Publications by authors named "Wendy K Chung"

497 Publications

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
June 2021

De novo and bi-allelic variants in AP1G1 cause neurodevelopmental disorder with developmental delay, intellectual disability, and epilepsy.

Am J Hum Genet 2021 Jun 3. Epub 2021 Jun 3.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.

Adaptor protein (AP) complexes mediate selective intracellular vesicular trafficking and polarized localization of somatodendritic proteins in neurons. Disease-causing alleles of various subunits of AP complexes have been implicated in several heritable human disorders, including intellectual disabilities (IDs). Here, we report two bi-allelic (c.737C>A [p.Pro246His] and c.1105A>G [p.Met369Val]) and eight de novo heterozygous variants (c.44G>A [p.Arg15Gln], c.103C>T [p.Arg35Trp], c.104G>A [p.Arg35Gln], c.229delC [p.Gln77Lys11], c.399_400del [p.Glu133Aspfs37], c.747G>T [p.Gln249His], c.928-2A>C [p.?], and c.2459C>G [p.Pro820Arg]) in AP1G1, encoding gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), associated with a neurodevelopmental disorder (NDD) characterized by mild to severe ID, epilepsy, and developmental delay in eleven families from different ethnicities. The AP1γ1-mediated adaptor complex is essential for the formation of clathrin-coated intracellular vesicles. In silico analysis and 3D protein modeling simulation predicted alteration of AP1γ1 protein folding for missense variants, which was consistent with the observed altered AP1γ1 levels in heterologous cells. Functional studies of the recessively inherited missense variants revealed no apparent impact on the interaction of AP1γ1 with other subunits of the AP-1 complex but rather showed to affect the endosome recycling pathway. Knocking out ap1g1 in zebrafish leads to severe morphological defect and lethality, which was significantly rescued by injection of wild-type AP1G1 mRNA and not by transcripts encoding the missense variants. Furthermore, microinjection of mRNAs with de novo missense variants in wild-type zebrafish resulted in severe developmental abnormalities and increased lethality. We conclude that de novo and bi-allelic variants in AP1G1 are associated with neurodevelopmental disorder in diverse populations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.05.007DOI Listing
June 2021

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

Genet Med 2021 May 30. Epub 2021 May 30.

Department of Medical Genetics, Centre for Applied Neurogenetics, University of British Columbia, Vancouver, BC, Canada.

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development.

Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b.

Results: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye.

Conclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01196-9DOI Listing
May 2021

UBA2 variants underlie a recognizable syndrome with variable aplasia cutis congenita and ectrodactyly.

Genet Med 2021 May 26. Epub 2021 May 26.

National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: The human chromosome 19q13.11 deletion syndrome is associated with a variable phenotype that includes aplasia cutis congenita (ACC) and ectrodactyly as specific features. UBA2 (ubiquitin-like modifier-activating enzyme 2) lies adjacent to the minimal deletion overlap region. We aimed to define the UBA2-related phenotypic spectrum in humans and zebrafish due to sequence variants and to establish the mechanism of disease.

Methods: Exome sequencing was used to detect UBA2 sequence variants in 16 subjects in 7 unrelated families. uba2 loss of function was modeled in zebrafish. Effects of human missense variants were assessed in zebrafish rescue experiments.

Results: Seven human UBA2 loss-of-function and missense sequence variants were detected. UBA2-phenotypes included ACC, ectrodactyly, neurodevelopmental abnormalities, ectodermal, skeletal, craniofacial, cardiac, renal, and genital anomalies. uba2 was expressed in zebrafish eye, brain, and pectoral fins; uba2-null fish showed deficient growth, microcephaly, microphthalmia, mandibular hypoplasia, and abnormal fins. uba2-mRNAs with human missense variants failed to rescue nullizygous zebrafish phenotypes.

Conclusion: UBA2 variants cause a recognizable syndrome with a wide phenotypic spectrum. Our data suggest that loss of UBA2 function underlies the human UBA2 monogenic disorder and highlights the importance of SUMOylation in the development of affected tissues.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01182-1DOI Listing
May 2021

Developmental basis of trachea-esophageal birth defects.

Dev Biol 2021 May 21;477:85-97. Epub 2021 May 21.

Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Center for Stem Cell & Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Electronic address:

Trachea-esophageal defects (TEDs), including esophageal atresia (EA), tracheoesophageal fistula (TEF), and laryngeal-tracheoesophageal clefts (LTEC), are a spectrum of life-threatening congenital anomalies in which the trachea and esophagus do not form properly. Up until recently, the developmental basis of these conditions and how the trachea and esophagus arise from a common fetal foregut was poorly understood. However, with significant advances in human genetics, organoids, and animal models, and integrating single cell genomics with high resolution imaging, we are revealing the molecular and cellular mechanisms that orchestrate tracheoesophageal morphogenesis and how disruption in these processes leads to birth defects. Here we review the current understanding of the genetic and developmental basis of TEDs. We suggest future opportunities for integrating developmental mechanisms elucidated from animals and organoids with human genetics and clinical data to gain insight into the genotype-phenotype basis of these heterogeneous birth defects. Finally, we envision how this will enhance diagnosis, improve treatment, and perhaps one day, lead to new tissue replacement therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ydbio.2021.05.015DOI Listing
May 2021

Neurodevelopmental Phenotypes in Individuals with Pathogenic Variants in CHAMP1.

Cold Spring Harb Mol Case Stud 2021 May 21. Epub 2021 May 21.

Columbia University

Background: De novo pathogenic variants in CHAMP1 (chromosome alignment maintaining phosphoprotein 1) that encodes kinetochore-microtubule associated protein on 13q34 cause a rare neurodevelopmental disorder.

Methods: We enrolled 14 individuals with pathogenic variants in CHAMP1 that were documented by exome sequencing or gene panel sequencing. Medical history interviews, seizure surveys, Vineland Adapted Behavior Scales Second Edition, and other behavioral surveys were completed by primary care givers of available participants in Simons Searchlight. Clinicians extracted clinical data from the medical record for two participants.

Results: We report on clinical features of fourteen individuals (ages 2-26) with de novo predicted loss of function variants in CHAMP1 and compare them with previously reported cases (total n=32). At least two individuals have the same de novo variant: p.(Ser181Cysfs*5), p.(Trp348*), p.(Arg398*), p.(Arg497*), or p.(Tyr709*). Common phenotypes include intellectual disability/developmental delay, language impairment, congenital and acquired microcephaly, behavioral problems including autism spectrum disorder, seizures, hypotonia, gastrointestinal issues of reflux and constipation, and ophthalmologic issues. Other rarely observed phenotypes include leukemia, failure to thrive and high pain tolerance.

Conclusion: Pathogenic variants in CHAMP1 are associated with a variable clinical phenotype of developmental delay/intellectual disability and seizures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/mcs.a006092DOI Listing
May 2021

Questioning the validity of clinically available breast cancer polygenic risk scores: comparison of two labs reveals discrepancies.

Fam Cancer 2021 May 18. Epub 2021 May 18.

Department of Pediatrics, Columbia University Irving Medical Center, 1150 St. Nicholas Ave, Russ Berrie Pavilion, 6th Fl, Rm620, New York, NY, 10032, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10689-021-00260-2DOI Listing
May 2021

Genomic medicine implementation protocols in the PhenX Toolkit: tools for standardized data collection.

Genet Med 2021 May 10. Epub 2021 May 10.

National Human Genome Research Institute, Bethesda, MD, USA.

Purpose: The PhenX Toolkit ( www.phenxtoolkit.org ), an online catalog of recommended measurement protocols, facilitates cross-study analyses for research with human participants. The PhenX Steering Committee recommended genomic medicine implementation as a new research domain, with the following scope: genomic knowledge and education (both patients and providers); implementation science; changes in management and treatment; return of results; patient outcomes; and ethical, legal, and social issues (ELSI) associated with genomic research.

Methods: A seven-member expert Working Group convened in October 2019 to identify well-established measurement protocols for a new genomic medicine implementation domain and used the established PhenX consensus process to select measurement protocols for inclusion in the PhenX Toolkit.

Results: The Working Group recommended 15 measurement protocols for inclusion in the PhenX Toolkit, with priority given to those with empirical evidence supporting validity. Consortia funded by the National Institutes of Health, and particularly the National Human Genome Research Institute, proved critical in identifying protocols with established utility in this research domain, and identified protocols that were developed through a rigorous process for scope elements that lacked formally validated protocols.

Conclusion: Use of these protocols, which were released in September 2020, can facilitate standard data collection for genomic medicine implementation research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01183-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108409PMC
May 2021

Rare variant analysis of 4241 pulmonary arterial hypertension cases from an international consortium implicates FBLN2, PDGFD, and rare de novo variants in PAH.

Genome Med 2021 May 10;13(1):80. Epub 2021 May 10.

Department of Pediatrics, Columbia University Irving Medical Center, 1150 St. Nicholas Avenue, Room 620, New York, NY, 10032, USA.

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined.

Methods: To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource - Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD.

Results: Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e-5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development.

Conclusions: Rare variant analysis of a large international consortium identified two new candidate genes-FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00891-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112021PMC
May 2021

Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.

Am J Hum Genet 2021 May;108(5):857-873

GeneDx, Gaithersburg, MD 20877, USA.

The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2021.04.001DOI Listing
May 2021

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

J Am Heart Assoc 2021 May 28;10(9):e017731. Epub 2021 Apr 28.

Wayne State University School of Medicine Detroit MI.

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (=0.005 and =0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.017731DOI Listing
May 2021

Variants in STXBP3 Are Associated With Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation.

J Crohns Colitis 2021 Apr 23. Epub 2021 Apr 23.

Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL, USA.

Background And Aims: Very early onset inflammatory bowel disease (VEOIBD) is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic etiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation.

Methods: Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss, and, in the majority, recurrent infections. Genetic etiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on PBMCs and functional studies with epithelial cell lines were employed.

Results: In each of the 10 patients, we identified damaging heterozygous or biallelic variants in Syntaxin-Binding Protein 3 gene (STXBP3), a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and led to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity.

Conclusion: Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ecco-jcc/jjab077DOI Listing
April 2021

Genotype and defects in microtubule-based motility correlate with clinical severity in -associated neurological disorder.

HGG Adv 2021 Apr 30;2(2). Epub 2021 Jan 30.

Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA.

KIF1A-associated neurological disorder (KAND) encompasses a group of rare neurodegenerative conditions caused by variants in ,a gene that encodes an anterograde neuronal microtubule (MT) motor protein. Here we characterize the natural history of KAND in 117 individuals using a combination of caregiver or self-reported medical history, a standardized measure of adaptive behavior, clinical records, and neuropathology. We developed a heuristic severity score using a weighted sum of common symptoms to assess disease severity. Focusing on 100 individuals, we compared the average clinical severity score for each variant with predictions of deleteriousness and location in the protein. We found increased severity is strongly associated with variants occurring in protein regions involved with ATP and MT binding: the P loop, switch I, and switch II. For a subset of variants, we generated recombinant proteins, which we used to assess transport by assessing neurite tip accumulation and to assess MT binding, motor velocity, and processivity using total internal reflection fluorescence microscopy. We find all modeled variants result in defects in protein transport, and we describe three classes of protein dysfunction: reduced MT binding, reduced velocity and processivity, and increased non-motile rigor MT binding. The rigor phenotype is consistently associated with the most severe clinical phenotype, while reduced MT binding is associated with milder clinical phenotypes. Our findings suggest the clinical phenotypic heterogeneity in KAND likely reflects and parallels diverse molecular phenotypes. We propose a different way to describe KAND subtypes to better capture the breadth of disease severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xhgg.2021.100026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054982PMC
April 2021

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry.

J Pediatr Endocrinol Metab 2021 May 13;34(5):633-638. Epub 2021 Apr 13.

Department of Pediatrics, Division of Molecular Genetics, Columbia University Medical Center, New York, NY,USA.

Objectives: There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY.

Methods: We used a tiered testing approach focusing initially on and and then expanding to exome sequencing for those individuals without identified mutations in or . The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%.

Results: Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in or . Less frequently, mutations were identified in , , , and . For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation.

Conclusions: Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1515/jpem-2020-0501DOI Listing
May 2021

Availability of Services and Caregiver Burden: Supporting Individuals With Neurogenetic Conditions During the COVID-19 Pandemic.

J Child Neurol 2021 Apr 8:8830738211001209. Epub 2021 Apr 8.

Simons Foundation, New York, NY, USA.

Because of the COVID-19 pandemic, in-person services for individuals with neurodevelopmental disabilities were disrupted globally, resulting in a transition to remote delivery of services and therapies. For individuals with neurogenetic conditions, reliance on nonclinical caregivers to facilitate all therapies and care was unprecedented. The study aimed to (1) describe caregivers' reported impact on their dependent's services, therapies, medical needs, and impact on themselves as a result of the COVID-19 pandemic and (2) assess the relationship between the extent of disruption of services and the degree of self-reported caregiver burden. Two online questionnaires were completed by caregivers participating in Simons Searchlight in April and May 2020. Surveys were completed by caregivers of children or dependent adults with neurodevelopmental genetic conditions in Simons Searchlight. Caregivers reported that the impact of the COVID-19 pandemic moderately or severely disrupted services, therapies, or medical supports. The majority of caregivers were responsible for providing some aspect of therapy. Caregivers reported "feeling stressed but able to deal with problems as they arise," and reported lower anxiety at follow-up. Caregivers reported that telehealth services were not meeting the needs of those with complex medical needs. Future surveys will assess if and how medical systems, educational programs, therapists, and caregivers adapt to the challenges arising during the COVID-19 pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/08830738211001209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033176PMC
April 2021

Reproductive decision-making in families containing multiple individuals with epilepsy.

Epilepsia 2021 May 4;62(5):1220-1230. Epub 2021 Apr 4.

G. H. Sergievsky Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.

Objective: This study evaluated factors influencing reproductive decision-making in families containing multiple individuals with epilepsy.

Methods: One hundred forty-nine adults with epilepsy and 149 adult biological relatives without epilepsy from families containing multiple affected individuals completed a self-administered questionnaire. Participants answered questions regarding their belief in a genetic cause of epilepsy (genetic attribution) and estimated risk of epilepsy in offspring of an affected person. Participants rated factors for their influence on their reproductive plans, with responses ranging from "much more likely" to "much less likely" to want to have a child. Those with epilepsy were asked, "Do you think you would have wanted more (or any) children if you had not had epilepsy?"

Results: Participants with epilepsy had fewer offspring than their unaffected relatives (mean = 1.2 vs. 1.9, p = .002), and this difference persisted among persons who had been married. Estimates of risk of epilepsy in offspring of an affected parent were higher among participants with epilepsy than among relatives without epilepsy (mean = 27.2 vs. 19.6, p = .002). Nineteen percent of participants with epilepsy responded that they would have wanted more children if they had not had epilepsy. Twenty-five percent of participants with epilepsy responded that "the chance of having a child with epilepsy" or "having epilepsy in your family" made them less likely to want to have a child. Having these genetic concerns was significantly associated with greater genetic attribution and estimated risk of epilepsy in offspring of an affected parent.

Significance: People with epilepsy have fewer children than their biological relatives without epilepsy. Beliefs about genetic causes of epilepsy contribute to concerns and decisions to limit childbearing. These beliefs should be addressed in genetic counseling to ensure that true risks to offspring and reproductive options are well understood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.16889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096692PMC
May 2021

Detailed Clinical and Psychological Phenotype of the X-linked -Related Neurodevelopmental Disorder.

Neurol Genet 2021 Feb 29;7(1):e551. Epub 2021 Jan 29.

Division of Child Neurology (J.M.B., O.T., D.R.-M., N.M.L., R.S., S.G.), Department of Neurology, Columbia University Irving Medical Center, New York, NY; Columbia University (C.P.), New York, NY; Division of Molecular Genetics (X.F., W.K.C.), Department of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY; Department of Neurology (O.D.), Comprehensive Epilepsy Center, New York University Langone School of Medicine; Barrow Neurological Institute at Phoenix Children's Hospital (R.F.), AZ, and Department of Child Health (R.F.), University of Arizona College of Medicine, Phoenix; Kinderarztliche Gemeinschaftspraxis (S.H.), Germany; Jane and John Justin Neurosciences (C.G.K.), Cook Children's Hospital, Fort Worth, TX; Department of Radiology (A.B.R.M.), Columbia University Irving Medical Center, New York, NY; Pediatric Neurology Unit (M.M.-G.), Virgen del Rocío University Hospital, Seville, Spain; Department of Medical Genetics (K.Y.N.), University of Alberta, Canada; Microgenomics srl (F.N.), NextClinics, Pavia, Italy; Human Pathology and Medical Genetics (A.P.), ASST Santi Paolo e Carlo, San Paolo Hospital, Milan, Italy; Child Neuropsychiatry Unit (A.P.), Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Italy; Division of Medical Genetics (A.P.), Department of Pediatrics, University of Utah School of Medicine, Salt Lake City; Department of Pediatrics (E.P.-D.S.), Weill Cornell Medical College, New York, NY; Greenwood Genetic Center (S.A.S.), Greenwood, SC; Centro de Genética Médica Jacinto de Magalhães (G.S.), Centro Hospitalar do Porto, Portugal; and G.H. Sergievsky Center (S.G.), Columbia University Irving Medical Center, New York, NY.

Objective: To expand the clinical phenotype of the X-linked -related neurodevelopmental disorder in 33 individuals.

Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.

Results: We expand our clinical characterization of -related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.

Conclusions: The spectrum of X-linked -related disorders continues to expand as the allelic spectrum and identification of affected males increases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXG.0000000000000551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954461PMC
February 2021

An electronic health record (EHR) log analysis shows limited clinician engagement with unsolicited genetic test results.

JAMIA Open 2021 Jan 1;4(1):ooab014. Epub 2021 Mar 1.

Department of Biomedical Informatics, Columbia University, New York, New York, USA.

How clinicians utilize medically actionable genomic information, displayed in the electronic health record (EHR), in medical decision-making remains unknown. Participating sites of the Electronic Medical Records and Genomics (eMERGE) Network have invested resources into EHR integration efforts to enable the display of genetic testing data across heterogeneous EHR systems. To assess clinicians' engagement with unsolicited EHR-integrated genetic test results of eMERGE participants within a large tertiary care academic medical center, we analyzed automatically generated EHR access log data. We found that clinicians viewed only 1% of all the eMERGE genetic test results integrated in the EHR. Using a cluster analysis, we also identified different user traits associated with varying degrees of engagement with the EHR-integrated genomic data. These data contribute important empirical knowledge about clinicians limited and brief engagements with unsolicited EHR-integrated genetic test results of eMERGE participants. Appreciation for user-specific roles provide additional context for why certain users were more or less engaged with the unsolicited results. This study highlights opportunities to use EHR log data as a performance metric to more precisely inform ongoing EHR-integration efforts and decisions about the allocation of informatics resources in genomic research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jamiaopen/ooab014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935499PMC
January 2021

16p11.2 deletion syndrome.

Curr Opin Genet Dev 2021 Mar 2;68:49-56. Epub 2021 Mar 2.

Simons Foundation, 160 Fifth Avenue, New York, NY 10010, United States.

The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders and autism spectrum disorder with an incidence of approximately 1/2000. Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%. Intelligence quotient is shifted 1.8 standard deviations lower than family controls without the deletion. Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%). Unprovoked seizures are common (24%) and readily treated and resolve with age in many. Obesity evolves throughout childhood and by adulthood 75% are obese. Congenital anomalies are more common than the general population. The deletion is associated with an increase in brain volumes across all areas of the brain, changes in the white matter microstructural properties, and early electrophysiological cortical responses from auditory cortex. Studies of genetically defined conditions, particularly CNVs that are not associated with profound disabilities, provide homogeneity to study genetic impact on brain development, structure, and function to better understand complex neurobehavioral phenotypes such as autism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gde.2021.01.011DOI Listing
March 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Early Pandemic Experiences of Autistic Adults: Predictors of Psychological Distress.

Autism Res 2021 Jun 8;14(6):1209-1219. Epub 2021 Feb 8.

Simons Foundation, New York, New York, USA.

The COVID-19 pandemic has disrupted lives around the world. Autistic adults are at higher risk for co-occurring medical and psychiatric conditions and may be more prone to difficulties adapting to pandemic-related changes and social distancing mandates and coping with ongoing uncertainties. On the other hand, the pandemic may lead to greater understanding and acceptance of accommodations in the broader community that may facilitate supports for autistic adults beyond the pandemic. To learn more about their early pandemic experiences, online surveys were sent to independent adults enrolled in the Simons Powering Autism Research Knowledge (SPARK). The first survey was open from March 30 to April 19, 2020; a follow-up survey sent to original responders was open from May 27 to June 6, yielding 396 participants with data for both surveys. We found that adults who were female, younger, had prior diagnoses of a mental health condition, personal COVID-19 experience (i.e., knowing someone who had symptoms or tested positive) or less frequent hope for the future reported the greatest negative impacts. Decrease in feelings of hopefulness over time predicted greater psychological distress at T2, accounting for T1 impact and distress levels and increases in total COVID-19 impact. Less perceived benefit of online services also predicted later distress. Although there tends to be a focus on coping with negative effects of the pandemic, mental health providers may consider approaches that focus on positives, such as fostering hope and understanding factors that facilitate benefit from online services. LAY SUMMARY: Autistic adults may be at risk for psychological distress during the COVID-19 pandemic. The current study suggests that autistic adults who were younger, female, had a mental health diagnosis before the pandemic and knew someone who showed symptoms or tested positive for COVID-19 reported more areas negatively impacted by COVID-19 and greater difficulty coping with those effects. Decreases in hope over time were associated with greater psychological distress. Less perceived benefit from online services also predicted distress 2 months later. These results suggest important areas to further explore as we develop supports for autistic adults during the pandemic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/aur.2480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014774PMC
June 2021

The psychiatric phenotypes of 1q21 distal deletion and duplication.

Transl Psychiatry 2021 Feb 4;11(1):105. Epub 2021 Feb 4.

Division of Psychological Medicine and Clinical Neurosciences, Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.

Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion [OR = 6.6 (95% CI: 1.4-40.1)], 55% for duplication carriers [8.3 (1.4-55.5)]) and anxiety disorders (24% [1.8 (0.4-8.4)] and 55% [10.0 (1.9-71.2)]). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-021-01226-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862693PMC
February 2021

MVP predicts the pathogenicity of missense variants by deep learning.

Nat Commun 2021 01 21;12(1):510. Epub 2021 Jan 21.

Department of Systems Biology, Columbia University, New York, NY, USA.

Accurate pathogenicity prediction of missense variants is critically important in genetic studies and clinical diagnosis. Previously published prediction methods have facilitated the interpretation of missense variants but have limited performance. Here, we describe MVP (Missense Variant Pathogenicity prediction), a new prediction method that uses deep residual network to leverage large training data sets and many correlated predictors. We train the model separately in genes that are intolerant of loss of function variants and the ones that are tolerant in order to take account of potentially different genetic effect size and mode of action. We compile cancer mutation hotspots and de novo variants from developmental disorders for benchmarking. Overall, MVP achieves better performance in prioritizing pathogenic missense variants than previous methods, especially in genes tolerant of loss of function variants. Finally, using MVP, we estimate that de novo coding variants contribute to 7.8% of isolated congenital heart disease, nearly doubling previous estimates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-20847-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820281PMC
January 2021