Publications by authors named "David Chitayat"

308 Publications

Risk of major malformations in infants after first-trimester exposure to benzodiazepines: Results from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications.

Depress Anxiety 2022 Jul 31. Epub 2022 Jul 31.

Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston, Massachusetts, USA.

Background: Perinatal anxiety affects 20% of women, and untreated maternal mental illness can cause deleterious effects for women and their children. Benzodiazepines are commonly used to treat anxiety disorders. The reported risk of congenital malformations after in utero benzodiazepine exposure has been inconsistent.

Methods: The Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications prospectively enrolls pregnant women with psychiatric illness who take one or more psychiatric medications. Participants are interviewed twice during pregnancy and at 12 weeks postpartum. Women taking any benzodiazepine during the first trimester of pregnancy were compared with a group of women taking psychiatric medication(s) other than benzodiazepines during pregnancy.

Results: A total of 1053 women were eligible for this analysis; N = 151 women who had taken a benzodiazepine during the first trimester, and the comparison group was N = 902 women. There were 5 (3.21%) major malformations in the exposure group and 32 (3.46%) in the comparison group (odds ratio 0.92; 95% confidence interval 0.35-2.41).

Conclusion: This ongoing pregnancy registry offers reassurance that benzodiazepines do not appear to have major teratogenic effects. The precision of relative risk estimate will improve as the number of participants increases. This and other pregnancy registries will better inform the reproductive safety of benzodiazepines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/da.23280DOI Listing
July 2022

Functional Expression of Multidrug-Resistance (MDR) Transporters in Developing Human Fetal Brain Endothelial Cells.

Cells 2022 Jul 21;11(14). Epub 2022 Jul 21.

Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.

There is little information about the functional expression of the multidrug resistance (MDR) transporters P-glycoprotein (P-gp, encoded by ) and breast cancer resistance protein (BCRP/) in the developing blood-brain barrier (BBB). We isolated and cultured primary human fetal brain endothelial cells (hfBECs) from early and mid-gestation brains and assessed P-gp/ and BCRP/ expression and function, as well as tube formation capability. Immunolocalization of the von Willebrand factor (marker of endothelial cells), zonula occludens-1 and claudin-5 (tight junctions) was detected in early and mid-gestation-derived hfBECs, which also formed capillary-like tube structures, confirming their BEC phenotype. P-gp and BCRP immunostaining was detected in capillary-like tubes and in the cytoplasm and nucleus of hfBECs. P-gp protein levels in the plasma membrane and nuclear protein fractions, as well as P-gp protein/ mRNA and BCRP protein levels decreased ( < 0.05) in hfBECs, from early to mid-gestation. No differences in P-gp or BCRP activity in hfBECs were observed between the two age groups. The hfBECs from early and mid-gestation express functionally competent P-gp and BCRP drug transporters and may thus contribute to the BBB protective phenotype in the conceptus from early stages of pregnancy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cells11142259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9323234PMC
July 2022

Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.

Brain 2022 Jul 19. Epub 2022 Jul 19.

Department of Human Genetics, Emory Healthcare, Atlanta, GA 30322, USA.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awac106DOI Listing
July 2022

KMT2D-NOTCH Mediates Coronary Abnormalities in Hypoplastic Left Heart Syndrome.

Circ Res 2022 Jul 28;131(3):280-282. Epub 2022 Jun 28.

Perinatal Institute, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH (Z.Y., Z.L., V.P.-G., M.G., Y.M., M.G.).

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.122.320783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308708PMC
July 2022

Correction: Gene therapy: perspectives from young adults with Leber's congenital amaurosis.

Eye (Lond) 2022 Feb 25. Epub 2022 Feb 25.

Genetics and Genome Biology (GGB) Program, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41433-022-01994-8DOI Listing
February 2022

Adapting obstetric and neonatal services during the COVID-19 pandemic: a scoping review.

BMC Pregnancy Childbirth 2022 Feb 11;22(1):119. Epub 2022 Feb 11.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, 700 University Avenue, Room 3-908, Toronto, ON, M5G 1X5, Canada.

Background: The provision of care to pregnant persons and neonates must continue through pandemics. To maintain quality of care, while minimizing physical contact during the Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV2) pandemic, hospitals and international organizations issued recommendations on maternity and neonatal care delivery and restructuring of clinical and academic services. Early in the pandemic, recommendations relied on expert opinion, and offered a one-size-fits-all set of guidelines. Our aim was to examine these recommendations and provide the rationale and context to guide clinicians, administrators, educators, and researchers, on how to adapt maternity and neonatal services during the pandemic, regardless of jurisdiction.

Method: Our initial database search used Medical subject headings and free-text search terms related to coronavirus infections, pregnancy and neonatology, and summarized relevant recommendations from international society guidelines. Subsequent targeted searches to December 30, 2020, included relevant publications in general medical and obstetric journals, and updated society recommendations.

Results: We identified 846 titles and abstracts, of which 105 English-language publications fulfilled eligibility criteria and were included in our study. A multidisciplinary team representing clinicians from various disciplines, academics, administrators and training program directors critically appraised the literature to collate recommendations by multiple jurisdictions, including a quaternary care Canadian hospital, to provide context and rationale for viable options.

Interpretation: There are different schools of thought regarding effective practices in obstetric and neonatal services. Our critical review presents the rationale to effectively modify services, based on the phase of the pandemic, the prevalence of infection in the population, and resource availability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12884-022-04409-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8840792PMC
February 2022

Diagnostic yield of genome sequencing for prenatal diagnosis of fetal structural anomalies.

Prenat Diagn 2022 06 1;42(7):822-830. Epub 2022 Feb 1.

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Objective: Genome sequencing (GS >30x) is beginning to be adopted as a comprehensive genome-wide test for the diagnosis of rare disease in the post-natal setting. Recent studies demonstrated the utility of exome sequencing (ES) in prenatal diagnosis, we investigate the potential benefits for GS to act as a comprehensive prenatal test for diagnosis of fetal abnormalities.

Methods: We performed GS on a prospective cohort of 37 singleton fetuses with ultrasound-identified structural abnormalities undergoing invasive prenatal testing. GS was performed in parallel with standard diagnostic testing, and the prioritized variants were classified according to ACMG guidelines and reviewed by a panel of board-certified laboratory and clinical geneticists.

Results: Diagnostic sequence variants were identified in 5 fetuses (14%), with pathogenic variants found in NIPBL, FOXF1, RERE, AMMECR1, and FLT4. A further 7 fetuses (19%) had variants of uncertain significance (VUS) that may explain the phenotypes. Importantly, GS also identified all pathogenic variants reported by clinical microarray (2 CNVs, 5%).

Conclusion: Prenatal GS offered diagnoses (sequence variants and CNVs) in 19% of fetuses with structural anomalies. GS has the potential of replacing multiple consecutive tests, including microarray, gene panels, and WES, to provide the most comprehensive analysis in a timely manner necessary for prenatal diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.6108DOI Listing
June 2022

Variants in cause progressive myoclonus epilepsy and developmental and epileptic encephalopathy.

Brain Commun 2021 18;3(4):fcab245. Epub 2021 Oct 18.

Department of Paediatrics, University of Oxford, Oxford OX1 3QX, UK.

The vacuolar H-ATPase is a large multi-subunit proton pump, composed of an integral membrane V0 domain, involved in proton translocation, and a peripheral V1 domain, catalysing ATP hydrolysis. This complex is widely distributed on the membrane of various subcellular organelles, such as endosomes and lysosomes, and plays a critical role in cellular processes ranging from autophagy to protein trafficking and endocytosis. Variants in , the brain-enriched isoform in the V0 domain, have been recently associated with developmental delay and epilepsy in four individuals. Here, we identified 17 individuals from 14 unrelated families with both with new and previously characterized variants in this gene, representing the largest cohort to date. Five affected subjects with biallelic variants in this gene presented with a phenotype of early-onset progressive myoclonus epilepsy with ataxia, while 12 individuals carried missense variants and showed severe developmental and epileptic encephalopathy. The R740Q mutation, which alone accounts for almost 50% of the mutations identified among our cases, leads to failure of lysosomal hydrolysis by directly impairing acidification of the endolysosomal compartment, causing autophagic dysfunction and severe developmental defect in . Altogether, our findings further expand the neurological phenotype associated with variants in this gene and provide a direct link with endolysosomal acidification in the pathophysiology of -related conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/braincomms/fcab245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665645PMC
October 2021

Semaphorin-Plexin Signaling: From Axonal Guidance to a New X-Linked Intellectual Disability Syndrome.

Pediatr Neurol 2022 01 18;126:65-73. Epub 2021 Oct 18.

Division of Neurology, Department of Pediatrics, Connecticut Children's, University of Connecticut, Farmington, Connecticut. Electronic address:

Background: Semaphorins and plexins are ligands and cell surface receptors that regulate multiple neurodevelopmental processes such as axonal growth and guidance. PLXNA3 is a plexin gene located on the X chromosome that encodes the most widely expressed plexin receptor in fetal brain, plexin-A3. Plexin-A3 knockout mice demonstrate its role in semaphorin signaling in vivo. The clinical manifestations of semaphorin/plexin neurodevelopmental disorders have been less widely explored. This study describes the neurological and neurodevelopmental phenotypes of boys with maternally inherited hemizygous PLXNA3 variants.

Methods: Data-sharing through GeneDx and GeneMatcher allowed identification of individuals with autism or intellectual disabilities (autism/ID) and hemizygous PLXNA3 variants in collaboration with their physicians and genetic counselors, who completed questionnaires about their patients. In silico analyses predicted pathogenicity for each PLXNA3 variant.

Results: We assessed 14 boys (mean age, 10.7 [range 2 to 25] years) with maternally inherited hemizygous PLXNA3 variants and autism/ID ranging from mild to severe. Other findings included fine motor dyspraxia (92%), attention-deficit/hyperactivity traits, and aggressive behaviors (63%). Six patients (43%) had seizures. Thirteen boys (93%) with PLXNA3 variants showed novel or very low allele frequencies and probable damaging/disease-causing pathogenicity in one or more predictors. We found a genotype-phenotype correlation between PLXNA3 cytoplasmic domain variants (exons 22 to 32) and more severe neurodevelopmental disorder phenotypes (P < 0.05).

Conclusions: We report 14 boys with maternally inherited, hemizygous PLXNA3 variants and a range of neurodevelopmental disorders suggesting a novel X-linked intellectual disability syndrome. Greater understanding of PLXNA3 variant pathogenicity in humans will require additional clinical, computational, and experimental validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2021.10.008DOI Listing
January 2022

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

J Med Genet 2021 Sep 20. Epub 2021 Sep 20.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2021-107897DOI Listing
September 2021

Gene therapy: perspectives from young adults with Leber's congenital amaurosis.

Eye (Lond) 2021 Sep 16. Epub 2021 Sep 16.

Genetics and Genome Biology (GGB) Program, The Hospital for Sick Children Research Institute, Toronto, ON, Canada.

Aims/purpose: To investigate Leber congenital amaurosis (LCA) patients' expectations, decision-making processes and gene therapy-related concerns.

Methods: Using a qualitative approach, we explored perceptions of gene therapy and clinical trials among individuals with LCA. Young adults with a clinical diagnosis of LCA were recruited through the Ocular Genetics Programme at the Hospital for Sick Children. Semi-structured interviews were conducted with ten patients and analysed following the principles of qualitative description.

Results: Study participants were aware of ongoing gene therapy research trials and actively sought information regarding advances in ophthalmology and vision restoration. The majority of participants would enrol or were enrolled in a gene-replacement therapy trial, while a minority was ambivalent or would not enrol if provided an opportunity. Participants attributed different values to clinical trials, which influenced their willingness to participate. Intrinsic factors related to coping, adaptation to vision loss and resilience also influenced decision-making.

Discussion: This study highlights the complex factors involved in gene-therapy-related decision-making and acts as a proponent for adopting patient-centred care strategies when counselling individuals considering gene therapy or clinical trial participation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41433-021-01763-zDOI Listing
September 2021

The phenotypic spectrum of AMER1-related osteopathia striata with cranial sclerosis: The first Canadian cohort.

Am J Med Genet A 2021 12 20;185(12):3793-3803. Epub 2021 Aug 20.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, London Health Sciences, Schulich School of Medicine, Western University, London, Ontario, Canada.

Osteopathia striata with cranial sclerosis (OSCS; OMIM# 300373) is a rare X-linked disorder caused by mutations of the AMER1 gene. OSCS is traditionally considered a skeletal dysplasia, characterized by cranial sclerosis and longitudinal striations in the long bone metaphyses. However, OSCS affects many body systems and varies significantly in phenotypic severity between individuals. This case series focuses on the phenotypic presentation and development of individuals with OSCS. We provide an account of 12 patients with OSCS, ranging from 5 months to 38 years of age. These patients were diagnosed with OSCS after genetic testing confirmed pathogenic mutations in AMER1. Patient consent was obtained for photos and participation. Data were collected regarding perinatal history, dysmorphic features, and review of systems. This case series documents common facial dysmorphology, as well as rare extraskeletal features of OSCS, including two patients with intestinal malrotation and two patients with pyloric stenosis. We share four apparently nonmosaic males with OSCS (one de novo and three maternal variants). We also provide a clinical update on a patient who was previously published by Chénier et al. (2012). American Journal of Medical Genetics Part A, 158, 2946-2952. More research is needed to investigate the links between genotype and phenotype and assess the long-term comorbidities and overall quality of life of individuals with OSCS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62452DOI Listing
December 2021

Reproductive Safety of Second-Generation Antipsychotics: Updated Data From the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

J Clin Psychiatry 2021 08 3;82(4). Epub 2021 Aug 3.

Massachusetts General Hospital, Ammon-Pinizzotto Center for Women's Mental Health, Boston, Massachusetts.

Second-generation antipsychotics (SGAs) are prescribed for a wide range of indications in women of reproductive age. The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) was established to determine the risk of major malformations among infants exposed to these medications during the first trimester relative to a comparison group of unexposed infants of mothers with histories of psychiatric morbidity.

Women, aged 18-45 years, with histories of psychiatric illness were prospectively followed through pregnancy and during the postpartum period. Pediatric and maternal medical records were obtained and screened for evidence of major malformations. Potential cases were adjudicated by a dysmorphologist who was blinded to drug exposure.. Recruitment to the Registry, which is based at the Ammon-Pinizzotto Center for Women's Mental Health at Massachusetts General Hospital (MGH), includes nationwide provider referral, self-referral, and advertisement through the MGH Center for Women's Mental Health website.

As of April 9, 2020, 1,906 women had enrolled, including 889 in the exposure group and 1,017 controls. A total of 1,311 women completed the study and were eligible for inclusion in the analysis. Medical records were obtained for 81.3% of participants. Among 640 live births in the exposure group, 16 (2.50%) had confirmed major malformations reported, and among 704 live births in the control group, 14 (1.99%) had confirmed major malformations reported. The estimated odds ratio for major malformations comparing exposed and unexposed infants was 1.48 (95% CI, 0.625-3.517).

Data from the Registry assessing SGAs as a class indicate that they are unlikely to have a major teratogenic effect. These findings provide pertinent information for women and their health care providers regarding decisions about atypical antipsychotic use during pregnancy.

ClinicalTrails.gov identifier: NCT01246765.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4088/JCP.20m13745DOI Listing
August 2021

Haploinsufficiency of SF3B2 causes craniofacial microsomia.

Nat Commun 2021 08 3;12(1):4680. Epub 2021 Aug 3.

Department of Pediatrics, Division of Craniofacial Medicine, University of Washington, Seattle, WA, USA.

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-24852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333351PMC
August 2021

Mapping the cellular origin and early evolution of leukemia in Down syndrome.

Science 2021 07;373(6551)

Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. Because Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular and developmental context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal hematopoietic cells and xenotransplantation. GATA binding protein 1 () mutations caused transient preleukemia when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 microRNAs affected predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117/KIT proto-oncogene (KIT) cells mediated the propagation of preleukemia and leukemia, and KIT inhibition targeted preleukemic stem cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abf6202DOI Listing
July 2021

Mild Idiopathic Infantile Hypercalcemia-Part 1: Biochemical and Genetic Findings.

J Clin Endocrinol Metab 2021 09;106(10):2915-2937

Division of Endocrinology and Diabetes and Center for Bone Health, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Context: Idiopathic infantile hypercalcemia (IIH), an uncommon disorder characterized by elevated serum concentrations of 1,25 dihydroxyvitamin D (1,25(OH)2D) and low parathyroid hormone (PTH) levels, may present with mild to severe hypercalcemia during the first months of life. Biallelic variants in the CYP24A1 or SLC34A1 genes are associated with severe IIH. Little is known about milder forms.

Objective: This work aims to characterize the genetic associations and biochemical profile of mild IIH.

Methods: This is a cross-sectional study including children between age 6 months and 17 years with IIH who were followed in the Calcium Clinic at the Hospital for Sick Children (SickKids), Toronto, Canada. Twenty children with mild IIH on calcium-restricted diets were evaluated. We performed a dietary assessment and analyzed biochemical measures including vitamin D metabolites and performed a stepwise molecular genetic analysis. Complementary biochemical assessments and renal ultrasounds were offered to first-degree family members of positive probands.

Results: The median age was 16 months. Median serum levels of calcium (2.69 mmol/L), urinary calcium:creatinine ratio (0.72 mmol/mmol), and 1,25(OH)2D (209 pmol/L) were elevated, whereas intact PTH was low normal (22.5 ng/L). Mean 1,25(OH)2D/PTH and 1,25(OH)2D/25(OH)D ratios were increased by comparison to healthy controls. Eleven individuals (55%) had renal calcification. Genetic variants were common (65%), with the majority being heterozygous variants in SLC34A1 and SLC34A3, while a minority showed variants of CYP24A1 and other genes related to hypercalciuria.

Conclusion: The milder form of IIH has a distinctive vitamin D metabolite profile and is primarily associated with heterozygous SLC34A1 and SLC34A3 variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475208PMC
September 2021

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Am J Hum Genet 2021 06 27;108(6):1053-1068. Epub 2021 Apr 27.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206150PMC
June 2021

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

J Hum Genet 2021 Oct 20;66(10):995-1008. Epub 2021 Apr 20.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-021-00925-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472897PMC
October 2021

Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.

EMBO Mol Med 2021 05 14;13(5):e13258. Epub 2021 Apr 14.

Section Cell Biology, Center for Molecular Medicine, Institute of Biomembranes, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41 and VPS41 ; VPS41 and VPS41 ) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41 enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41 /VPS41 abolished the neuroprotective function of VPS41 against α-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/emmm.202013258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103106PMC
May 2021

Genetic counselling for infertile men of known and unknown etiology.

Transl Androl Urol 2021 Mar;10(3):1479-1485

Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

Of the couples trying to conceive (had frequent, unprotected sexual intercourse for a year or longer) 15% will experience infertility with the annual incidence of infertility estimated at 1.2 couples per 1,000 total in the general population. Male factors contribute to over 50% of the cases with 7% of the male population experiencing infertility. Not being able to conceive a child is emotionally traumatic and frustrating and can affect the person's self esteem and the couple's relationship. Major progress has been achieved in identifying the etiology of male infertility and especially the genetic causes. However, in about 40% of the male infertility cases, the etiology remains unknown and both the diagnosis and/or treatment are a challenge. Genetic testing to determine the underlying genetic cause of infertility is not 100% and genes involved are still being discovered. Consequently, negative genetic test results do not rule out a genetic cause. Thus, genetic counselling should include information regarding the genetic etiology, if known, and the treatment options available. Furthermore, when the infertile couple/male is seeking assisted reproductive technology (ART) using intracytoplasmic sperm injection (ICSI), genetic counselling should include information regarding the risk of transmitting the genetic disorder, causing the male infertility, to the offspring. Therefore, the provision of genetic counselling is an integral component in the investigation and treatment of male infertility. This article will discuss the genetic counselling approach in cases with male infertility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/tau-2019-gcmi-09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039627PMC
March 2021

Tumor surveillance for children and adolescents with cancer predisposition syndromes: The psychosocial impact reported by adolescents and caregivers.

Pediatr Blood Cancer 2021 08 31;68(8):e29021. Epub 2021 Mar 31.

Department of Pediatrics, Division of Hematology-Oncology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Purpose: Individuals with cancer predisposition syndromes (CPS) are often followed in cancer screening programs, which aim to detect early stage tumors. While cancer surveillance has the potential to improve patient outcomes, its psychosocial impact is uncharacterized in the pediatric population. We examined the cancer surveillance experience from the perspectives of adolescents and parents of children at risk of developing cancer.

Patients And Methods: Using grounded theory and thematic analysis qualitative methodology, we conducted semi-structured interviews with parents and adolescents, separately. Interviews were transcribed verbatim and coded separately to derive overlapping and unique themes.

Results: We completed 20 semi-structured interviews (11 parents and nine adolescents). Positive experiences were related to feelings of reassurance and taking a proactive approach. Both adolescents and parents experienced worry, related to practical aspects of screening, and related to the reminder of cancer risk that manifests with surveillance appointments. This worry was cyclical, associated with appointments, and generally waned over time. Participants felt that the benefits of surveillance outweighed perceived challenges. Open communication with health care providers, and equipping parents/adolescents with vocabulary to discuss their diagnosis and care with others, were felt to be important for mitigating worries associated with cancer risk and surveillance.

Conclusion: Parents and adolescents experience worry associated with surveillance for CPS, which may warrant regular psychosocial support, particularly during the first year following CPS diagnosis. Enhancing communication with the health care team and among and beyond immediate family members represents an additional important strategy to mitigate adverse experiences and perceptions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pbc.29021DOI Listing
August 2021

Reproductive safety of aripiprazole: data from the Massachusetts General Hospital National Pregnancy Registry for Atypical Antipsychotics.

Arch Womens Ment Health 2021 08 12;24(4):659-667. Epub 2021 Mar 12.

Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston, MA, USA.

Aripiprazole has become one of the most commonly prescribed psychotropics, making a more comprehensive understanding of its reproductive safety profile a priority. The goal of the current analysis was to determine the risk of major malformations in infants exposed during the first trimester of pregnancy to aripiprazole compared to infants whose mothers had psychiatric diagnoses but did not use an atypical antipsychotic during pregnancy. The National Pregnancy Registry for Atypical Antipsychotics is a prospective pharmacovigilance program in which pregnant women are enrolled and interviewed during pregnancy and the postpartum period. Medical records are assessed to confirm presence or absence of major malformations. Pregnant women ages 18-45 with psychiatric diagnoses are enrolled. As of April 2020, N = 848 women who had delivered infants were eligible for analyses. A total of 158 women with first trimester exposure to aripiprazole were compared to 690 controls. For 163 infants born to women in the exposed group, seven major malformations were confirmed (4.29%), compared to fourteen of the 690 unexposed infants (1.99%). The unadjusted odds ratio for major malformations between aripiprazole-exposed and unexposed infants was 2.21 (95% confidence interval [CI] = (0.88, 5.57) The adjusted odds ratio for major malformations was 1.35 (95% confidence interval [CI] = (0.43, 4.20). After adjustment for confounding variables, the risk of major malformations after first trimester exposure to aripiprazole was not significant compared to controls. While these results are reassuring, they are limited by relatively small numbers of participants. Future analyses with larger numbers are expected to provide more of a complete and precise reproductive safety profile regarding aripiprazole use during pregnancy. Trial registration: clinicaltrials.gov NCT01246765.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00737-021-01115-6DOI Listing
August 2021

Prenatally diagnosed omphaloceles: Report of 92 cases and association with Beckwith-Wiedemann syndrome.

Prenat Diagn 2021 Jun 17;41(7):798-816. Epub 2021 Mar 17.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Objective: Describe the prevalence, perinatal and long-term outcomes of Beckwith-Wiedemann syndrome (BWS) among prenatally detected omphaloceles.

Methods: All prenatally diagnosed omphaloceles from 2010 to 2015 within a single tertiary care centre were identified. An echocardiogram and detailed fetal ultrasound were performed, and amniocentesis was offered with karyotype/microarray analysis and BWS molecular testing. Perinatal, neonatal, and long-term outcomes were retrieved for BWS cases.

Results: Among 92 omphaloceles, 62 had additional anomalies. Abnormal karyotypes were identified in 23/62 (37%) non-isolated and 2/30 (7%) isolated cases. One BWS case (5%) was identified among non-isolated omphaloceles and six BWS cases (37.5%) were identified among isolated omphaloceles after exclusion of aneuploidy. Among 19 BWS cases, 21% were conceived by ART. All omphaloceles underwent primary closure. Prenatally, macrosomia and polyhydramnios were seen in 42%. Macroglossia and nephromegaly were more commonly detected postnatally. Preterm birth occurred in 10/19 (53%) cases and cesarean deliveries were performed in 7/19 (40%) cases. Overall mortality was 20% (4/19). Embryonal tumors were diagnosed in 2/16 (12.5%) children, and neurodevelopmental outcomes were normal in 9/12 (75%) survivors.

Conclusions: After excluding aneuploidy, BWS was identified in 37.5% and 5% of isolated and non-isolated omphaloceles, respectively. Omphaloceles were small-moderate size with good long-term surgical and neurodevelopmental outcomes when isolated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5930DOI Listing
June 2021

The role of digital tools in the delivery of genomic medicine: enhancing patient-centered care.

Genet Med 2021 06 2;23(6):1086-1094. Epub 2021 Mar 2.

Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.

Purpose: Alternative models of genetic counseling are needed to meet the rising demand for genomic sequencing. Digital tools have been proposed as a method to augment traditional counseling and reduce burden on professionals; however, their role in delivery of genetic counseling is not established. This study explored the role of the Genomics ADvISER, a digital decision aid, in delivery of genomic counseling.

Methods: We performed secondary analysis of 52 pretest genetic counseling sessions that were conducted over the course of a randomized controlled trial evaluating the effectiveness of the Genomics ADvISER. As part of the trial, participants were randomized to receive standard counseling or use the tool and then speak with a counselor. A qualitative interpretive description approach using thematic analysis and constant comparison was used for analysis.

Results: In the delivery of genomic counseling, the Genomics ADvISER contributed to enhancing counseling by (1) promoting informed dialogue, (2) facilitating preference-sensitive deliberation, and (3) deepening personalization of decisions, all of which represent fundamental principles of patient-centered care: providing clear high-quality information, respecting patients' values, preferences, and expressed needs, and providing emotional support.

Conclusion: This study demonstrates that our digital tool contributed to enhancing patient-centered care in the delivery of genomic counseling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01112-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9306004PMC
June 2021

Heterozygous NOTCH1 deletion associated with variable congenital heart defects.

Clin Genet 2021 06;99(6):836-841

The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Pathogenic heterozygous variants in the NOTCH1 gene are known to be associated with both left and right-sided congenital cardiac anomalies with strikingly incomplete penetrance and variable phenotypic expressivity. De novo NOTCH1 whole gene deletion has been reported rarely in the literature and its association with cardiac defects is less well established. Here, we report four cases of NOTCH1 gene deletion from two families associated with a spectrum of congenital heart defects from bicuspid aortic valve to complex cardiac anomalies. This is the first description of a familial NOTCH1 deletion, showing apparently high penetrance, which may be unique to this mechanism of disease. Immunohistochemical staining of cardiac tissue demonstrated reduced levels of NOTCH1 expression in both the left and right ventricular outflow tracts. These cases suggest that haploinsufficiency caused by NOTCH1 gene deletion is associated with both mild and severe cardiac defects, similar to those caused by pathogenic variants in the gene, but with apparently higher, if not complete, penetrance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13948DOI Listing
June 2021

The point-of-care use of a facial phenotyping tool in the genetics clinic: Enhancing diagnosis and education with machine learning.

Am J Med Genet A 2021 04 8;185(4):1151-1158. Epub 2021 Feb 8.

Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children University of Toronto, Toronto, Ontario, Canada.

Computer-assisted pattern recognition platforms, such as Face2Gene® (F2G), can facilitate the diagnosis of children with rare genetic syndromes by comparing a patient's features to known genetic diagnoses. Our work designed, implemented, and evaluated an innovative model of care in clinical genetics in a heterogeneous and multicultural patient population that utilized this facial phenotyping software at the point-of-care. We assessed the performance of F2G by comparing the suggested diagnoses to the patient's confirmed molecular diagnosis. Providers' overall experiences with the technology and trainees' educational experiences were assessed with questionnaires. We achieved an overall diagnostic yield of 57%. This increased to 82% when cases diagnosed with syndromes not recognized by F2G were removed. The mean rank of a confirmed diagnosis in the top 10 was 2.3 (CI 1.5-3.2) and the mean gestalt score 37.6%. The most commonly suggested diagnoses were Noonan syndrome, mucopolysaccharidosis, and 22q11.2 deletion syndrome. Our qualitative assessment revealed that clinicians and trainees saw value using the tool in practice. Overall, this work helped to implement an innovative patient care delivery model in clinical genetics that utilizes a facial phenotyping tool at the point-of-care. Our data suggest that F2G has utility in the genetics clinic as a clinical decision support tool in diverse populations, with a majority of patients having their eventual diagnosis listed in the top 10 suggested syndromes based on a photograph alone. It shows promise for further integration into clinical care and medical education, and we advocate for its continued use, adoption and refinement along with transparent and accountable industrial partnerships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62092DOI Listing
April 2021

Brain and Placental Pathology in Fetal COL4A1 Related Disease.

Pediatr Dev Pathol 2021 May-Jun;24(3):175-186. Epub 2021 Jan 21.

Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Introduction: Although fetal brain injury due to gene mutation is well documented, fetal central nervous system (CNS) and placental histopathology lack description. We report CNS and placental pathology in fetal cases with symptomatic mutation.

Methods: We retrieved four autopsy cases of COL4A1 related disease, confirmed by genetic sequencing after fetal brain injury was detected.

Results: One case was a midgestation fetus with residua of ventricular zone hemorrhage and normal placental villi. Three cases were 30-32 week gestation fetuses: two demonstrated CNS small vessel thrombosis, with CNS injury. Both demonstrated high grade placental fetal vascular malperfusion (FVM). One additionally showed villous dysmorphism, the other demonstrated mild villous immaturity. The fetus whose placenta demonstrated high grade FVM was growth restricted. A fourth fetus demonstrated schizencephaly with a CNS arteriopathy with smooth muscle cell degeneration and cerebral infarcts; the placenta demonstrated severe villous dysmorphism and low grade FVM.

Discussion: These cases confirm that small vessel disease is important in producing intracranial pathology in mutation. We report an arteriopathy distinct from microvascular thrombosis and demonstrate that placental pathology is common in fetal COL4A1 related disease. This tentatively suggests that placental pathology may contribute to CNS abnormalities by affecting circulatory sufficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1093526620984083DOI Listing
November 2021
-->