Search

The combination of short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS, OMIM: 602471) has been reported as an ultra-rare, autosomal-recessive developmental disorder with unique skeletal anomalies. To the present date, only four affected individuals have been reported. There are several striking orthopaedic diagnoses within the SAMS syndrome. In particular, the scapulohumoral synostosis and the bilateral congenital ventral dislocation of the hips. The purpose of this report is to underline the importance of recognizing pathognomic features of SAMS syndrome. Whenever a bilateral congenital ventral dislocation of the hips and/or a scapulohumoral synostosis is found or clinically suspected, SAMS syndrome should be considered as the primary diagnosis until proven otherwise.

The effects of environmental agents on cerebellar development are profound, and this organ has not been given the attention that is deserving of it, based on its importance in motor, cognitive, and behavioral functions. This chapter will review select agents associated with teratogenic effects on cerebellar structure and function. Mechanisms of teratogenesis and genetic influences will be addressed. The emerging role of effects of environmental agents and effect on the epigenetic mechanisms and gene expression are discussed. Prenatal alcohol exposure and fetal alcohol spectrum disorder will be discussed in greater detail, as this disorder is the most common teratogenic disorder affecting humans. Indeed, many of the phenotypic effects of FASD are the result of cerebellar injury and dysfunction.

UBE2A-related X-linked intellectual disability is characterized by a distinctive facial phenotype (dense eyebrows and eyelashes, synophrys, hypertelorism, upslanted palpebral fissures, wide mouth, and thin lips), generalized hirsutism, hypoplastic genitalia, short stature, hypotonia, seizures, and severe intellectual disability. Five affected males in two families are described here and compared with the previously reported 17 males in eight families. The new cases are notable for the absence of nail dystrophy, previously considered a defining manifestation, and for the presence of hypogammaglobulinemia and adult-onset ataxia.

BackgroundKabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal.MethodsAn international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed.ResultsThe authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented.ConclusionAs targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

Recessive mutations in FRAS1-related extracellular matrix 1 (FREM1) are associated with two rare genetic disorders, Manitoba-oculo-tricho-anal (MOTA) and bifid nose with or without anorectal and renal anomalies (BNAR). Fraser syndrome is a more severe disorder that shows phenotypic overlap with both MOTA and anorectal and renal anomalies and results from mutations in FRAS1, FREM2 and GRIP1. Heterozygous missense mutations in FREM1 were reported in association with isolated trigonocephaly with dominant inheritance and incomplete penetrance. Moreover, large deletions encompassing FREM1 have been reported in association with a syndromic form of trigonocephaly and were designated as trigonocephaly type 2. Trigonocephaly results from premature closure of the metopic suture and typically manifests as a form of nonsyndromic craniosynostosis. We report on 20 patients evaluated for developmental delay and without abnormal metopic suture. Chromosomal microarray analysis revealed heterozygous FREM1 deletions in 18 patients and in 4 phenotypically normal parents. Two patients were diagnosed with MOTA and had homozygous FREM1 deletions. Therefore, although our results are consistent with the previous reports of homozygous deletions causing MOTA, we report no association between heterozygous FREM1 deletions and trigonocephaly in this cohort.

Objective: To compare the characteristics of mothers of children with Fetal Alcohol Spectrum Disorder (FASD) with mothers of typically developing control children. Methods: The study utilized a cross-sectional, observational design, using active case ascertainment. Biological mothers were interviewed using a standardized retrospective questionnaire to collect data on demographics, living environment, pregnancy history, nutrition, alcohol and other drug use prior to and following pregnancy recognition. Results: A total of 173 mothers were interviewed. Of these, 19 had a child who was diagnosed with FASD, five had a child who had received a deferred FASD diagnosis, and 37 had children who were selected into the control group as typically developing children. The remaining 112 mothers had children who did not meet diagnostic criteria for FASD. The mothers of children with FASD did not differ significantly from mothers of the control group children with respect to age, ethnicity, marital status, and employment status at the time of pregnancy. However, mothers of children with FASD had lower levels of education (p &lt, 0.01) and were more likely to have received financial support (p &lt, 0.05) at the time of pregnancy, to have smoked tobacco (p &lt, 0.001), and to have used marijuana or hashish (p &lt, 0.01) prior to pregnancy recognition, compared with mothers of control children. All mothers of children with FASD reported alcohol consumption prior to pregnancy recognition, however, only 10.5% reported alcohol consumption following pregnancy recognition. None of the mothers interviewed reported any drug use following pregnancy recognition. Conclusions: Population-based preventive interventions, including repeated screening, monitoring, and education regarding the effects of alcohol use, as well as other substances, before and during pregnancy, are needed to eliminate risk for FASD and other negative consequences on child and maternal health.

Fetal alcohol spectrum disorder (FASD) is characterized by a combination of neurological, developmental, and congenital defects that may occur as a consequence of prenatal alcohol exposure. Earlier reports showed that large chromosomal anomalies may link to FASD. Here, we examined the prevalence and types of copy number variations (CNVs) in FASD cases previously diagnosed by a multidisciplinary FASD team in sites across Canada. We genotyped 95 children with FASD and 87 age-matched, typically developing controls on the Illumina Human Omni2.5 SNP (single nucleotide polymorphisms) array platform. We compared their CNVs with those of 10 851 population controls to identify rare CNVs (

Fetal alcohol spectrum disorder (FASD) describes a constellation of physical, cognitive, neurologic, and behavioral impairments resulting from prenatal exposure to alcohol. FASD is recognized as being one of the most common causes of preventable brain injury in children. There had long been concerns that some youth in conflict with the law may be affected with FASD given repetitive patterns of offending and apparent lack of understanding of the consequences of their actions. In 2004, funding was received from Justice Canada for a pilot project with a cross-departmental steering committee working together to determine a best way of working across systems to provide FASD assessments to these youth. It was recognized that provision of timely FASD assessments would allow the court to provide more meaningful sentences taking into account the youth’s strengths and challenges and enhance the changes of decreased recidivism and increased changes of rehabilitation. This paper describes the basic science around FASD and its diagnosis, provides a history of the FASD Youth Justice Program, and reports on legal issues, structure, statistics, accomplishments, and ongoing future challenges.

Fetal alcohol spectrum disorder (FASD) is a common neurodevelopmental problem, but neuropathologic descriptions are rare and focused on the extreme abnormalities. We conducted a retrospective survey (1980–2016) of autopsies on 174 individuals with prenatal alcohol exposure or an FASD diagnosis. Epidemiologic details and neuropathologic findings were categorized into 5 age groups. Alcohol exposure was difficult to quantify. When documented, almost all mothers smoked tobacco, many abused other substances, and prenatal care was poor or nonexistent. Placental abnormalities were common (68%) in fetal cases. We identified micrencephaly (brain weight

Background Fetal alcohol spectrum disorder (FASD) is one of the most disabling potential outcomes of prenatal alcohol exposure. The population-based prevalence of FASD among the general population of Canada was unknown. The objective of this study was to determine the population-based prevalence of FASD among elementary school students, aged 7 to 9 years, in the Greater Toronto Area (GTA) in Ontario, Canada. Methods This screening study used a cross-sectional, observational design utilizing active case ascertainment, along with retrospective collection of prenatal alcohol exposure information. Data collection involved two phases. Phase I consisted of taking growth measurements, a dysmorphology examination, and obtaining a history of behavioral and/or learning problems. Phase II consisted of a neurodevelopmental assessment, maternal interview, and behavioral observations/ratings by parents/guardians. Final diagnostic screening conclusions were made by consensus by a team of experienced multidisciplinary experts during case conferences, using the 2005 Canadian guidelines for FASD diagnosis. The prevalence of FASD was estimated, taking into consideration the selection rate, which was used to account for students who dropped out or were lost to follow-up during each phase. Monte Carlo simulations were employed to derive the confidence interval (CI) for the point estimates. Results A total of 2555 students participated. A total of 21 cases of suspected FASD were identified. The prevalence of FASD was estimated to be 18.1 per 1000, or about 1.8%. Using a less conservative approach (sensitivity analysis), the prevalence of FASD was estimated to be 29.3 per 1000, or about 2.9%. Therefore, the population-based prevalence of FASD is likely to range between 2 and 3% among elementary school students in the GTA in Ontario, Canada. Conclusions This study provides the first population-based estimate of the prevalence of FASD in Canada. The estimate is approximately double or possibly even triple previous crude estimates. FASD prevalence exceeds that of other common birth defects such as Down’s syndrome, spina bifida, trisomy 18, as well as autism spectrum disorder in Canada. More effective prevention strategies targeting alcohol use during pregnancy, surveillance of FASD, and timely interventions and support to individuals with FASD and their families are urgently needed. Electronic supplementary material The online version of this article (10.1186/s12889-019-7213-3) contains supplementary material, which is available to authorized users.

The high association between youth with fetal alcohol spectrum disorder (FASD) and encounters with the law justifies the need for effective means to identify FASD youth in the justice system. This chapter will review the extent of the issue and present a comparison between two screening approaches used at the Manitoba Youth Centre to identify youth at risk for FASD. The chapter will outline information about the history, development and outcomes of youth diagnosed with FASD through the Manitoba Youth Justice FASD Program. Youth who receive an FASD diagnosis can receive additional supports for treatment and management of their disorder. Ultimately, this will increase the well-being of young offenders afflicted with FASD by increasing the fairness and appropriateness of sentences, and tailoring the rehabilitation and treatment.

Item does not contain fulltext Defects in primary cilium biogenesis underlie the ciliopathies, a growing group of genetic disorders. We describe a whole-genome siRNA-based reverse genetics screen for defects in biogenesis and/or maintenance of the primary cilium, obtaining a global resource. We identify 112 candidate ciliogenesis and ciliopathy genes, including 44 components of the ubiquitin-proteasome system, 12 G-protein-coupled receptors, and 3 pre-mRNA processing factors (PRPF6, PRPF8 and PRPF31) mutated in autosomal dominant retinitis pigmentosa. The PRPFs localize to the connecting cilium, and PRPF8- and PRPF31-mutated cells have ciliary defects. Combining the screen with exome sequencing data identified recessive mutations in PIBF1, also known as CEP90, and C21orf2, also known as LRRC76, as causes of the ciliopathies Joubert and Jeune syndromes. Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants. Our global, unbiased approaches provide insights into ciliogenesis complexity and identify roles for unanticipated pathways in human genetic disease.

This systematic review and meta-analysis estimates prevalence of fetal alcohol spectrum disorder among children and youth in the general population by country and international region.

Background Fetal alcohol spectrum disorder (FASD) is a developmental disorder that manifests through a range of cognitive, adaptive, physiological, and neurobiological deficits resulting from prenatal alcohol exposure. Although the North American prevalence is currently estimated at 2–5%, FASD has proven difficult to identify in the absence of the overt physical features characteristic of fetal alcohol syndrome. As interventions may have the greatest impact at an early age, accurate biomarkers are needed to identify children at risk for FASD. Building on our previous work identifying distinct DNA methylation patterns in children and adolescents with FASD, we have attempted to validate these associations in a different clinical cohort and to use our DNA methylation signature to develop a possible epigenetic predictor of FASD. Methods Genome-wide DNA methylation patterns were analyzed using the Illumina HumanMethylation450 array in the buccal epithelial cells of a cohort of 48 individuals aged 3.5–18 (24 FASD cases, 24 controls). The DNA methylation predictor of FASD was built using a stochastic gradient boosting model on our previously published dataset FASD cases and controls (GSE80261). The predictor was tested on the current dataset and an independent dataset of 48 autism spectrum disorder cases and 48 controls (GSE50759). Results We validated findings from our previous study that identified a DNA methylation signature of FASD, replicating the altered DNA methylation levels of 161/648 CpGs in this independent cohort, which may represent a robust signature of FASD in the epigenome. We also generated a predictive model of FASD using machine learning in a subset of our previously published cohort of 179 samples (83 FASD cases, 96 controls), which was tested in this novel cohort of 48 samples and resulted in a moderately accurate predictor of FASD status. Upon testing the algorithm in an independent cohort of individuals with autism spectrum disorder, we did not detect any bias towards autism, sex, age, or ethnicity. Conclusion These findings further support the association of FASD with distinct DNA methylation patterns, while providing a possible entry point towards the development of epigenetic biomarkers of FASD. Electronic supplementary material The online version of this article (10.1186/s13148-018-0439-6) contains supplementary material, which is available to authorized users.

This paper discusses the current state of knowledge and practice for diagnosing fetal alcohol spectrum disorder (FASD). The strengths and challenges of different models of diagnosis are compared. Some models require a team approach for evaluation, while other approaches assume that a clinician in his or her office provides a diagnosis based on a review of the patient’s medical and social history, behaviour, and physical examination. The author reviews the emergence of new information from recent advances in genetics, imaging, and electrophysiology that has the potential to lead to changes in practice and improved reliability of an FASD diagnosis.

Women with a mutation in BRCA1 or BRCA2 face a lifetime risk of breast cancer of approximately 80 %. Tamoxifen treatment of the first cancer has been associated with a reduction in the risk of a subsequent contralateral cancer. We studied 1,504 women with a known BRCA1 or BRCA2 mutation, 411 women with bilateral breast cancer (cases) and 1,093 women with unilateral breast cancer (controls) in a matched case-control study. Control women were of similar age and had a similar age of diagnosis of first breast cancer as the cases. For each woman who used tamoxifen, the starting and stopping dates were abstracted and the duration of tamoxifen use was calculated. Three hundred and thirty-one women had used tamoxifen (22 %); of these 84 (25 %) had completed four or more years of tamoxifen, the remainder stopped prematurely or were current users. For women with up to 1 year of tamoxifen use, the odds ratio for contralateral breast cancer was 0.37 (95 % CI 0.20-0.69; p = 0.001) compared to women with no tamoxifen use. Among women with 1-4 years of tamoxifen use the odds ratio was 0.53 (95 % CI 0.32-0.87; p = 0.01). Among women with four or more years of tamoxifen use the odds ratio was 0.83 (95 % CI 0.44-1.55; p = 0.55). Short-term use of tamoxifen for chemoprevention in BRCA1 and BRCA2 mutation carriers may be as effective as a conventional 5-year course of treatment.

Short stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) has been reported previously to be a rare, autosomal-recessive developmental disorder with other, unique rhizomelic skeletal anomalies. These include bilateral humeral hypoplasia, humeroscapular synostosis, pelvic abnormalities, and proximal defects of the femora. To identify the genetic basis of SAMS, we used molecular karyotyping and whole-exome sequencing (WES) to study small, unrelated families. Filtering of variants from the WES data included segregation analysis followed by comparison of in-house exomes. We identified a homozygous 306 kb microdeletion and homozygous predicted null mutations of GSC, encoding Goosecoid homeobox protein, a paired-like homeodomain transcription factor. This confirms that SAMS is a human malformation syndrome resulting from GSC mutations. Previously, Goosecoid has been shown to be a determinant at the Xenopus gastrula organizer region and a segment-polarity determinant in Drosophila. In the present report, we present data on Goosecoid protein localization in staged mouse embryos. These data and the SAMS clinical phenotype both suggest that Goosecoid is a downstream effector of the regulatory networks that define neural-crest cell-fate specification and subsequent mesoderm cell lineages in mammals, particularly during shoulder and hip formation. Our findings confirm that Goosecoid has an essential role in human craniofacial and joint development and suggest that Goosecoid is an essential regulator of mesodermal patterning in mammals and that it has specific functions in neural crest cell derivatives.

Classical lissencephaly may be associated with cerebellar hypoplasia and when significant cerebellar abnormalities occur, defects in proteins encoded by TUBA1A, RELN, and very-low-density lipoprotein receptor ( VLDLR) genes have been reported. We present a neonate with a severe neurologic phenotype associated with hypotonia, oropharyngeal incoordination that required a gastric tube for feeding, intractable epilepsy, and congenital cataracts. Her brain magnetic resonance imaging (MRI) showed classical lissencephaly, ventriculomegaly, absent corpus callosum, globular and vertical hippocampi, and severe cerebellar and brainstem hypoplasia. She died at 6 weeks of age. No specific molecular diagnosis was made. This likely represents a previously undescribed genetic lissencephaly syndrome.

Background: Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol’s effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Methods: Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. Results: After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. Conclusions: These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

The consequences of prenatal alcohol exposure were first described more than 40 years ago.[1][1],[2][2] The term “fetal alcohol syndrome” (FAS) was first used to describe the cluster of birth defects due to prenatal alcohol exposure (including growth restriction, craniofacial abnormalities and

Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS. © 2012 The American Society of Human Genetics.

Duplications of 7q11.23, deleted in Williams-Beuren Syndrome, have been implicated in autism spectrum disorders (ASDs). A 1.5 Mb duplication was identified in one girl with severe expressive language deficits and anxiety among 1,142 ASD individuals screened for this duplication. Family-based association studies of Tag-SNPs in three genes (STX1A , CYLN2 and GTF2i) in two multiplex autism family cohorts revealed strong association of two GTF2i SNPs and their haplotype in Cohort 1 and the combined families. The risk alleles and haplotype were associated with severe problems in social interaction and excessive repetitive behaviors. Our findings suggest the GTF2i gene is important in the etiology of autism in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors.

Purpose: Leftover newborn spots can provide a powerful research tool as a population-wide DNA bank. Some provinces/states store them for more than 20 years; however, parents are usually not informed of the retention of leftover newborn spots. To examine the opinions of Canadian geneticists regarding permission for leftover newborn spots storage for research purposes and the associated risks, a web-based survey was distributed to all members of the Canadian College of Medical Geneticists with a valid e-mail address (n 209) and completed by 78 respondents (37%). Results: The majority of respondents (73%) favored opt-out notification for retention of samples that would be held for longer than 2 years. For research on multifactorial conditions using leftover newborn spots originally banked without parental permission, geneticists favored different types of permission depending on the level of identifiable information attached to samples. Thirty-eight percent were concerned that information pamphlets that state that leftover newborn spots will be stored and may be “a source of DNA for research” would lead to a decreased participation in newborn screening. Twenty-eight percent believed that group stigma or family anxiety was likely to result from using nonidentified leftover newborn spots to study multifactorial conditions. Conclusion: The concerns of this knowledgeable cohort supports the critical importance of public engagement about both the potential risks and societal benefits associated with the use of leftover newborn spots in research as policy for leftover newborn spots is developed. Genet Med 2011:13(4):305–313.

IntroductionThe aim of this paper is to provide a protocol for a systematic review assessing the effectiveness of evidence from randomised controlled trials comparing fetal alcohol spectrum disorders pharmacological and non-pharmacological interventions with placebo/dummy interventions or usual standards of care in children and adolescents (Methods and analysisThe following electronic databases will be searched: Medline (Ovid), Cumulative Index of Nursing and Allied Health Plus with Full text (EBSCO), Cochrane Central Register of Controlled Trials (Cochrane Library—Wiley), PsycINFO (ProQuest) and Proquest DissertationsandTheses will be searched from inception to March 2017 for relevant citations of published trials using individualised search strategies prepared for database. We will also search the reference lists of relevant articles and conference proceedings. Two reviewers will independently assess each study against predetermined inclusion/exclusion criteria and extract data including population characteristics, types and duration of interventions and outcomes from included trials. Internal validity will be assessed using the Cochrane Risk of Bias Tool. Primary outcome measures will be improvements in symptoms, including: hyperactivity, impulsivity and attention as measured by standard rating scales. Secondary outcome measures will include improvements in physical and mental health domains, as well as cognitive, behavioural, social and educational skills as measured by rating scales, standardised psychometric tests of IQ and memory, grade repetition, literacy tests and diagnosis of mental health disorder.Ethics and disseminationEthical approval will not be obtained since it is not required for systematic reviews as there are no concerns regarding patient privacy. The results of this review will be disseminated through publication in a peer-review journal and presented at relevant conferences.PROSPERO registration numberCRD42013005996.

It has been almost 25 years since the Chernobyl nuclear accident in Ukraine. We review relevant data derived from published reports originating in the Former Soviet Union. We cite census data from Ukraine and research studies from Western Europe that analyzed the effect of radiation on genetics and health outcome in the exposed populations. We also present philatelic materials that pictorially captured that fateful event in history.

Cytogenetic studies of a 16-year-old female with behaviour and learning problems revealed that one X chromosome had additional material inserted at Xq21. Fluoroescence in situ hybridization (FISH) analysis showed that the inserted segment contained heterochromatin and adjacent euchromatin of chromosome 1 origin. The karyotype of this patient was established as: 46,X,der(X)ins(X;?)(q21;?).ish der(X) ins(X;1)(q21;q12q21)(wcpl +). Chromosome replication studies demonstrated a random pattern of X inactivation, suggesting that the inserted material may be too ‘small.’ to skew lyonization. The consequences of this abnormal X chromosome in relation to the clinical phenotype are discussed.

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P

The Hutterian Bretheren is an isolated population living on the North American prairies, the current community exceeding 40,000 in number. Their unique genetic history has contributed to a founder effect, which is reflected in the Mendelian disorders present in this population today. Genetic studies in the Hutterite population have led to the identification of a number of genes over the last several years and highlights the power of this population for gene identification. However, for the more than 30 autosomal recessive conditions currently recognized in this population, the gene or Hutterite specific mutation remains to be identified for over half and novel autosomal recessive syndromes continue to be recognized. This review summarizes what is currently understood about the molecular etiology of the Mendelian disorders and highlights the cardinal features of those disorders that are unique to or over-represented in this population.

Adults with fetal alcohol syndrome (FAS) and the subsets of individuals with attenuated phenotype subsumed under the umbrella term of fetal alcohol spectrum disorder (FASD) provide clinicians with a challenge. Compounding this, FASD is different from most genetic syndromes since a specific diagnostic biological test is not available. The diagnosis first needs to be suspected and confirmation requires a diagnostic assessment that is best carried out in the context of a multi-disciplinary team approach. There is surprisingly little research published on the prevalence, natural history, medical, and social complications relevant to adults with FASD. The evidence that is emerging suggests that this disorder is common, and that services to diagnose and treat these individuals are limited. Adults with FASD have a higher incidence of impairments in social adaptive and executive function, and a higher degree of psychopathology when compared to the general population. The impact of FASD has significant and serious effects on those affected with FASD, their families, and our communities. There is a need for improved access to diagnosis, and more research and evaluation of interventions currently in use. In this paper, we describe the current diagnostic criteria, the differential diagnosis, the prevalence, natural history, the behavioral and mental health consequences, medical and social management issues, and interventions for adults affected with this disorder.

Nephronophthisis (NPHP), an autosomal recessive kidney disease, is the most frequent genetic cause of end-stage renal failure in the first three decades of life. Positional cloning of the six known NPHP genes has linked its pathogenesis to primary cilia function. Here we identify mutation of GLIS2 as causing an NPHP-like phenotype in humans and mice, using positional cloning and mouse transgenics, respectively. Kidneys of Glis2 mutant mice show severe renal atrophy and fibrosis starting at 8 weeks of age. Differential gene expression studies on Glis2 mutant kidneys demonstrate that genes promoting epithelial-to-mesenchymal transition and fibrosis are upregulated in the absence of Glis2. Thus, we identify Glis2 as a transcription factor mutated in NPHP and demonstrate its essential role for the maintenance of renal tissue architecture through prevention of apoptosis and fibrosis.

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

Prenatal alcohol (ethanol) exposure (PAE) is the underlying cause for a variety of birth defects and neurodevelopmental deficits referred to as “Fetal Alcohol Spectrum Disorders (FASD)”. The more visible phenotypes caused by PAE include growth retardation, and characteristic craniofacial abnormalities associated with functional and structural damage to the central nervous system. Ethanol is a teratogenic agent itself; but it can also alter gene expression. These changes may contribute to the spectrum of effects and different phenotypes that are dependent on alcohol metabolism, as well as the timing and duration of alcohol exposure. Evidence from both human patients and animal models show that genetic factors and epigenetic mechanisms such as DNA methylation, histone post-translational modifications and noncoding RNAs, contribute to the gene expression changes caused by ethanol. Not all embryos that are exposed to alcohol during development exhibit FASD symptoms after birth. FASD patients may present severe birth defects, while others are normal in physical appearance but present a variety of cognitive and behavioral difficulties. It has been hypothesized that maternal and paternal genetic factors may contribute to the sensitivity, resistance or vulnerability of the fetus to alcohol. Moreover, the epigenome is highly sensitive to a multitude of environmental insults including PAE. Studies also show ‘transgenerational’ effects of alcohol. In such cases, maternal or paternal preconception alcohol consumption could lead to FASD-like phenotypes in the newborn. Thus, the phenotypes in FASD can be modified by interplay between maternal/paternal genetic factors and epigenetic mechanisms. This current review summarizes the contribution of genetic and epigenetic mechanisms in FASD pathobiology, and how this information could be utilized for prevention, early diagnosis and potentially treatment of the affected individuals.

Objective To evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation. Design A matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer. Setting Genetic clinics. Patient(s) Detailed information regarding treatment of infertility was collected from a routinely administered questionnaire. Intervention(s) None. Main Outcome Measure(s) Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment. Result(s) There was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18–2.33) and the subsequent risk of ovarian cancer. Conclusion(s) Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation.

Background Alcohol-related neurodevelopmental disorder (ARND) falls under the umbrella of fetal alcohol spectrum disorder (FASD). Diagnosis of ARND is difficult because individuals do not demonstrate the characteristic facial features associated with fetal alcohol syndrome (FAS). While attentional problems in ARND are similar to those found in attention-deficit/hyperactivity disorder (ADHD), the underlying impairment in attention pathways may be different. Methods Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) was conducted at 3 T. Sixty-three children aged 10 to 14 years diagnosed with ARND, ADHD, and typically developing (TD) controls performed a single-feature and a feature-conjunction visual search task. Results Dorsal and ventral attention pathways were activated during both attention tasks in all groups. Significantly greater activation was observed in ARND subjects during a single-feature search as compared to TD and ADHD groups, suggesting ARND subjects require greater neural recruitment to perform this simple task. ARND subjects appear unable to effectively use the very efficient automatic perceptual ‘pop-out’ mechanism employed by TD and ADHD groups during presentation of the disjunction array. By comparison, activation was lower in ARND compared to TD and ADHD subjects during the more difficult conjunction search task as compared to the single-feature search. Analysis of DTI data using tract-based spatial statistics (TBSS) showed areas of significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the right inferior longitudinal fasciculus (ILF) in ARND compared to TD subjects. Damage to the white matter of the ILF may compromise the ventral attention pathway and may require subjects to use the dorsal attention pathway, which is associated with effortful top-down processing, for tasks that should be automatic. Decreased functional activity in the right temporoparietal junction (TPJ) of ARND subjects may be due to a reduction in the white matter tract’s ability to efficiently convey information critical to performance of the attention tasks. Conclusions Limited activation patterns in ARND suggest problems in information processing along the ventral frontoparietal attention pathway. Poor integrity of the ILF, which connects the functional components of the ventral attention network, in ARND subjects may contribute to the attention deficits characteristic of the disorder.

Background Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec. Methods Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype–phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis. Results This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s. Conclusions Our genotype–phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.

Although it is generally accepted that the proportion of children diagnosed with pervasive developmental disorders (PDDs) has increased in the past two decades, there is no consensus on the prevalence of these conditions. The accompanying large rise in demand for services, together with uncertainty regarding the extent to which the observed increases are due to a true change in risk, has made PDDs a major public health concern. As few data exist on the prevalence of PDDs in Canada, the aim of this study was to estimate the prevalence of diagnosed PDDs in two Canadian provinces (Manitoba and Prince Edward Island (PEI)) and compare characteristics of diagnosed cases between the two regions. To obtain the estimates, children under the age of 15 years with a PDD diagnosis who lived in either province in 2002 were identified by workers at Children’s Special Services, a provincial government program that supports children with special needs in Manitoba, and by the PEI provincial early intervention coordinator (Department of Social Services and Seniors) and special education autism coordinator (Department of Education). The findings show that the prevalence among children 1–14 years of age was 28.4 per 10,000 (95% confidence interval: 26.1–30.8) in Manitoba and 35.2 per 10,000 (95% confidence interval: 28.2–43.4) in PEI. In Manitoba, children of aboriginal identity with PDDs (8.3%) were significantly underrepresented compared with the general population of aboriginal children living off native reserves (15.6%). Sex ratio, sibling risk, and age at initial diagnosis were similar in the two provinces. These findings can serve as a baseline from which to monitor the prevalence of these conditions over time, providing valuable data for researchers, planners, and service providers.