improved our ability to quickly identify the genetic etiology, which can impact management. There are successes with the use of growth hormone in individuals with SHOX deficiencies, asfotase alfa in hypophosphatasia, and some promising data for c-type natriuretic peptide for those with achondroplasia. One needs to consider that a patient with short stature has a skeletal dysplasia as options for management may be available.

Key Clinical Message Thanatophoric dysplasia is typically a neonatal lethal condition. However, for those rare individuals who do survive, there is the development of seizures, progression of craniocervical stenosis, ventilator dependence, and limitations in motor and cognitive abilities. Families must be made aware of these issues during the discussion of management plans.

Background: Rare diseases often present in the first days and weeks of life and may require complex management in the setting of a neonatal intensive care unit (NICU). Exhaustive consultations and traditional genetic or metabolic investigations are costly and often fail to arrive at a final diagnosis when no recognizable syndrome is suspected. For this pilot project, we assessed the feasibility of next-generation sequencing as a tool to improve the diagnosis of rare diseases in newborns in the NICU. Methods: We retrospectively identified and prospectively recruited newborns and infants admitted to the NICU of the Children’s Hospital of Eastern Ontario and the Ottawa Hospital, General Campus, who had been referred to the medical genetics or metabolics inpatient consult service and had features suggesting an underlying genetic or metabolic condition. DNA from the newborns and parents was enriched for a panel of clinically relevant genes and sequenced on a MiSeq sequencing platform (Illumina Inc.). The data were interpreted with a standard informatics pipeline and reported to care providers, who assessed the importance of genotype–phenotype correlations. Results: Of 20 newborns studied, 8 received a diagnosis on the basis of next-generation sequencing (diagnostic rate 40%). The diagnoses were renal tubular dysgenesis, SCN1A-related encephalopathy syndrome, myotubular myopathy, FTO deficiency syndrome, cranioectodermal dysplasia, congenital myasthenic syndrome, autosomal dominant intellectual disability syndrome type 7 and Denys–Drash syndrome. Interpretation: This pilot study highlighted the potential of next-generation sequencing to deliver molecular diagnoses rapidly with a high success rate. With broader use, this approach has the potential to alter health care delivery in the NICU.

Meconium ileus is most often associated with mutations in the CFTR gene; however recently, mutations in GUCY2C in the Bedouin population have also been shown to result in this phenotype. This gene codes for an intestinal transmembrane receptor that generates cyclic GMP, which activates cystic fibrosis transmembrane receptor. We report a third family that supports the association of variants in the GUCY2C gene with meconium ileus (MI). A Lebanese kindred was studied and individuals affected with MI had either homozygous or compound heterozygous variants in GUCY2C. The earliest manifestation of the affected individuals was the presence of second trimester fetal echogenic bowel, thus resulting in the expansion of the differential diagnosis of this ultrasound finding.

Resume Objectif Offrir, aux medecins, aux sages-femmes, aux conseillers genetiques et aux chercheurs cliniques oeuvrant dans le domaine des soins preconceptionnels ou prenatals, des recommandations au sujet du depistage des porteurs de thalassemie et d'hemoglobinopathies (p. ex. drepanocytose et autres troubles qualitatifs de l'hemoglobine). Issues Determiner les populations a depister et les tests qu'il est approprie d'offrir, en vue de minimiser les variations de pratique au Canada. Resultats Des recherches ont ete menees dans la base de donnees Medline afin d'en tirer les articles pertinents, publies entre 1986 et 2007, portant sur le depistage des porteurs de thalassemie et d'hemoglobinopathies. Les manuels cles ont egalement ete examines. Les recommandations ont ete quantifiees au moyen des lignes directrices sur l'evaluation des resultats elaborees par le Groupe d'etude canadien sur les soins de sante preventifs. Valeurs Les donnees tirees des recherches menees dans Medline ont ete analysees par le comite sur la genetique de la Societe des obstetriciens et gynecologues du Canada (SOGC) et le comite de diagnostic prenatal du College canadien des geneticiens medicaux (CCGM). Avantages, desavantages et couts Le depistage des personnes courant un risque accru d'etre des porteurs de thalassemie et d'hemoglobinopathies peut identifier les couples qui courent un risque de l'ordre de 25 % de connaitre une grossesse presentant un trouble genetique significatif pour lequel l'etablissement d'un diagnostic prenatal est possible. Idealement, le depistage devrait etre effectue avant la conception. Cependant, pour une proportion importante de patientes, le depistage se deroulera au cours de la grossesse et les contraintes de temps associees a l'obtention des resultats du depistage peuvent donner lieu a de la detresse psychologique. La presente directive clinique ne comporte pas d'analyse de la rentabilite. Recommandations 1.Le depistage des porteurs de thalassemie et d'hemoglobinopathies devrait etre offert aux femmes lorsqu'elles et/ou leurs partenaires sont identifies comme appartenant a une population ethnique dont les membres courent un risque accru d'etre porteurs. Idealement, ce depistage devrait etre effectue avant la conception ou encore des que possible au cours de la grossesse. (II-2A) 2.Le depistage devrait etre compose d'un hemogramme, ainsi que d'une electrophorese de l'hemoglobine ou d'une chromatographie liquide a haute performance de l'hemoglobine. Cette exploration devrait comprendre une analyse quantitative de l'HbA2 et de l'HbF. De plus, lorsque l'on constate une microcytose (volume cellulaire moyen 3.Lorsque le depistage initial d'une patiente est anormal (p. ex. il revele la presence d'une microcytose ou d'une hypochromie avec ou sans hausse du taux d'HbA2, ou encore celle d'une variante de l'Hb a la suite d'une electrophorese ou d'une chromatographie liquide a haute performance), il faudrait egalement proceder au depistage de son partenaire. Ce depistage devrait comprendre un hemogramme, ainsi qu'une HPLC ou une electrophorese de l'hemoglobine, une analyse quantitative de l'HbA2 et de l'HbF, et une coloration des corps de Heinz. (III-A) 4.Lorsque l'on constate que les deux partenaires sont porteurs de thalassemie ou d'une variante Hb (ou d'une combinaison de thalassemie et d'une variante de l'hemoglobine), ceux-ci doivent etre orientes vers des services de counseling genetique, idealement au cours de la periode preconception ou le plus tot possible au cours de la grossesse. Des etudes moleculaires supplementaires peuvent s'averer necessaires pour clarifier le statut de porteur des parents et, donc, le risque que court le foetus. (II-3A) 5.Le diagnostic prenatal devrait etre offert a la femme enceinte / au couple qui courent le risque d'avoir un foetus affecte par une thalassemie ou une hemoglobinopathie significative sur le plan clinique. Le diagnostic prenatal devrait etre effectue a la suite de l'obtention du consentement eclaire de la patiente. Lorsque le depistage prenatal a ete refuse, un depistage devrait etre mene chez l'enfant afin de permettre le diagnostic precoce et l'orientation vers un centre d'hematologie pediatrique, le cas echeant. (II-3A) 6.Le diagnostic prenatal par analyse de l'ADN peut etre effectue au moyen de cellules obtenues par prelevement de villosites choriales ou amniocentese. En ce qui concerne ceux qui refusent le depistage effractif et qui courent un risque d'anasarque foetoplacentaire liee a l'hemoglobine Bart (α-thalassemie a deletion de quatre genes), il est egalement possible de proceder, au sein d'un centre disposant d'une certaine experience en la matiere, a des echographies foetales detaillees en serie visant l'evaluation du rapport cardiothoracique foetal (normal 7.La constatation d'une anasarque foetoplacentaire, au moment de l'echographie menee au cours du deuxieme ou du troisieme trimestre chez une patiente enceinte dont l'origine ethnique l'expose a un risque accru d'α-thalassemie, devrait donner immediatement lieu a une analyse visant a determiner le statut de porteur d'α-thalassemie de la patiente en question et de son partenaire. (III-A) Validation La presente directive clinique a ete redigee par le comite sur la genetique de la Societe des obstetriciens et gynecologues du Canada (SOGC) et le comite de diagnostic prenatal du College canadien des geneticiens medicaux (CCGM), et analysee et approuvee par le comite executif et le Conseil de la SOGC et le conseil d'administration du CCGM.

Resume Objectif Offrir aux medecins de famille, aux conseillers genetiques, aux geneticiens medicaux, aux sages-femmes et aux obstetriciens-gynecologues du Canada des recommandations quant au depistage du X fragile au sein de la population obstetricale-gynecologique. Methodes Des recherches ont ete menees dans MEDLINE, la Cochrane Library , des revues specialisees et des manuels en vue d'en tirer les articles, publies en anglais entre 1966 et mars 2008, portant sur les issues du depistage du X fragile. Parmi les termes de recherche, on trouvait les suivants: fragile X , screening , prenatal testing , pregnancy outcome , premutation , trinucleotide repeats et ovarian failure . Tous les types d'etude ont ete analyses. Les resultats issus d'essais comparatifs randomises ont ete consideres comme etant ceux qui etaient de la plus grande qualite, suivis des resultats issus d'etudes de cohorte. Les etudes cles sur lesquelles sont fondees les recommandations font l'objet de references. Les donnees soutenant chacune des recommandations font l'objet d'un resume s'accompagnant de commentaires evaluatifs et de references. Le present document constitue un resume de l'information. Resultats La qualite des resultats signales dans le present document a ete decrite au moyen des criteres etablis dans le rapport du Groupe d'etude canadien sur les soins de sante preventifs. Recommandations 1.Toute intervention de depistage du syndrome du X fragile ne doit etre mise en oeuvre qu'a la suite de l'offre de services de counseling exhaustifs et de l'obtention du consentement eclaire de la patiente se soumettant au depistage. (III-A) 2.Le depistage du X fragile est indique pour les femmes qui presentent des antecedents familiaux de syndrome du X fragile, de syndrome tremblements/ataxie associe a un X fragile ou d'insuffisance ovarienne prematuree (chez plus d'un membre de la famille), si la structure genealogique indique qu'elles courent le risque d'avoir herite du gene mutant. L'orientation vers les services d'un geneticien medical a des fins de counseling et d'evaluation devrait etre envisagee dans de tels cas. (II-2A) 3.Le depistage du X fragile est indique pour les femmes qui presentent des antecedents personnels d'autisme ou de retard mental / du developpement d'etiologie inconnue, ou dont la famille compte au moins un homme presentant ces pathologies (dans un segment genealogique de trois generations). (II-2A) 4.Le depistage du X fragile est indique pour les femmes qui connaissent des problemes genesiques ou de fertilite associes a des taux eleves d'hormone folliculostimulante avant l'âge de 40 ans. (III-A) 5.Le depistage prenatal par prelevement de villosites choriales ou amniocentese devrait etre offert aux femmes chez lesquelles la presence d'une premutation ou d'une mutation complete du gene « X fragile » (FMR-1) a ete confirmee. (II-2A) La tenue d'une intervention diagnostique genetique pre-implantation constitue une autre option genesique. (III-A) 6.Le depistage collectif du syndrome du X fragile pour toutes les femmes en âge de procreer est faisable. Cependant, cette intervention ne devrait etre envisagee qu'en presence d'un programme provincial / regional etant en mesure de proceder au depistage et de conseiller adequatement la population ciblee quant a la signification et aux implications des resultats. (II-2B)

Objective To provide Canadian family physicians, genetic counsellors, medical geneticists, midwives, and obstetrician-gynaecologists with recommendations regarding screening for fragile X in the obstetrical and gynaecological population. Methods Medline, the Cochrane Library, journals, and textbooks were searched for English-language articles, published between 1966 and March 2008, relating to fragile X testing outcomes. Search terms included fragile X, screening, prenatal testing, pregnancy outcome, premutation, trinucleotide repeats, and ovarian failure. All study types were reviewed. Randomized controlled trial results were considered evidence of the highest quality, followed by results of cohort studies. Key individual studies on which the recommendations are based are referenced. Supporting data for each recommendation are summarized with evaluative comments and references. This document represents an abstraction of the information. Evidence The quality of evidence reported in this document has been described using the criteria outlined in the report of the Canadian Task Force on Preventive Health Care. Recommendations 1.Any testing for fragile X syndrome must occur only following thorough counselling and with the informed consent of the woman to be tested. (III-A) 2.Fragile X testing is indicated for a woman with a family history of fragile X syndrome, fragile X tremor/ataxia syndrome, or premature ovarian failure (in more than one family member) if the pedigree structure indicates that she is at risk of inheriting the mutated gene. Referral to a medical geneticist for counselling and assessment should be considered in these cases. (II-2A) 3.Fragile X testing is indicated for women who have a personal history of autism or mental retardation/developmental delay of an unknown etiology or who have at least one male relative with these conditions within a three-generation pedigree. (II-2A) 4.Fragile X testing is indicated for women who have reproductive or fertility problems associated with an elevated level of follicle stimulating hormone before the age of 40. (III-A) 5.Prenatal fetal testing via chorionic villus sampling or amniocentesis should be offered to women who are confirmed to be carriers of a premutation or full mutation of the fragile X gene (FMR-1). (II-2A) Pre-implantation genetic diagnosis is available as another reproductive option. (III-A) 6.Population screening for fragile X syndrome for all women in the reproductive age-range is feasible. However, it should be considered only when there is a provincial/regional program that can test and adequately counsel the targeted population about the meaning and implications of the results. (II-2B)

Resume Objectif Determiner le taux de perte post-intervention associee a l'amniocentese genetique menee au deuxieme trimestre. Issue Reduction des taux de biopsie benigne. Avantages Offrir de meilleurs conseils aux femmes au sujet des risques et des avantages de l'amniocentese genetique menee au deuxieme trimestre, et s'assurer que les femmes beneficient de renseignements / de services de counseling suffisants pour prendre une decision quant au depistage. Declaration sommaire Chaque patiente compte un risque de subir une perte post-intervention qui lui est propre et qui depend de multiples variables.

Resume Objectif Elaborer un document de consensus canadien enoncant des recommandations sur le depistage maternel de l'aneuploidie foetale (p. ex. syndrome de Down et trisomie 18) pendant la grossesse. Options Le depistage de l'aneuploidie foetale pendant la grossesse a debute au milieu des annees 1960; l'âge maternel etait alors utilise a titre de test de depistage. De nouvelles percees, dans le domaine du depistage a partir du serum maternel et par echographie, nous permettent dorenavant d'offrir un test non effractif de depistage a toutes les patientes enceintes, et ce, afin d'evaluer leur risque d'accoucher d'un foetus presentant le syndrome de Down ou une trisomie 18 et de determiner si la tenue de tests effractifs de diagnostic prenatal s'avere necessaire. Le present document examine les options disponibles en matiere de depistage non effractif et formule des recommandations a l'intention des patientes et des professionnels de la sante au Canada. Issues Offrir un depistage non effractif du syndrome de Down ou de la trisomie 18 a toutes les femmes enceintes. Le diagnostic prenatal effractif serait limite aux femmes qui obtiennent, a la suite du depistage non effractif, des resultats se situant au-dela d'un niveau de risque seuil preetabli ou aux femmes enceintes qui auront 40 ans au moment de l'accouchement et qui, a la suite du counseling, choisissent de passer directement a l'amniocentese / au prelevement des villosites choriales (PVC). Parmi les options de depistage non effractif actuellement disponibles, on trouve l'âge maternel conjointement avec (1) un depistage au cours du premier trimestre (DPT) (clarte nucale, marqueurs biochimiques seriques maternels); (2) un depistage serique au cours du deuxieme trimestre; ou (3) un depistage integre en deux etapes, lequel comprend un depistage serique au cours du premier et du deuxieme trimestres, avec ou sans clarte nucale (DPI, DPI serique, contingent et sequentiel). Ces options sont examinees et des recommandations sont formulees. Resultats Une recherche a ete menee dans MEDLINE afin d'en tirer les articles, publies entre 1982 et 2006, portant sur le sujet. Des sondages sur la pratique ont ete menes partout au Canada. Une ebauche de document de consensus a ete redigee et examinee par les membres du comite. Valeurs La qualite des resultats et la classification des recommandations ont ete etablies en fonction des discussions menees et du consensus atteint par les comites de la SOGC (genetique, imagerie diagnostique) et du CCGM (diagnostic prenatal). Avantages, desavantages et couts La presente directive clinique a pour objectif de reduire le nombre des amniocenteses qui ne sont effectuees qu'en fonction du seul âge maternel. Cela a pour avantage de reduire le nombre des grossesses normales qui prennent fin en raison de complications attribuables aux interventions effractives. Tous les tests de depistage comptent un taux intrinseque de faux positif, ce qui peut provoquer une anxiete injustifiee. Une analyse couts-avantages detaillee de la mise en oeuvre de la presente directive clinique reste encore a effectuer, puisque cela necessiterait des donnees de surveillance sanitaire et des ressources de recherche en sante qui ne sont pas disponibles a l'heure actuelle; neanmoins, ces facteurs se doivent d'etre evalues par des initiatives provinciales et territoriales dans le cadre d'une approche prospective.

Objective: To develop a Canadian consensus document with recommendations on maternal screening for fetal aneuploidy (e.g., Down syndrome and trisomy 18) in pregnancy. Options: Pregnancy screening for fetal aneuploidy started in the mid 1960s, using maternal age as the screening test. New developments in maternal serum and ultrasound screening have made it possible to offer all pregnant patients a non-invasive screening test to assess their risk of having a fetus with Down syndrome or trisomy18 to determine whether invasive prenatal diagnosis tests are necessary. This document will review the

Segmental spinal dysgenesis (SSD) is a rare congenital spinal abnormality characterized by segmental dysgenesis or agenesis of the thoracolumbar or lumbar spine, congenital kyphosis, and abnormal configuration of the underlying spinal cord. A unique feature of SSD is that the vertebrae are present above and below the defect, and there is often a lower cord segment in the caudal spinal canal. We report a fetal MRI case of SSD with postmortem and neuropathological correlations. Our report confirms already published findings including the presence of a neurenteric cyst but is the first to document anterior spinal artery segmental agenesis in SSD.

Resume Objectif Fournir des recommandations aux medecins et aux sages-femmes qui offrent des services prenatals ou avant la conception portant sur le depistage des porteurs de troubles genetiques chez les personnes d'origine juive ashkenaze Options Offrir le depistage des porteurs de la maladie de Tay-Sachs (MTS) seulement ou elargir le depistage en vue de couvrir d'autres troubles dont la frequence accrue au sein de la population juive ashkenaze est bien connue. Issues Offrir, au sein de la population juive ashkenaze, le depistage des porteurs de pathologies de facon a ce que les avantages pour le couple l'emportent sur les risques, dont la detresse psychologique attribuable aux interventions de depistage et de diagnostic. Minimiser les variations de pratique au Canada en ce qui concerne le depistage des porteurs chez les personnes d'origine juive ashkenaze. Resultats Des recherches ont ete menees dans la base de donnees MEDLINE afin d'en tirer les articles pertinents, publies entre janvier 1966 et decembre 2004, portant sur le depistage des porteurs et les troubles genetiques chez les personnes d'origine juive ashkenaze. De plus, un sondage a ete mene aupres des specialistes en medecine fœto-maternelle et des geneticiens medicaux canadiens en vue de prendre connaissance des pratiques et des opinions actuelles sur le sujet. Valeurs Les resultats du sondage et les donnees issues des recherches menees dans la base de donnees MEDLINE ont ete analyses par le comite de diagnostic prenatal du College canadien des geneticiens medicaux (CCGM) et le comite de genetique de la Societe des obstetriciens et gynecologues du Canada (SOGC). Les recommandations ont ete quantifiees au moyen des lignes directrices sur l'evaluation des resultats elaborees par le Groupe d'etude canadien sur l'examen medical periodique. Avantages, desavantages et couts Le depistage des couples d'origine juive ashkenaze permet d'identifier les couples qui courent un risque de l'ordre de 25 % d'avoir un enfant presentant un trouble genetique important. Toutefois, la sensibilite des tests offerts n'est pas de 100 % chez les personnes d'origine juive ashkenaze et est considerablement moindre ou encore inconnue chez les personnes n'etant pas d'origine juive ashkenaze. Il est possible que le depistage identifie des couples ou l'un des membres est porteur, tandis que l'autre est negatif. Compte tenu du fait qu'un tel couple courrait de faibles risques (sans pour autant etre inexistants) d'avoir un enfant affecte, le depistage pourrait entrainer de la detresse psychologique, des interventions diagnostiques prenatales superflues et peut-etre meme l'interruption de grossesses normales. La presente directive clinique ne comprend pas d'analyse des couts. Recommandations 1.Le depistage des porteurs de la MTS, (II-2A) de la maladie de Canavan et de la dysautonomie familiale devrait etre offert aux couples d'origine juive ashkenaze. (III-A) 2.Le depistage des porteurs d'autres troubles pour lesquels une frequence accrue a ete constatee chez les personnes d'origine juive ashkenaze (p. ex. syndrome de Bloom, anemie de Fanconi, maladie de Gaucher, glycogenose de type 1a, mucolipidose de type IV, maladie de Niemann-Pick de type 1A, fibrose kystique) devrait etre offert en presence d'antecedents familiaux positifs. (III–A) 3.Lorsque seulement un des membres du couple est d'origine juive ashkenaze, le depistage ne devrait etre offert que pour la MTS. (II-2A) 4.Lorsque seulement un des membres du couple est d'origine juive ashkenaze, le depistage de la maladie de Canavan ou de la dysautonomie familiale (DF) ne devrait pas etre offert, et ce, en raison de la faible frequence du statut de porteur et des limites du depistage des porteurs (faible taux de detection chez les personnes n'etant pas d'origine juive ashkenaze). (III-D) 5.Lorsque les deux partenaires sont porteurs de la meme pathologie autosomique recessive, ils courent un risque d'avoir un enfant affecte de l'ordre de 25 %. Ils devraient etre orientes vers des services de counseling genetique, que ce soit avant la conception ou pendant la grossesse. Le diagnostic prenatal serait alors offert et effectue conformement a la decision eclairee de la patiente. Le diagnostic prenatal consisterait en une analyse de l'ADN effectuee a partir de cellules obtenues par biopsie des villosites choriales ou amniocentese. (II-3A) Validation La presente directive clinique a ete redigee par le comite sur le diagnostic prenatal du CCGM et le comite de genetique de la SOGC, et approuvee par le conseil d'administration du CCGM et le comite executif de la SOGC.

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

We report on nine unrelated children fitting a diagnosis of Carey-Fineman-Ziter syndrome (CFZS). All children presented with Mobius sequence, Pierre Robin complex (6/9) or micrognathia, and hypotonia. Some had primary hypoventilation, delayed development, and acral anomalies. The neuropathological investigations performed in two patients showed a combination of dysplastic lesions (neuronal heterotopias) and encephaloclastic changes consisting of small foci of necrosis with microcalcifications. The mother of a third child had severe trauma during her 2nd month of pregnancy. Based on a review of the literature on MS and CFZS, we suggest designating as "Robin-Mobius phenotype" a distinct clinical variant of MS with extensive brainstem involvement, Robin complex, hypotonia without specific muscle disorder, clubfeet and variable acral anomalies. This condition appears to bear a higher risk of mental handicap and perhaps a higher recurrence risk than "common" MS. Neuropathology and neuroimaging are suggestive, at least in some cases, of a vascular disruption, which could be exogenous, or secondary to a genetic predisposition. Etiologic heterogeneity seems likely and, in that respect, the original CFZS family could represent a private syndrome fitting on the "Robin-Mobius" spectrum. Despite the existence of two familial reports, recurrence risk is probably much lower than 25%, although exact figures cannot be extracted from the available literature.

Background Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. Conclusions This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.

Myelodysplastic Syndrome (MDS) is a problem of ineffective hematopoesis, due to a clonal disorder of the hematopoetic stem cells. MDS is rare in children and considered premalignant as it often progresses to leukemia over time. There are known inherited predisposing conditions to MDS that have been reported in the literature. We describe the case of a 12-year-old girl with multiple dysmorphic features, short stature, and developmental delay with a new diagnosis of MDS (RAEB) with no confirmed genetic diagnosis linking all these features together. We propose that her underlying syndromic diagnosis may have predisposed her to MDS.

To provide recommendations to physicians, midwives, genetic counsellors, and clinical laboratory scientists involved in pre-conceptional or prenatal care regarding carrier screening for thalassemia and hemoglobinopathies (e.g., sickle cell anemia and other qualitative hemoglobin disorders).To determine the populations to be screened and the appropriate tests to offer to minimize practice variations across Canada.The Medline database was searched for relevant articles published between 1986 and 2007 on carrier screening for thalassemia and hemoglobinopathies. Key textbooks were also reviewed. Recommendations were quantified using the Evaluation of Evidence guidelines developed by the Canadian Task Force on Preventive Health Care.The evidence collected from the Medline search was reviewed by the Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG) and the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC).Screening of individuals at increased risk of being carriers for thalassemia and hemoglobinopathies can identify couples with a 25% risk of having a pregnancy with a significant genetic disorder for which prenatal diagnosis is possible. Ideally, screening should be done pre-conceptionally. However, for a significant proportion of patients, the screening will occur during the pregnancy, and the time constraint for obtaining screening results may result in psychological distress. This guideline does not include a cost analysis.1. Carrier screening for thalassemia and hemoglobinopathies should be offered to a woman if she and/or her partner are identified as belonging to an ethnic population whose members are at higher risk of being carriers. Ideally, this screening should be done pre-conceptionally or as early as possible in the pregnancy. (II-2A) 2. Screening should consist of a complete blood count, as well as hemoglobin electrophoresis or hemoglobin high performance liquid chromatography. This investigation should include quantitation of HbA2 and HbF. In addition, if there is microcytosis(mean cellular volume80 fL) and/or hypochromia (mean cellular hemoglobin27 pg) in the presence of a normal hemoglobin electrophoresis or high performance liquid chromatography the patient should be investigated with a brilliant cresyl blue stained blood smear to identify H bodies. A serum ferritin (to exclude iron deficiency anemia) should be performed simultaneously. (III-A) 3. If a woman's initial screening is abnormal (e.g., showing microcytosis or hypochromia with or without an elevated HbA2, or a variant Hb on electrophoresis or high performance liquid chromatography) then screening of the partner should be performed. This would include a complete blood count as well as hemoglobin electrophoresis or HPLC, HbA2 and HbF quantitation,and H body staining. (III-A) 4. If both partners are found to be carriers of thalassemia or an Hb variant, or of a combination of thalassemia and a hemoglobin variant, they should be referred for genetic counselling. Ideally,this should be prior to conception, or as early as possible in the pregnancy. Additional molecular studies may be required to clarify the carrier status of the parents and thus the risk to the fetus. (II-3A) 5. Prenatal diagnosis should be offered to the pregnant woman/couple at risk for having a fetus affected with a clinically significant thalassemia or hemoglobinopathy. Prenatal diagnosis should be performed with the patient's informed consent. If prenatal diagnosis is declined, testing of the child should be done to allow early diagnosis and referral to a pediatric hematology centre, if indicated. (II-3A) 6. Prenatal diagnosis by DNA analysis can be performed using cells obtained by chorionic villus sampling or amniocentesis. Alternatively for those who decline invasive testing and are at risk of hemoglobin Bart's hydrops fetalis (four-gene deletion alpha-thalassemia), serial detailed fetal ultrasound for assessment of the fetal cardiothoracic ratio (normal0.5) should be done in a centre that has experience conducting these assessments for early identification of an affected fetus. If an abnormality is detected, a referral to a tertiary care centre is recommended for further assessment and counselling. Confirmatory studies by DNA analysis of amniocytes should be done if a termination of pregnancy is being considered. (II-3A) 7. The finding of hydrops fetalis on ultrasound in the second or third trimester in women with an ethnic background that has an increased risk of alpha-thalassemia should prompt immediate investigation of the pregnant patient and her partner to determine their carrier status for alpha-thalassemia. (III-A) VALIDATION: This guideline has been prepared by the Prenatal Diagnosis Committee of the Canadian College of Medical Geneticists (CCMG) and the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and approved by the Board of Directors of the CCMG and the Executive and Council of the SOGC.

Objective To determine the postprocedure loss rate for mid-trimester genetic amniocentesis. Outcome Reduction of benign biopsy rates. Benefits To provide better advice for women about the risks and benefits of mid-trimester genetic amniocentesis, and to ensure that women are given sufficient information/counselling to make a decision about screening. Summary Statement The risk of postprocedure loss is unique to the individual and is based on multiple variables.

ContextHereditary diffuse gastric cancer is caused by germline mutations in the epithelial cadherin (CDH1) gene and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer.ObjectiveTo determine whether recurring germline CDH1 mutations occurred due to independent mutational events or common ancestry.Design, Setting, and PatientsThirty-eight families diagnosed clinically with hereditary diffuse gastric cancer were accrued between November 2004 and January 2006 and were analyzed for CDH1 mutations as part of an ongoing study at the British Columbia Cancer Agency. Twenty-six families had at least 2 gastric cancer cases with 1 case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.Main Outcome MeasuresClassification of family members as carriers or noncarriers of CDH1 mutations. Haplotype analysis to assess recurring mutations for common ancestry was performed on 7 families from this study and 7 previously reported families with the same mutations.ResultsThirteen mutations (6 novel) were identified in 15 of the 38 families (40% detection rate). The 1137G>A splicing mutation and the 1901C>T (A634V) missense/splicing mutation occurred on common haplotypes in 2 families but on different haplotypes in a third family. The 2195G>A (R732Q) missense/splicing mutation occurred in 2 families on different haplotypes. The 2064-2065delTG mutation occurred on a common haplotype in 2 families. Two families from this study plus 2 additional families carrying the novel 2398delC mutation shared a common haplotype, suggesting a founder effect. All 4 families originate from the southeast coast of Newfoundland. Due to concentrations of lobular breast cancer cases, 2 branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these 4 families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40% (95% confidence interval [CI], 12%-91%) for males and 63% (95% CI, 19%-99%) for females and the risk for breast cancer in female mutation carriers was 52% (95% CI, 29%-94%).ConclusionsRecurrent CDH1 mutations in families with hereditary diffuse gastric cancer are due to both independent mutational events and common ancestry. The presence of a founder mutation from Newfoundland is strongly supported.Published online June 3, 2007 (doi:10.1001/jama.297.21.2360).

Background Rare disease can present in the first days and weeks of life and is associated with significant morbidity and mortality. The genetic and clinical heterogeneity of these conditions can pose a significant challenge for diagnosis. Objective To evaluate the diagnostic utility of the Illumina TruSightTM One panel, we performed Next-generation sequencing (NGS) for a series of 20 newborns presenting with features suggestive of a Mendelian disease in the Neonatal Intensive Care Unit (NICU). Design/methods Twenty patients were recruited from the NICU at the Children’s Hospital of Eastern Ontario. Inclusion criteria required a complex medical presentation (congenital anomalies, abnormalities in growth and/or neurological features). We used a family-based trio approach. Target enrichment was performed with the Illumina TruSightTM One Sequencing Panel kit. This panel targets 4,813 genes that are deemed clinically-relevant and referred to as the “clinome”. Sequencing was performed on the Illumina MiSeq. NextGene software (v2.3.4.4) was used for analyses. Time from sample acquisition to data analysis was possible in 7 working days. Results/conclusion To date, 13 trios were sequenced and analysed. A molecular diagnosis was made in 5 of 13 patients, comparable to the rate obtained by whole-exome sequencing from the literature. Positive cases included bi-allelic mutations in WDR19 and ACE, an X-linked mutation in MTM1, homozygous mutations in FTO, and a de novo mutation in SCN1A. Clinome sequencing has the potential to improve our ability to efficiently diagnose rare diseases in the NICU by providing a cost-effective tool to evaluate the clinically relevant portion of the genome in a week’s time.

For references, please see Appendix 1, available at [www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.131551/-/DC1][1] The test analyzes fragments of DNA derived from the placenta circulating in maternal blood. The sensitivity and specificity of noninvasive prenatal testing depend on the chromosome being