Lethal multiple pterygium syndrome, large cystic hygroma, and cleft palate: Rare and severe fetal presentations of RYR1- and NEB-related congenital myopathies.

Congenital myopathies are a genetically heterogeneous group of neuromuscular disorders that commonly present with congenital hypotonia and weakness but can also present broadly. The most severe presentation is neonatal with arthrogryposis and, rarely, fetal akinesia and pterygia, features also seen in lethal multiple pterygium syndrome (LMPS). We describe two fetuses with similar phenotype, including hydrops fetalis, large cystic hygromas, bilateral talipes, and fetal akinesia in the second trimester. Genetic diagnoses were made using exome sequencing. Both fetuses had a severe form of congenital myopathy. In the first fetus, we identified two novel compound heterozygous likely pathogenic variants consistent with autosomal recessive RYR1-related congenital myopathy (congenital myopathy 1B). In the second fetus, we identified two likely pathogenic variants, one of which is novel, likely in trans consistent with a diagnosis of autosomal recessive NEB-related congenital myopathy. Reaching a genetic diagnosis for these fetuses allowed the families to receive accurate genetic counseling for future pregnancies. These fetuses highlight the genetic and phenotypic heterogeneity of LMPS, and support a broad approach to genetic testing.

Molecular characterization of 13 patients with PIK3CA-related overgrowth spectrum using a targeted deep sequencing approach.

Activating variants in the PIK3CA gene cause a heterogeneous spectrum of disorders that involve congenital or early-onset segmental/focal overgrowth, now referred to as PIK3CA-related overgrowth spectrum (PROS). Historically, the clinical diagnoses of patients with PROS included a range of distinct syndromes, including CLOVES syndrome, dysplastic megalencephaly, hemimegalencephaly, focal cortical dysplasia, Klippel-Trenaunay syndrome, CLAPO syndrome, fibroadipose hyperplasia or overgrowth, hemihyperplasia multiple lipomatosis, and megalencephaly capillary malformation-polymicrogyria (MCAP) syndrome. MCAP is a sporadic overgrowth disorder that exhibits core features of progressive megalencephaly, vascular malformations, distal limb malformations, cortical brain malformations, and connective tissue dysplasia. In 2012, our research group contributed to the identification of predominantly mosaic, gain-of-function variants in PIK3CA as an underlying genetic cause of the syndrome. Mosaic variants are technically more difficult to detect and require implementation of more sensitive sequencing technologies and less stringent variant calling algorithms. In this study, we demonstrated the utility of deep sequencing using the Illumina TruSight Oncology 500 (TSO500) sequencing panel in identifying variants with low allele fractions in a series of patients with PROS and suspected mosaicism: pathogenic, mosaic PIK3CA variants were identified in all 13 individuals, including 6 positive controls. This study highlights the importance of screening for low-level mosaic variants in PROS patients. The use of targeted panels with deep sequencing in clinical genetic testing laboratories would improve diagnostic yield and accuracy within this patient population.

The emerging spectrum of fetal acetylcholine receptor antibody-related disorders (FARAD).

In utero exposure to maternal antibodies targeting the fetal acetylcholine receptor isoform (fAChR) can impair fetal movement, leading to arthrogryposis multiplex congenita (AMC). Fetal AChR antibodies have also been implicated in apparently rare, milder myopathic presentations termed fetal acetylcholine receptor inactivation syndrome (FARIS). The full spectrum associated with fAChR antibodies is still poorly understood. Moreover, since some mothers have no myasthenic symptoms, the condition is likely underreported, resulting in failure to implement effective preventive strategies. Here we report clinical and immunological data from a multicentre cohort (n = 46 cases) associated with maternal fAChR antibodies, including 29 novel and 17 previously reported with novel follow-up data. Remarkably, in 50% of mothers there was no previously established myasthenia gravis (MG) diagnosis. All mothers (n = 30) had AChR antibodies and, when tested, binding to fAChR was often much greater than that to the adult AChR isoform. Offspring death occurred in 11/46 (23.9%) cases, mainly antenatally due to termination of pregnancy prompted by severe AMC (7/46, 15.2%), or during early infancy, mainly from respiratory failure (4/46, 8.7%). Weakness, contractures, bulbar and respiratory involvement were prominent early in life, but improved gradually over time. Facial (25/34; 73.5%) and variable peripheral weakness (14/32; 43.8%), velopharyngeal insufficiency (18/24; 75%) and feeding difficulties (16/36; 44.4%) were the most common sequelae in long-term survivors. Other unexpected features included hearing loss (12/32; 37.5%), diaphragmatic paresis (5/35; 14.3%), CNS involvement (7/40; 17.5%) and pyloric stenosis (3/37; 8.1%). Oral salbutamol used empirically in 16/37 (43.2%) offspring resulted in symptom improvement in 13/16 (81.3%). Combining our series with all previously published cases, we identified 21/85 mothers treated with variable combinations of immunotherapies (corticosteroids/intravenous immunoglobulin/plasmapheresis) during pregnancy either for maternal MG symptom control (12/21 cases) or for fetal protection (9/21 cases). Compared to untreated pregnancies (64/85), maternal treatment resulted in a significant reduction in offspring deaths (P < 0.05) and other complications, with treatment approaches involving intravenous immunoglobulin/ plasmapheresis administered early in pregnancy most effective. We conclude that presentations due to in utero exposure to maternal (fetal) AChR antibodies are more common than currently recognized and may mimic a wide range of neuromuscular disorders. Considering the wide clinical spectrum and likely diversity of underlying mechanisms, we propose 'fetal acetylcholine receptor antibody-related disorders' (FARAD) as the most accurate term for these presentations. FARAD is vitally important to recognize, to institute appropriate management strategies for affected offspring and to improve outcomes in future pregnancies. Oral salbutamol is a symptomatic treatment option in survivors.

De novo variants in the PABP domain of PABPC1 lead to developmental delay.

PURPOSE: The study aimed to investigate the role of PABPC1 in developmental delay (DD). METHODS: Children were examined by geneticists and pediatricians. Variants were identified using exome sequencing and standard downstream bioinformatics pipelines. We performed in silico molecular modeling and coimmunoprecipitation to test if the variants affect the interaction between PABPC1 and PAIP2. We performed in utero electroporation of mouse embryo brains to enlighten the function of PABPC1. RESULTS: We describe 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1. Further symptoms were seizures and behavioral disorders. Molecular modeling predicted that the variants are pathogenic and would lead to decreased binding affinity to messenger RNA metabolism-related proteins, such as PAIP2. Coimmunoprecipitation confirmed this because it showed a significant weakening of the interaction between mutant PABPC1 and PAIP2. Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not. CONCLUSION: Pathogenic variants in the PABP domain lead to DD, possibly because of interference with the translation initiation and subsequently an impaired neurogenesis in cortical development.

Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists.

PURPOSE AND SCOPE: The aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems. METHODS OF STATEMENT DEVELOPMENT: A multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context. The statement was circulated for comments to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors on 19 February 2021. RESULTS AND CONCLUSIONS: The use of prenatal GWS is indicated for the investigation of multiple fetal anomalies. Its use in the context of isolated fetal anomaly should be guided by available resources and current evidence, which is continually changing. During pregnancy, GWS should be ordered by, or in collaboration with, a medical geneticist. It should be used following detailed phenotyping to interrogate known disease genes, preferably using a trio approach, following detailed fetal phenotyping. Testing should be done with an overall aim to help in the management of the pregnancy, delivery and postnatal care. It should be guided by personal utility of the test for the pregnant person and clinical utility for pregnancy and birth management, as outlined herein. Genetic counselling is crucial in making the parental decision an informed decision. Chromosomal microarray analysis should be completed in parallel or prior to GWS and should be preceded by Quantitative Fluorescent PCR (QF-PCR) for detection of common aneuploidies. In normal circumstances, only pathogenic and likely pathogenic variants with a high likelihood of being associated with the identified fetal anomalies should be reported. Reporting of secondary findings, defined as purposeful analysis of variants in a set of medically actionable genes, should not, by default, be performed in the prenatal context. Laboratories should only report incidental findings that reveal risk of a significant Mendelian condition during infancy and childhood. Should a laboratory have a policy for reporting incidental findings in medically actionable adult-onset conditions, they should only be reported with explicit opt-in consent signed by the tested individuals. Genetic counselling is crucial in disclosing the test results and the implications the results may have for the fetus. It should be emphasised that negative results do not rule out a genetic diagnosis nor guarantee a good prognosis. Postnatal phenotyping and reanalysis of existing data should be considered. Families should be given the opportunity to participate in research studies as appropriate. These recommendations will be routinely re-evaluated as knowledge of the diagnostic and clinical utility of fetal GWS during pregnancy improves.

Mainstreaming Genetic Testing for Adult Patients With Autosomal Dominant Polycystic Kidney Disease.

PURPOSE: Genetic testing results are currently obtained approximately 1 year after referral to a medical genetics team for autosomal dominant polycystic kidney disease (ADPKD). We evaluated a mainstream genetic testing (MGT) pathway whereby the nephrology team provided pre-test counseling and selection of patients with suspected ADPKD for genetic testing prior to direct patient interaction by a medical geneticist. SOURCES OF INFORMATION: A multidisciplinary team of nephrologists, genetic counselors, and medical geneticists developed an MGT pathway for ADPKD using current testing criteria for adult patient with suspected ADPKD and literature from MGT in oncology. METHODS: An MGT pathway was assessed using a prospective cohort and compared to a retrospective cohort of 56 patients with ADPKD who received genetic testing using the standard, traditional pathway prior to implementing the MGT for ADPKD. The mainstream pathway was evaluated using time to diagnosis, diagnostic yield, and a patient survey to assess patient perceptions of the MGT pathway. KEY FINDINGS: We assessed 26 patients with ADPKD using the MGT and 18 underwent genetic testing with return of results. Of them, 52 patients had data available for analysis in the traditional control cohort. The time for return of results using our MGT pathway was significantly shorter with a median time to results of 6 months compared to 12 months for the traditional pathway. We identified causative variants in 61% of patients, variants of uncertain significance in 28%, and 10% had negative testing which is in line with expectations from the literature. The patient surveys showed high satisfaction rates with the MGT pathway. LIMITATIONS: This report is an evaluation of a new genetic testing pathway restricted to a single, publicly funded health care center. The MGT pathway involved a prospective collection of a limited number of patients with ADPKD with comparison to a retrospective cohort of patients with ADPKD evaluated by standard testing. IMPLICATIONS: A MGT pathway using clearly defined criteria and commercially available gene panels for ADPKD can be successfully implemented in a publicly funded health care system to reduce the time required to obtain genetic results.

MOTIF: Actuellement, les résultats du dépistage génétique pour la maladie polykystique rénale autosomique dominante (ADPKD) sont obtenus environ un an après l'aiguillage en médecine génique. Nous avons évalué un parcours de dépistage génétique intégré (DGI) où l'équipe de néphrologie fournit des conseils pré-dépistage et sélectionne les patients soupçonnés d'ADPKD pour un test génétique avant l'interaction directe du patient avec un généticien médical. SOURCES: Une équipe multidisciplinaire constituée de néphrologues, de conseillers en génétique et de généticiens médicaux a développé un parcours de DGI à partir des critères existants pour les patients adultes soupçonnés d'ADPKD et de la littérature portant sur le DGI en oncologie. MÉTHODOLOGIE: Le parcours de DGI a été évalué dans une cohorte prospective puis comparé à une cohorte rétrospective de 56 patients atteints d'ADPKD ayant subi un dépistage génétique selon le parcours traditionnel, avant la mise en œuvre d'un parcours de DGI pour l'ADPKD. Le parcours intégré a été évalué en tenant compte du temps requis pour poser le diagnostic, du rendement diagnostique et d'un sondage auprès des patients évaluant leurs perceptions à l'égard du parcours lui-même. PRINCIPAUX RÉSULTATS: Le parcours de DGI a permis d'évaluer 26 patients atteints d'ADPKD, dont 18 ont subi des tests génétiques avec retour des résultats. Dans la cohorte témoin (dépistage traditionnel), 52 patients disposaient de données disponibles pour l'analyse. Le délai médian pour l'obtention des résultats était significativement plus court avec le parcours de DGI qu'avec le parcours traditionnel (6 mois c. 12 mois). Des variantes causales ont été relevées chez 61 % des patients, 28 % des patients présentaient des variantes de signification incertaine et 10 % ont obtenu des résultats négatifs, ce qui est conforme aux attentes posées par les résultats rapportés dans la littérature. Les sondages menés auprès des patients ont montré des taux de satisfaction élevés à l'égard du parcours de DGI. LIMITES: Ce rapport constitue l'évaluation d'un nouveau parcours de dépistage génétique limitée à un seul centre de soins de santé public. Ce parcours de DGI a été évalué dans une cohorte prospective formée d'un nombre limité de patients atteints d'ADPKD par rapport à une cohorte rétrospective de patients atteints d'ADPKD évalués par la méthode traditionnelle. IMPLICATIONS: Un parcours de DGI utilisant des critères clairement définis et des panels génétiques pour l'ADPKD disponible commercialement peut être mis en œuvre avec succès dans un système de santé public et accélérer l'obtention des résultats génétiques.

Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.

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.

Perinatal outcome and prognostic factors of fetal megacystis diagnosed at 11-14 week's gestation.

OBJECTIVES: To evaluate aneuploidy rate, prognostic factors, and perinatal outcomes following a diagnosis of fetal megacystis at 11-14 week's gestation. METHODS: A retrospective study of first trimester fetal megacystis from 2010 to 2020 was performed, including ultrasound finding, perinatal outcomes, pathology reports, genetic tests, and neonatal investigations. RESULTS: A total of 98 cases of first trimester fetal megacystis was identified with an overall aneuploidy rate of 12%. There were 54% live births and 46% fetal losses including spontaneous fetal demise and elective termination. Among the 45 fetal losses, 64% had additional structural abnormalities at index ultrasound and final diagnoses were achievable in 64% cases. Among the 53 livebirths, additional ultrasound abnormalities were detected in only 1 fetus and spontaneous resolution of megacystis was detected in 96% of cases. The two cases where fetal megacystis persisted had major postnatal diagnoses: cloacal malformation and megacystis-microcolon-intestinal hypoperistalsis syndrome, respectively. Our data showed LBD ≥ 12 mm was the best individual predictor of adverse perinatal outcome and all 11 cases of lower urinary tract obstruction (LUTO) were diagnosed in fetuses with LBD ≥ 12 mm. CONCLUSIONS: First trimester ultrasound provides important prognostic factors and isolated megacystis <12 mm is associated with a positive outcome.

A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y.

Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing ∼97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.

Failure of NIPT to detect constitutional chromoanasynthesis involving chromosome 21 in a case of fetal hydrops-A case report.

We report a case of a de novo ring 21 complex chromosomal rearrangement in a fetus presenting with hydrops. Noninvasive prenatal testing (NIPT) failed to detect the imbalance. This case highlights the need to understand the various limitations and strengths of NIPT technology when counseling patients.

Atypical Prenatal Ultrasound Presentation and Neuropathological Findings in a Neonate With Alpha Thalassemia Major: A Case Report.

Alpha thalassemia major is a hemoglobinopathy caused by the inactivation or deletion of all 4 α-globin alleles. We describe a case of α-thalassemia major with atypical ultrasound and neuropathological findings. The mother had her first prenatal visit at 27 4/7 gestational weeks. Ultrasound revealed a hydropic fetus with multiple anomalies. However, the middle cerebral artery peak systolic velocity (MCA-PSV) suggested that the likelihood of fetal anemia was low. Given the poor prognosis of hydrops fetalis, the parents opted for termination of pregnancy. The neonate died shortly after birth. Autopsy revealed a markedly hydropic female infant with severe limb reduction defects and, in contrast to what was suggested by the prenatal MCA-PSV measurement, unequivocal signs of severe anemia. The brain showed diffuse white matter gliosis. Genetic testing subsequently identified HBA1 and HBA2 deletions, consistent with α-thalassemia major. This case highlights the potential pitfall of MCA-PSV, which is nowadays considered the gold standard for noninvasive detection of fetal anemia. In addition, this is 1 of 2 published case reports detailing neuropathological findings in a fetus or neonate with α-thalassemia major and the first to link α-thalassemia major with diffuse white matter gliosis.

Next-Generation Sequencing Using a Cardiac Gene Panel in Prenatally Diagnosed Cardiac Anomalies.

OBJECTIVE: Most prenatally identified congenital heart defects (CHDs) are the sole structural anomaly detected; however, there is a subgroup of cases where the specific genetic cause will impact prognosis, including chromosome abnormalities and single-gene causes. Next-generation sequencing of all the protein coding regions in the genome or targeted to genes involved in cardiac development is currently possible in the prenatal period, but there are minimal data on the clinical utility of such an approach. This study assessed the outcome of a CHD gene panel that included single-gene causes of syndromic and non-syndromic CHDs. METHOD: Sixteen cases with a fetal CHD identified on prenatal ultrasound were studied using a 108 CHD gene panel. DNA was extracted from cultured amniocytes. RESULTS: There was no diagnostic pathogenic variant identified in these cases. There was an average of 2.9 reportable variants identified per case and the majority of them were variants of uncertain significance. CONCLUSION: Next-generation sequencing has the potential for increased genetic diagnosis for fetal anomalies. However, the large number of variants and the absence of an examinable patient make the interpretation of these variants challenging.

Beta cell function and clinical course in three siblings with thiamine-responsive megaloblastic anemia (TRMA) treated with thiamine supplementation.

Three siblings with thiamine-responsive megaloblastic anemia (TRMA) with a homozygous c.454delGGCATinsAT mutation in SLC19A2 are described. The index case presented at 14 months' old with severe non-ketotic hyperglycemia, dehydration, seizures and sinovenous thrombosis. She was started on insulin and developed sensorineural hearing loss around 2 years old. Two siblings were found to have the same mutation and were started on thiamine. One sibling developed transient hyperglycemia after several years of thiamine supplementation of 12 mg/kg that resolved with an increased thiamine dose (23 mg/kg). A younger sibling continues to remain diabetes-free on thiamine (24 mg/kg). The clinical course in this family suggests that there is an effect of thiamine on pancreatic beta cell function in patients with TRMA given the resolution of impaired fasting glucose with increasing thiamine dose in one sibling and the lack of diabetes to date in the siblings that were treated early with thiamine.

Prenatal Array Comparative Genomic Hybridization in Fetuses With Structural Cardiac Anomalies.

OBJECTIVES: To examine the diagnostic performance of array comparative genomic hybridization (CGH) for fetal cardiac anomalies in two medium-sized Canadian prenatal genetics clinics. METHODS: We prospectively recruited 22 pregnant women with fetal structural cardiac anomalies, normal rapid aneuploidy detection, and FISH for 22q11.2 testing for array CGH analysis. RESULTS: One case had an 8p deletion that was also visible on karyotype and included the GATA4 gene, which has been associated with congenital heart disease. Two cases had inherited pathogenic copy number variants (CNVs) of variable expressivity and penetrance: one was a duplication of 16p11.2 and the other a deletion of 15q11.2. One case had the incidental finding of being a carrier of a recessive disease unrelated to the cardiac anomaly. CONCLUSIONS: Of these prospectively recruited cases of fetal cardiac anomalies, 14% had a pathogenic result on array CGH. Pathogenic CNVs of variable penetrance and expressivity were a significant proportion of the positive results identified. These CNVs are generally associated with neurodevelopmental issues and may or may not have been associated with the fetus' underlying congenital heart disease. Array CGH increases the diagnostic yield in this group of patients; however, certain CNVs remain a challenge for counselling in the prenatal setting.

Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists.

PURPOSE AND SCOPE: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. METHODS OF STATEMENT DEVELOPMENT: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. RESULTS AND CONCLUSIONS: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely re-evaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally.

CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems.

BACKGROUND: The chromodomain helicase DNA binding domain (CHD) proteins modulate gene expression via their ability to remodel chromatin structure and influence histone acetylation. Recent studies have shown that CHD2 protein plays a critical role in embryonic development, tumor suppression and survival. Like other genes encoding members of the CHD family, pathogenic mutations in the CHD2 gene are expected to be implicated in human disease. In fact, there is emerging evidence suggesting that CHD2 might contribute to a broad spectrum of neurodevelopmental disorders. Despite growing evidence, a description of the full phenotypic spectrum of this condition is lacking. METHODS: We conducted a multicentre study to identify and characterise the clinical features associated with haploinsufficiency of CHD2. Patients with deletions of this gene were identified from among broadly ascertained clinical cohorts undergoing genomic microarray analysis for developmental delay, congenital anomalies and/or autism spectrum disorder. RESULTS: Detailed clinical assessments by clinical geneticists showed recurrent clinical symptoms, including developmental delay, intellectual disability, epilepsy, behavioural problems and autism-like features without characteristic facial gestalt or brain malformations observed on magnetic resonance imaging scans. Parental analysis showed that the deletions affecting CHD2 were de novo in all four patients, and analysis of high-resolution microarray data derived from 26,826 unaffected controls showed no deletions of this gene. CONCLUSIONS: The results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.

Novel mutations in geleophysic dysplasia type 1.

Geleophysic dysplasia (GD) is a rare genetic disorder characterized by acromelic dysplasia. Geleophysic dysplasia type 1 (MIM 231050) is autosomal recessive and is caused by homozygous or compound heterozygous mutation in the ADAMTSL2 (a disintegrin and metalloproteinase with thrombosponding repeats-like 2) gene. Geleophysic dysplasia type 2 (MIM 614185) is autosomal dominant and is caused by heterozygous mutation in the fibrillin 1 (FBN1) gene. Here, we present the clinical and histopathologic findings in a child with GD with newly identified ADAMTSL2 mutations. The 1st mutation was probably a pathogenic one, c.[1934G>A] p.[Arg645His], located in exon 13; the 2nd, in intron 8, was probably changing a splice site. While the light and electron microscopic findings were similar to those previously described, hydrocephalus due to aqueductal stenosis might be a new associated finding in these patients. This child with these 2 novel mutations also had an aggressive clinical course with early-onset progressive cardiac valvular disease.