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To evaluate the impact of implementing commercial whole exome sequencing (WES) and targeted gene panel testing in pregnancies with fetal anomalies.A retrospective chart review of 124 patients with sequencing performed by commercial laboratories.The diagnostic yield of WES and panel testing was 21.5% and 26%, respectively, based on likely pathogenic (LP) or pathogenic (P) variants. Forty-two percent of exomes and 32% of panels analysed had one or more variants of uncertain significance (VUS) reported. A multidisciplinary in-depth review of the fetal phenotype, disease phenotype, variant data, and, in some patients, additional prenatal or postnatal investigations increased the diagnostic yield by 5% for exome analysis and 6% for panel analysis.The diagnostic yield of WES and panel testing combined was 23% based on LP and P variants. Although the reporting of VUS contributed to a 5% increase in diagnostic yield for WES and 6% for panels, the large number of VUS reported by commercial laboratories has significant resource implications. Our results support the need for greater adherence to the recommendations on the prenatal reporting of VUS and the importance of a multidisciplinary approach that brings together clinical and laboratory expertise in prenatal genetics and genomics.

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.

Brachydactyly type A1 is an autosomal dominant disorder primarily characterized by hypoplasia/aplasia of the middle phalanges of digits 2–5. Human and mouse genetic perturbations in the BMP-SMAD signaling pathway have been associated with many brachymesophalangies, including BDA1, as causative mutations in IHH and GDF5 have been previously identified. GDF5 interacts directly as the preferred ligand for the BMP type-1 receptor BMPR1B and is important for both chondrogenesis and digit formation. We report pathogenic variants in BMPR1B that are associated with complex BDA1. A c.975A>C (p.(Lys325Asn)) was identified in the first patient displaying absent middle phalanges and shortened distal phalanges of the toes in addition to the significant shortening of middle phalanges in digits 2, 3 and 5 of the hands. The second patient displayed a combination of brachydactyly and arachnodactyly. The sequencing of BMPR1B in this individual revealed a novel c.447-1G>A at a canonical acceptor splice site of exon 8, which is predicted to create a novel acceptor site, thus leading to a translational reading frameshift. Both mutations are most likely to act in a dominant-negative manner, similar to the effects observed in BMPR1B mutations that cause BDA2. These findings demonstrate that BMPR1B is another gene involved with the pathogenesis of BDA1 and illustrates the continuum of phenotypes between BDA1 and BDA2.

Children with fetal alcohol spectrum disorder (FASD) or prenatal alcohol exposure (PAE) frequently exhibit impairment on tasks measuring inhibition. The objective of this study was to determine if a performance-based relationship exists between psychometric tests and eye movement tasks in children with FASD. Participants for this dataset were aged 5–17 years and included those diagnosed with an FASD (n = 72), those with PAE but no clinical FASD diagnosis (n = 21), and typically developing controls (n = 139). Participants completed a neurobehavioral test battery, which included the NEPSY-II subtests of auditory attention, response set, and inhibition. Each participant completed a series of saccadic eye movement tasks, which included the antisaccade and memory-guided tasks. Both the FASD and the PAE groups performed worse than controls on the subtest measures of attention and inhibition. Compared with controls, the FASD group made more errors on the antisaccade and memory-guided tasks. Among the combined FASD/PAE group, inhibition and switching errors were negatively correlated with direction errors on the antisaccade task but not on the memory-guided task. There were no significant correlations in the control group. These data suggests that response inhibition deficits in children with FASD/PAE are associated with difficulty controlling saccadic eye movements which may point to overlapping brain regions damaged by prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests that are used during FASD diagnosis, and may therefore help with early identification of children who would benefit from a multidisciplinary diagnostic assessment.

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation “epi-signature” in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder.

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.

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.

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.

Brachydactyly A1 (BDA1) is an autosomal dominant disorder characterized by shortness of all middle phalanges of the hands and toes, shortness of the proximal phalanges of the first digit, and short stature. Missense mutations in the Indian Hedgehog gene (IHH) are known to cause BDA1, and a second locus has been mapped to chromosome 5p. In a consanguineous French Canadian kindred with BDA1, both IHH and the 5p locus were excluded. Microsatellites flanking GDF5 on chromosome 20q were found to cosegregate with the disease. Sequencing of the GDF5 coding region revealed that a mildly affected individual in the family was heterozygous, and that all of the severely affected individuals were homozygous for a novel missense c.1195C>T mutation that predicts a p.Arg399Cys substitution at a highly conserved amino acid. Functional analysis demonstrated that although the p.Arg399Cys mutant is able to stimulate chondrogenesis, it is much less effective than wild-type GDF5. This data confirms genetic heterogeneity in BDA1, demonstrates that mutations upstream of IHH can result in BDA1, and shows that BDA1 can result from semidominant mutations in GDF5.

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the 'Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.

Prenatal exposure to alcohol can result in a spectrum of adverse developmental outcomes, collectively termed fetal alcohol spectrum disorders (FASDs). This study evaluated deficits in sensory, motor and cognitive processing in children with FASD that can be identified using eye movement testing. Our study group was composed of 89 children aged 8-15 years with a diagnosis within the FASD spectrum [i.e. fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), and alcohol-related neurodevelopmental disorder (ARND)], and 92 controls. Subjects looked either towards (prosaccade) or away from (antisaccade) a peripheral target that appeared on a computer monitor, and eye movements were recorded with a mobile, video-based eye tracker. We hypothesized that: (i) differences in the magnitude of deficits in eye movement control exist across the three diagnostic subgroups; and (ii) children with FASD display a developmental delay in oculomotor control. Children with FASD had increased saccadic reaction times (SRTs), increased intra-subject variability in SRTs, and increased direction errors in both the prosaccade and antisaccade tasks. Although development was associated with improvements across tasks, children with FASD failed to achieve age-matched control levels of performance at any of the ages tested. Moreover, children with ARND had faster SRTs and made fewer direction errors in the antisaccade task than children with pFAS or FAS, although all subgroups were different from controls. Our results demonstrate that eye tracking can be used as an objective measure of brain injury in FASD, revealing behavioral deficits in all three diagnostic subgroups independent of facial dysmorphology.

Background: Prenatal exposure to alcohol can result in a spectrum of adverse developmental outcomes in offspring, collectively termed fetal alcohol spectrum disorders (FASD). Deficits in executive function—the psychological processes involved in controlling voluntary goal-oriented behavior—are prevalent in FASD. Oculomotor tasks have been designed as highly sensitive tools to evaluate components of executive function. Because of the extensive overlap in the brain areas controlling eye movements and those affected in FASD, we hypothesized that individuals with FASD display specific neurobehavioral abnormalities that can be quantified with eye movement testing. Methods: Subjects (8–12 years old) were instructed to look either toward (prosaccade) or away from (antisaccade) a stimulus that appeared in the peripheral visual field. Two fixation conditions were used. In the gap condition, the central fixation point (FP) was removed before the appearance of the peripheral stimulus; in the overlap condition, the FP remained illuminated. Saccadic reaction times (SRTs, time from stimulus appearance to saccade initiation), direction errors (saccades made in the incorrect direction relative to instruction), and express saccades (short-latency: SRT 5 90–140 ms) were measured to assess automatic and volitional saccade control. Results: Compared with controls, FASD children had elongated reaction times, excessive direction errors, and no express saccades. Metric analysis of correct prosaccades revealed a trend toward increased saccadic duration and decreased saccadic velocity in FASD subjects. Conclusion: These results reflect deficits in executive function and motor control, and are consistent with dysfunction of the frontal lobes, possibly due to disrupted inhibitory mechanisms. Therefore, eye movement tasks may be powerful and easy tools for assessing executive function deficits in FASD.

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.

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Previous studies have demonstrated that children with Fetal Alcohol Spectrum Disorder (FASD) exhibit deficits in measures of eye movement control that probe aspects of visuospatial processing and working memory. The goal of the present study was to examine, in a large cohort of children with FASD, prenatal alcohol exposure (PAE) but not FASD, and typically developing control children, the relationship between performance in eye movement tasks and standardized psychometric tests that assess visuospatial processing and working memory. Participants for this dataset were drawn from a large, multi-site investigation, and included children and adolescents aged 5–17 years diagnosed with an FASD (n = 71), those with PAE but no clinical FASD diagnosis (n = 20), and typically developing controls (n = 111). Participants completed a neurobehavioral test battery and a series of saccadic eye movement tasks. The FASD group performed worse than controls on the psychometric and eye movement measures of working memory and visuospatial skills. Within the FASD group, digit recall, block recall, and animal sorting were negatively correlated with sequence errors on the memory-guided task, and arrows was negatively correlated with prosaccade endpoint error. There were no significant correlations in the control group. These data suggest that psychometric tests and eye movement control tasks may assess similar domains of cognitive function, and these assessment tools may be measuring overlapping brain regions damaged due to prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests and are able to assess multiple domains of cognition simultaneously, thereby allowing for an efficient and accurate assessment.

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.

Acrodysostosis is characterized by nasal hypoplasia, peripheral dysostosis, variable short stature, and intellectual impairment. Recently, mutations in PRKAR1A were reported in patients with acrodysostosis and hormone resistance. Subsequently, mutations in a phosphodiesterase gene (PDE4D) were identified in seven sporadic cases. We sequenced PDE4D in seven acrodysostosis patients from five families. Missense mutations were identified in all cases. Families showed de novo inheritance except one family with three affected children whose father was subsequently found to have subtle features of acrodysostosis. There were no recurrent mutations. Short stature and endocrine resistance are rare in this series; however, cognitive involvement and obesity were frequent. This last finding is relevant given PDE4D is insulin responsive and potentially involved in lipolysis. PDE4D encodes a cyclic AMP regulator and places PDE4D-related acrodysostosis within the same family of diseases as pseudohypoparathyroidism, pseudopseudohypoparathyroidism, PRKAR1A-related acrodysostosis and brachydactyly-mental retardation syndrome; all characterized by cognitive impairment and short distal extremities.

Background Holoprosencephaly (HPE), the most common malformation of the human forebrain, may result from mutations in over 12 genes. Sonic Hedgehog (SHH) was the first such gene discovered; mutations in SHH remain the most common cause of nonchromosomal HPE. The severity spectrum is wide, ranging from incompatibility with extrauterine life to isolated midline facial differences. Objective To characterise genetic and clinical findings in individuals with SHH mutations. Methods Through the National Institutes of Health and collaborating centres, DNA from approximately 2000 individuals with HPE spectrum disorders were analysed for SHH variations. Clinical details were examined and combined with published cases. Results This study describes 396 individuals, representing 157 unrelated kindreds, with SHH mutations; 141 (36%) have not been previously reported. SHH mutations more commonly resulted in non-HPE (64%) than frank HPE (36%), and non-HPE was significantly more common in patients with SHH than in those with mutations in the other common HPE related genes (p

We describe the identification and clinical presentation of four individuals from three unrelated families with hemizygous deletions involving the DPYD gene at chromosome 1p21.3. DPYD encodes dihydropyrimidine dehydrogenase, which is the initial and rate-limiting enzyme in the catabolism of pyrimidine bases. All four individuals described met diagnostic criteria for autism spectrum disorder with severe speech delay. Patient 1's deletion was originally reported in 2008, and more detailed clinical information is provided. Subsequently, this male individual was found to have a missense mutation in the X-linked PTCHD1 autism susceptibility gene, which may also contribute to the phenotype. Patients 2 and 3 are siblings with a novel deletion encompassing the DPYD gene. In their mother, the genomic region deleted from chromosome 1p21.3 was inserted into chromosome 10. A fourth proband had a novel 10-kb intragenic deletion of exon 6 of the DPYD gene detected on a higher resolution microarray. Our study suggests that hemizygous deletions involving the DPYD locus present with variable phenotypes which can include speech delay and autistic features, and may also be influenced by additional mutations in other genes, issues which need to be considered in genetic counseling.

Background: Chronic prenatal alcohol exposure causes a spectrum of deleterious effects in offspring, collectively termed fetal alcohol spectrum disorders (FASD), and deficits in executive function are prevalent in FASD. The goal of this research was to test the hypothesis that children with FASD exhibit performance deficits in tasks that assess attention, planning and spatial working memory. Methods: Subjects (8–15 years male and female children) with a diagnosis of fetal alcohol syndrome (FAS), partial FAS (pFAS), or alcohol-related neurodevelopmental disorder (ARND), and age- and sex-matched controls, completed four tasks selected from the Cambridge Neuropsychological Tests Automated Battery (CANTAB®). Results: Compared with age-matched control children (n = 92), subjects with FASD (n = 89) exhibited longer reaction and decision times (effect size range; Cohen's d = .51 to .73), suggesting deficits in attention. Children with FASD demonstrated deficits in planning and spatial working memory that became more pronounced when task difficulty increased. The largest effect size in this study population (Cohen’s d = 1.1) occurred in the spatial working memory task. Only one outcome measure revealed differences across the diagnostic subgroups, although all groups were different from control. Conclusion: This study demonstrates that deficits in multiple executive function domains, including set shifting, planning and strategy use, attention and spatial working memory, can be assessed in children with FASD using an easy to administer, brief battery of computer-based neuropsychological tasks. The tasks appear to be equally sensitive for brain injury resulting from prenatal exposure to alcohol, regardless of the presence of facial dysmorphology.

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.

Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2. Germline mutations of INI1 predispose to the development of rhabdoid tumors of the brain, kidney and extra-renal tissues, consistent with its function as a tumor suppressor gene. We now describe five patients with germline deletions in chromosome band 22q11.2 that included the INI1 gene locus, leading to the development of rhabdoid tumors. Two patients had phenotypic findings that were suggestive but not diagnostic for DiGeorge/Velocardiofacial syndrome (DGS/VCFS). The other three infants had highly aggressive disease with multiple tumors at the time of presentation. The extent of the deletions was determined by fluorescence in situ hybridization and high-density oligonucleotide based single nucleotide polymorphism arrays. The deletions in the two patients with features of DGS/VCFS were distal to the region typically deleted in patients with this genetic disorder. The three infants with multiple primary tumors had smaller but overlapping deletions, primarily involving INI1. The data suggest that the mechanisms underlying the deletions in these patients may be similar to those that lead to DGS/VCFS, as they also appear to be mediated by related, low copy repeats (LCRs) in 22q11.2. These are the first reported cases in which an association has been established between recurrent, interstitial deletions mediated by LCRs in 22q11.2 and a predisposition to cancer.

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).

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 Möbius 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-Möbius 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-Möbius" 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.

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