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Background: Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by loss-of-function mutation in the NF1 gene. Segmental or mosaic NF1 (MNF) is an uncommon presentation of the NF1 result of postzygotic mutations that present with subtle localised clinical findings. Objectives: Our study’s objectives were to describe the clinical characteristics of children with MNF. Methods: We conducted a cross-sectional study of children diagnosed with MNF at the Hospital for Sick Children in Toronto, Canada, from January 1992 to September 2012. Data were abstracted from health records and analysed using a standardised data collection form approved by our hospital Research Ethics Board. Results: We identified 60 patients with MNF; 32 of 60 (53.3%) were female. Mean ± SD age at first assessment was 10.6 ± 4.6 years. The most common initial physical manifestation in 39 of 60 (65.0%) patients was localised pigmentary changes only, followed by plexiform neurofibromas only in 10 of 60 (16.7%) and neurofibromas only in 9 of 60 (15.0%). Unilateral findings were seen in 46 of 60 (76.7%) patients. Most common associations identified included learning disabilities (7/60; 12%) and bony abnormalities (6/60; 10.0%). Conclusions: MNF is an underrecognised condition with potential implications for patients. Children mostly present with pigmentary anomalies only. Most patients do not develop associated findings or complications before adulthood, but long-term follow-up will help determine outcomes and possible associations. Recognition and confirmation of the diagnosis is important to provide follow-up and genetic counselling to patients.

Genetic counselors are trained health care professionals who effectively integrate both psychosocial counseling and information-giving into their practice. Preparing genetic counseling students for clinical practice is a challenging task, particularly when helping them develop effective and active counseling skills. Resistance to incorporating these skills may stem from decreased confidence, fear of causing harm or a lack of clarity of psycho-social goals. The author reflects on the personal challenges experienced in teaching genetic counselling students to work with psychological and social complexity, and proposes a Genetic Counseling Adaptation Continuum model and methodology to guide students in the use of advanced counseling skills.

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 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

Inactivating SPRED1 mutations cause Legius syndrome, an autosomal dominant RASopathydescribed in 20071. Like Neurofibromatosis Type 1 (NF1), features include cafe-au-lait macules and skin fold freckling. Although neurofibromas, optic gliomas, Lisch nodules, tibial pseudarthrosis and nerve sheath tumors are not seen in Legius syndrome, other symptoms and signs common to the RASopathies such as Noonan-like facial features, pulmonary stenosis, pectus deformity and learning disabilities are reported2,3. This article is protected by copyright. All rights reserved.

We reviewed the health records of pediatric patients with 22q11.2 deletion syndrome (22q11.2 DS) seen over a 5-year period in our 22q11.2 DS multidisciplinary clinic. We determined the prevalence of thyroid dysfunction in this population, in comparison to general population data. Statistical tests were applied to investigate trends in gender differences, thyroid disease subtype and co-morbid conditions in the patients identified with thyroid disease. Of 169 subjects (92 male, 77 female) 9.5% had overt thyroid disease; of these, 1.8% had hyperthyroidism and 7.7% had hypothyroidism; 42% of patients with subclinical or prodromal thyroid disease progressed to overt disease. Our data indicate that thyroid disease prevalence in the 22q11DS pediatric population is significantly higher than that in the general pediatric population Furthermore, over 1/3 of patients in our study population who presented with subclinical thyroid disease progressed to overt disease, requiring medical therapy. Thyroid disease screening should be incorporated into routine medical management of children with 22q11.2 DS. Guidelines for screening individuals with 22q11.2 DS are presented.

22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, estimated to affect up to 1 in 2,000 live births. Major features of this multisystem condition include congenital anomalies, developmental delay, and an array of early- and later-onset medical and psychiatric disorders. Advances in pediatric care ensure a growing population of adults with 22q11.2DS. Informed by an international panel of multidisciplinary experts and a comprehensive review of the existing literature concerning adults, we present the first set of guidelines focused on managing the neuropsychiatric, endocrine, cardiovascular, reproductive, psychosocial, genetic counseling, and other issues that are the focus of attention in adults with 22q11.2DS. We propose practical strategies for the recognition, evaluation, surveillance, and management of the associated morbidities.Genet Med advance online publication 08 January 2015Genetics in Medicine (2014); doi:10.1038/gim.2014.175. ispartof: Genetics in Medicine vol:17 issue:8 pages:599-609 ispartof: location:United States status: published

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.

The standard of care for first-tier clinical investigation of the aetiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy-number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion–deletions (indels) and single-nucleotide variant (SNV) mutations. Whole-genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilised WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a fourfold increase in diagnostic rate over CMA (8%; P value=1.42E−05) alone and more than twofold increase in CMA plus targeted gene sequencing (13%; P value=0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.