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1. Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

Author: Sissy Bassani, Jacqueline Chrast, Giovanna Ambrosini, Norine Voisin, Frédéric Schütz, Alfredo Brusco, Fabio Sirchia, Lydia Turban, Susanna Schubert, Rami Abou Jamra, Jan-Ulrich Schlump, Desiree DeMille, Pinar Bayrak-Toydemir, Gary Rex Nelson, Kristen Nicole Wong, Laura Duncan, Mackenzie Mosera, Christian Gilissen, Lisenka E. L. M. Vissers, Rolph Pfundt, Rogier Kersseboom, Hilde Yttervik, Geir Åsmund Myge Hansen, Marie Falkenberg Smeland, Kameryn M. Butler, Michael J. Lyons, Claudia M. B. Carvalho, Chaofan Zhang, James R. Lupski, Lorraine Potocki, Leticia Flores-Gallegos, Rodrigo Morales-Toquero, Florence Petit, Binnaz Yalcin, Annabelle Tuttle, Houda Zghal Elloumi, Lane McCormick, Mary Kukolich, Oliver Klaas, Judit Horvath, Marcello Scala, Michele Iacomino, Francesca Operto, Federico Zara, Karin Writzl, Aleš Maver, Maria K. Haanpää, Pia Pohjola, Harri Arikka, Anneke J. A. Kievit, Camilla Calandrini, Christian Iseli, Nicolas Guex, and Alexandre Reymond
Subjects: Mesomelic dysplasia, Horseshoe kidney, Intellectual disability, Transcriptome, Zebrafish model, Medicine, Genetics, QH426-470
Abstract: Abstract Background We previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects. Methods Evolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants. Results We identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness. To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation. Conclusions Our results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.
Published: 2024
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2. Investigation of the Genetic Determinants of Telangiectasia and Solid Organ Arteriovenous Malformation Formation in Hereditary Hemorrhagic Telangiectasia (HHT)

Author: Kevin J. Whitehead, Doruk Toydemir, Whitney Wooderchak-Donahue, Gretchen M. Oakley, Bryan McRae, Angelica Putnam, Jamie McDonald, and Pinar Bayrak-Toydemir
Subjects: hereditary hemorrhagic telangiectasia, somatic, biallelic, tissue, telangiectasia, AVM, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract: Telangiectases and arteriovenous malformations (AVMs) are the characteristic lesions of Hereditary Hemorrhagic Telangiectasia (HHT). Somatic second-hit loss-of-function variations in the HHT causative genes, ENG and ACVRL1, have been described in dermal telangiectasias. It is unclear if somatic second-hit mutations also cause the formation of AVMs and nasal telangiectasias in HHT. To investigate the genetic mechanism of AVM formation in HHT, we evaluated multiple affected tissues from fourteen individuals. DNA was extracted from fresh/frozen tissue of 15 nasal telangiectasia, 4 dermal telangiectasia, and 9 normal control tissue biopsies, from nine unrelated individuals with HHT. DNA from six formalin-fixed paraffin-embedded (FFPE) AVM tissues (brain, lung, liver, and gallbladder) from five individuals was evaluated. A 736 vascular malformation and cancer gene next-generation sequencing (NGS) panel was used to evaluate these tissues down to 1% somatic mosaicism. Somatic second-hit mutations were identified in three in four AVM biopsies (75%) or half of the FFPE (50%) samples, including the loss of heterozygosity in ENG in one brain AVM sample, in which the germline mutation occurred in a different allele than a nearby somatic mutation (both are loss-of-function mutations). Eight of nine (88.9%) patients in whom telangiectasia tissues were evaluated had a somatic mutation ranging from 0.68 to 1.96% in the same gene with the germline mutation. Six of fifteen (40%) nasal and two of four (50%) dermal telangiectasia had a detectable somatic second hit. Additional low-level somatic mutations in other genes were identified in several telangiectasias. This is the first report that nasal telangiectasias and solid organ AVMs in HHT are caused by very-low-level somatic biallelic second-hit mutations.
Published: 2024
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3. P398: A rare report of a child with mosaic trisomy 4

Author: Lauren Bartik, Elena Repnikova, Eric Rush, Jennifer Roberts, Erin Baldwin, John Carey, Lorenzo Botto, John O'Shea, Ting Wen, Pinar Bayrak-Toydemir, Rong Mao, Undiagnosed Diseases Network, and Bonnie Sullivan
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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4. O20: Beyond the genome: RNA sequencing resolves unique diagnostic challenges

Author: Robert Lewis, Makenzie Fulmer, Jian Zhao, Lucilla Pizzo, Ting Wen, John O'Shea, Thomas Nicholas, Steven Boyden, David Viskochil, Nicola Longo, Ashley Andrews, Erin Baldwin, Matt Velinder, Russell Butterfield, Karin Dent, Kourtney Santucci, Austin Larson, Rong Mao, Lorenzo Botto, and Pinar Bayrak-Toydemir
Subjects: Genetics, QH426-470, Medicine
Published: 2024
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5. Combining genetic constraint with predictions of alternative splicing to prioritize deleterious splicing in rare disease studies

Author: Michael J. Cormier, Brent S. Pedersen, Pinar Bayrak-Toydemir, and Aaron R. Quinlan
Subjects: Genomic medicine, Rare disease, Genomics, Splicing, Alternative splicing, Noncanonical cryptic splicing, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract: Abstract Background Despite numerous molecular and computational advances, roughly half of patients with a rare disease remain undiagnosed after exome or genome sequencing. A particularly challenging barrier to diagnosis is identifying variants that cause deleterious alternative splicing at intronic or exonic loci outside of canonical donor or acceptor splice sites. Results Several existing tools predict the likelihood that a genetic variant causes alternative splicing. We sought to extend such methods by developing a new metric that aids in discerning whether a genetic variant leads to deleterious alternative splicing. Our metric combines genetic variation in the Genome Aggregate Database with alternative splicing predictions from SpliceAI to compare observed and expected levels of splice-altering genetic variation. We infer genic regions with significantly less splice-altering variation than expected to be constrained. The resulting model of regional splicing constraint captures differential splicing constraint across gene and exon categories, and the most constrained genic regions are enriched for pathogenic splice-altering variants. Building from this model, we developed ConSpliceML. This ensemble machine learning approach combines regional splicing constraint with multiple per-nucleotide alternative splicing scores to guide the prediction of deleterious splicing variants in protein-coding genes. ConSpliceML more accurately distinguishes deleterious and benign splicing variants than state-of-the-art splicing prediction methods, especially in “cryptic” splicing regions beyond canonical donor or acceptor splice sites. Conclusion Integrating a model of genetic constraint with annotations from existing alternative splicing tools allows ConSpliceML to prioritize potentially deleterious splice-altering variants in studies of rare human diseases.
Published: 2022
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6. P243: The Utah NeoSeq Project: Developing and implementing genomic sequencing in acute neonatal care

Author: Sabrina Malone-Jenkins, Brian Shayota, Chelsea Solorzano, Rachel Palmquist, Steven Boyden, Barry Moore, Thomas Nicholas, Rong Mao, Pinar Bayrak-Toydemir, Katherine Noble, Andrew Farrell, Edgar Hernandez, Shawn Rynearson, Carson Holt, Alistair Ward, Najla Al-Sweel, Jian Zhao, Makenzie Fulmer, Lucilla Pizzo, Ting Wen, John O'Shea, Robert Lewis, Hayley Reynolds, Eric Fredrickson, Kelsey Nicholson, David Pattison, Hunter Best, Luca Brunelli, Mark Yandell, Gabor Marth, Aaron Quinlan, John Carey, Martin Tristani-Firouzi, and Joshua Bonkowsky
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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7. O31: Risk allele evidence curation, classification, and reporting: Recommendations from the ClinGen Low Penetrance/Risk Allele Working Group

Author: Matthew Lebo, Marcie Steeves, Katherine Benson, Laura Conlin, Mythily Ganapathi, Vaidehi Jobanputra, Minjie Luo, Deqiong Ma, Kelly McGoldrick, Blake Palculict, Heidi Rehm, Panagiotis Sergouniotis, Samantha Schilit, Pinar Bayrak-Toydemir, Tatiana Tvrdik, Nicholas Watkins, Lauren Zec, Wenying Zhang Zhang, and Ryan Schmidt
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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8. P462: Importance of genomic reanalysis to uncover medical unknowns: A UDN case with phenotypic extension of spondyloepimetaphyseal dysplasia with hypomyelinating leukodystrophy

Author: Makenzie Fulmer, Matt Velinder, Ashley Andrews, Russell Butterfield, Rong Mao, Kourtney Santucci, Lorenzo Botto, and Pinar Bayrak-Toydemir
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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9. P499: RNA-sequencing positional gene enrichment is a useful tool in resolving cases of X chromosome copy number variation

Author: Robert Lewis, David Viskochil, Ashley Andrews, Karin Dent, Rong Mao, Lorenzo Botto, and Pinar Bayrak-Toydemir
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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10. P516: RNASeq analysis identifies the pathogenicity of inherited synonymous splice-region variant in NEB, confirming a diagnosis of neonatal nemaline myopathy 2

Author: Barry Moore, Thomas Nicholas, Rong Mao, Brian Shayota, Steven Boyden, Chelsea Solorzano, Rachel Palmquist, Pinar Bayrak-Toydemir, Katherine Noble, Andrew Farrell, Edgar Hernandez, Shawn Rynearson, Carson Holt, Alistair Ward, Eric Fredrickson, Kelsey Nicholson, David Pattison, Jian Zhao, Makenzie Fulmer, Lucilla Pizzo, Ting Wen, John O'Shea, Robert Lewis, Hayley Reynolds, Betsy Ostrander, Hunter Best, Luca Brunelli, Mark Yandell, Gabor Marth, Aaron Quinlan, John Carey, Martin Tristani-Firouzi, Joshua Bonkowsky, and Sabrina Malone-Jenkins
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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11. P524: Novel variants in EFL1 lead to a potential diagnosis of Shwachman-Diamond syndrome 2

Author: John O'Shea, Jian Zhao, Pinar Bayrak-Toydemir, David Viskochil, Ashley Andrews, Lorenzo Botto, and Rong Mao
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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12. P542: Overcoming polymer-induced variation in fragile X and Huntington disease repeat expansion assays

Author: Scott Reading, Mohamed Jama, Pinar Bayrak-Toydemir, Hunter Best, Eric Fredrickson, Makenzie Fulmer, Rong Mao, Sherin Shaaban, and Yuan Ji
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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13. P585: Rapid genome sequencing identifies a de novo SNAP25 variant for neonatal congenital myasthenic syndrome

Author: Ting Wen, Hayley Reynolds, Andrew Farrell, Barry Moore, Steven Boyden, Thomas Nicholas, Shawn Rynearson, Carson Holt, Christine Miller, Katherine Noble, Dawn Bentley, Rachel Palmquist, Betsy Ostrander, Stephanie Manberg, Joshua Bonkowsky, Brian Shayota, Sabrina Malone-Jenkins, Pinar Bayrak-Toydemir, and Rong Mao
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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14. P595: Novel molecular mechanism in Malan syndrome uncovered through detailed genome sequencing reanalysis, exon-level array and RNA-seq

Author: Jian Zhao, Nicola Longo, Robert Lewis, Thomas Nicholas, Steven Boyden, Ashley Andrews, Austin Larson, Pinar Bayrak-Toydemir, Lorenzo Botto, and Rong Mao
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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15. P665: Recommendations for the improvement of diagnostic yields in rare disease cases through the integration of structural variants into analytical pipelines

Author: Thomas Nicholas, Andrew Farrell, Shawn Rynearson, Carson Holt, Steven Boyden, Barry Moore, Najla Al-Sweel, Christine Miller, Lucilla Pizzo, Chelsea Solorzano, Rachel Palmquist, Ashley Andrews, Rong Mao, Pinar Bayrak-Toydemir, Eric Fredrickson, Katherine Noble, Brian Shayota, Joshua Bonkowsky, John Carey, Sabrina Malone-Jenkins, Lorenzo Botto, and Aaron Quinlan
Subjects: Genetics, QH426-470, Medicine
Published: 2023
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16. Effective variant filtering and expected candidate variant yield in studies of rare human disease

Author: Brent S. Pedersen, Joe M. Brown, Harriet Dashnow, Amelia D. Wallace, Matt Velinder, Martin Tristani-Firouzi, Joshua D. Schiffman, Tatiana Tvrdik, Rong Mao, D. Hunter Best, Pinar Bayrak-Toydemir, and Aaron R. Quinlan
Subjects: Medicine, Genetics, QH426-470
Abstract: Abstract In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.
Published: 2021
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17. Comprehensive variant calling from whole‐genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia

Author: Thomas J. Nicholas, Najla Al‐Sweel, Andrew Farrell, Rong Mao, Pinar Bayrak‐Toydemir, Christine E. Miller, Dawn Bentley, Rachel Palmquist, Barry Moore, Edgar J. Hernandez, Michael J. Cormier, Eric Fredrickson, Katherine Noble, Shawn Rynearson, Carson Holt, Mary Anne Karren, Joshua L. Bonkowsky, Martin Tristani‐Firouzi, Mark Yandell, Gabor Marth, Aaron R. Quinlan, Luca Brunelli, Reha M. Toydemir, Brian J. Shayota, John C. Carey, Steven E. Boyden, and Sabrina Malone Jenkins
Subjects: Genetics, QH426-470
Abstract: Abstract Background Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases. Methods As part of the Utah NeoSeq project, we used a research‐based, rapid whole‐genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left‐sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect. Results Using both a novel, alignment‐free and traditional alignment‐based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the ZFPM2 gene, which is associated with both CDH and various congenital heart defects. Conclusions Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short‐read sequencing and underscore the utility of WGS as a first‐line diagnostic tool.
Published: 2022
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18. Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an 'HHT‐like' syndrome in children

Author: Joshua Hodgson, Lidia Ruiz‐Llorente, Jamie McDonald, Oliver Quarrell, Kelechi Ugonna, James Bentham, Rebecca Mason, Jennifer Martin, David Moore, Katie Bergstrom, Pinar Bayrak‐Toydemir, Whitney Wooderchak‐Donahue, Nicholas W. Morrell, Robin Condliffe, Carmelo Bernabeu, and Paul D. Upton
Subjects: bone morphogenetic protein, hereditary hemorrhagic telangiectasia, pulmonary arterial hypertension, pulmonary arteriovenous malformations, Genetics, QH426-470
Abstract: Abstract Background Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra‐rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases. Methods Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE‐luciferase reporter cell line (HMEC1‐BRE). Proteins were expressed for assessment of secretion and processing. Results Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum‐derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9. Conclusion Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or “HHT‐like” telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs.
Published: 2021
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19. Clin.iobio: A Collaborative Diagnostic Workflow to Enable Team-Based Precision Genomics

Author: Alistair Ward, Matt Velinder, Tonya Di Sera, Aditya Ekawade, Sabrina Malone Jenkins, Barry Moore, Rong Mao, Pinar Bayrak-Toydemir, and Gabor Marth
Subjects: genomics, clinical, software, visualization, collaboration, diagnostics, Medicine
Abstract: The primary goal of precision genomics is the identification of causative genetic variants in targeted or whole-genome sequencing data. The ultimate clinical hope is that these findings lead to an efficacious change in treatment for the patient. In current clinical practice, these findings are typically returned by expert analysts as static, text-based reports. Ideally, these reports summarize the quality of the data obtained, integrate known gene–phenotype associations, follow allele segregation and affected status within the sequenced samples, and weigh computational evidence of pathogenicity. These findings are used to prioritize the variant(s) most likely to cause the given patient’s phenotypes. In most diagnostic settings, a team of experts contribute to these reports, including bioinformaticians, clinicians, and genetic counselors, among others. However, these experts often do not have the necessary tools to review genomic findings, test genetic hypotheses, or query specific gene and variant information. Additionally, team members often rely on different tools and methods based on their given expertise, resulting in further difficulties in communicating and discussing genomic findings. Here, we present clin.iobio—a web-based solution to collaborative genomic analysis that enables diagnostic team members to focus on their area of expertise within the diagnostic process, while allowing them to easily review and contribute to all steps of the diagnostic process. Clin.iobio integrates tools from the popular iobio genomic visualization suite into a comprehensive diagnostic workflow, encompassing (1) genomic data quality review, (2) dynamic phenotype-driven gene prioritization, (3) variant prioritization using a comprehensive set of knowledge bases and annotations, (4) and an exportable findings summary. In conclusion, clin.iobio is a comprehensive solution to team-based precision genomics, the findings of which stand to inform genomic considerations in clinical practice.
Published: 2022
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20. Targeted gene panel sequencing for the rapid diagnosis of acutely ill infants

Author: Luca Brunelli, Sabrina M. Jenkins, James M. Gudgeon, Steven B. Bleyl, Christine E. Miller, Tatiana Tvrdik, Shale A. Dames, Betsy Ostrander, Josue A. F. Daboub, Brandon A. Zielinski, Erin K. Zinkhan, Hunter R. Underhill, Theodore Wilson, Joshua L. Bonkowsky, Christian C. Yost, Lorenzo D. Botto, Justin Jenkins, Theodore J. Pysher, Pinar Bayrak‐Toydemir, and Rong Mao
Subjects: genetic diagnosis, neonatology, newborn, precision medicine, rapid sequencing, Genetics, QH426-470
Abstract: Abstract Background Exome/genome sequencing (ES/GS) have been recently used in neonatal and pediatric/cardiac intensive care units (NICU and PICU/CICU) to diagnose and care for acutely ill infants, but the effectiveness of targeted gene panels for these purposes remains unknown. Methods RapSeq, a newly developed panel targeting 4,503 disease‐causing genes, was employed on selected patients in our NICU/PICU/CICU. Twenty trios were sequenced from October 2015 to March 2017. We assessed diagnostic yield, turnaround times, and clinical consequences. Results A diagnosis was made in 10/20 neonates (50%); eight had de novo variants (ASXL1, CHD, FBN1, KMT2D, FANCB, FLNA, PAX3), one was a compound heterozygote for CHAT, and one had a maternally inherited GNAS variant. Preliminary reports were generated by 9.6 days (mean); final reports after Sanger sequencing at 16.3 days (mean). In all positive infants, the diagnosis changed management. In a case with congenital myasthenia, diagnosis and treatment occurred at 17 days versus 7 months in a historical control. Conclusions This study shows that a gene panel that includes the majority of known disease‐causing genes can rapidly identify a diagnosis in a large number of tested infants. Due to simpler deployment and interpretation and lower costs, this approach might represent an alternative to ES/GS in the NICU/PICU/CICU.
Published: 2019
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21. Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Author: Carmelo Bernabeu, Pinar Bayrak-Toydemir, Jamie McDonald, and Michelle Letarte
Subjects: hereditary hemorrhagic telangiectasia (HHT), second-hit, arteriovenous malformation (AVM), endoglin, ALK1, Smad4, inflammation, Medicine
Abstract: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved.
Published: 2020
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22. Genetic Variants Associated with Port-Wine Stains.

Author: Alice Frigerio, Karol Wright, Whitney Wooderchak-Donahue, Oon T Tan, Rebecca Margraf, David A Stevenson, J Fredrik Grimmer, and Pinar Bayrak-Toydemir
Subjects: Medicine, Science
Abstract: Port-wine stains (PWS) are capillary malformations, typically located in the dermis of the head and neck, affecting 0.3% of the population. Current theories suggest that port-wine stains are caused by somatic mutations that disrupt vascular development.Understanding PWS genetic determinants could provide insight into new treatments.Our study used a custom next generation sequencing (NGS) panel and digital polymerase chain reaction to investigate genetic variants in 12 individuals with isolated port-wine stains. Importantly, affected and healthy skin tissue from the same individual were compared. A subtractive correction method was developed to eliminate background noise from NGS data. This allowed the detection of a very low level of mosaicism.A novel somatic variant GNAQ, c.547C>G, p.Arg183Gly was found in one case with 4% allele frequency. The previously reported GNAQ c.548G>A, p.Arg183Gln was confirmed in 9 of 12 cases with an allele frequency ranging from 1.73 to 7.42%. Digital polymerase chain reaction confirmed novel variants detected by next generation sequencing. Two novel somatic variants were also found in RASA1, although neither was predicted to be deleterious.This is the second largest study on isolated, non-syndromic PWS. Our data suggest that GNAQ is the main genetic determinant in this condition. Moreover, isolated port-wine stains are distinct from capillary malformations seen in RASA1 disorders, which will be helpful in clinical evaluation.
Published: 2015
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23. The Shunt of It

Author: Brittany M. Scarpato, Jamie McDonald, Pinar Bayrak-Toydemir, C. Gregory Elliott, Barbara C. Cahill, Lyska L. Emerson, and Lynn M. Keenan
Subjects: Pulmonary and Respiratory Medicine, Cardiology and Cardiovascular Medicine, Critical Care and Intensive Care Medicine
Published: 2023

24. A Framework of Critical Considerations in Clinical Exome Reanalyses by Clinical and Laboratory Standards Institute

Author: Marco L. Leung, Jianling Ji, Samuel Baker, Jillian G. Buchan, Theru A. Sivakumaran, Bryan L. Krock, Rebecca Hutchins, Pinar Bayrak-Toydemir, John Pfeifer, Maria Laura Cremona, Birgit Funke, and Avni B. Santani
Subjects: Exome Sequencing, Humans, Molecular Medicine, Exome, Clinical Laboratory Services, Laboratories, Laboratories, Clinical, Pathology and Forensic Medicine
Abstract: Exome reanalysis is useful for providing molecular diagnoses for previously uninformative samples. However, challenges exist in implementing a practical solution for clinicians and laboratories. This study complements the current literature by providing practical considerations for patient-level and cohort-level reanalyses. The Clinical and Laboratory Standards Institute assembled the Document Development Committee and an interpretation working group that developed the framework for reevaluation of exome-based data. We describe two distinct but complementary approaches toward exome reanalyses: clinician-initiated patient-level reanalysis, and laboratory-initiated cohort-level reanalysis. We highlight the advantages and constraints for both approaches, and provide a high-level conceptual guide for ordering clinicians and laboratories through the critical decision pathways. Because clinical exome sequencing continues to be the standard of care in genetics, exome reanalysis would be critical in increasing the overall diagnostic yield. A systematic guide will facilitate the efficient adoption of reevaluation of exome data for laboratories, health care professionals, genetic counselors, and clinicians.
Published: 2022

25. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author: Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen
Subjects: 0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract: Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.
Published: 2021

26. ARF1-related disorder: phenotypic and molecular spectrum

Author: Jean-Madeleine de Sainte Agathe, Ben Pode-Shakked, Sophie Naudion, Vincent Michaud, Benoit Arveiler, Patricia Fergelot, Jean Delmas, Boris Keren, Céline Poirsier, Fowzan S Alkuraya, Brahim Tabarki, Eric Bend, Kellie Davis, Martina Bebin, Michelle L Thompson, Emily M Bryant, Matias Wagner, Iris Hannibal, Jerica Lenberg, Martin Krenn, Kristen M Wigby, Jennifer R Friedman, Maria Iascone, Anna Cereda, Térence Miao, Eric LeGuern, Emanuela Argilli, Elliott Sherr, Oana Caluseriu, Timothy Tidwell, Pinar Bayrak-Toydemir, Caroline Hagedorn, Melanie Brugger, Katharina Vill, Francois-Dominique Morneau-Jacob, Wendy Chung, Kathryn N Weaver, Joshua W Owens, Ammar Husami, Bimal P Chaudhari, Brandon S Stone, Katie Burns, Rachel Li, Iris M de Lange, Margaux Biehler, Emmanuelle Ginglinger, Bénédicte Gérard, Rolf W Stottmann, and Aurélien Trimouille
Subjects: Genetics, Developmental defects, epilepsy, human genetics, sequence analysis, DNA, Genetics (clinical), ddc
Abstract: PurposeARF1was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum ofARF1-related neurodevelopmental disorder.MethodsWe collected detailed phenotypes of an international cohort of individuals (n=17) withARF1variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.ResultsDe novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) inARF1were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.ConclusionWe confirm the role ofARF1in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.
Published: 2022

27. A novel DPH5-related diphthamide-deficiency syndrome causing embryonic lethality or profound neurodevelopmental disorder

Author: Suma P. Shankar, Kristin Grimsrud, Louise Lanoue, Alena Egense, Brandon Willis, Johanna Hörberg, Lama AlAbdi, Klaus Mayer, Koray Ütkür, Kristin G. Monaghan, Joel Krier, Joan Stoler, Maha Alnemer, Prabhu R. Shankar, Raffael Schaffrath, Fowzan S. Alkuraya, Ulrich Brinkmann, Leif A. Eriksson, Kent Lloyd, Katherine A. Rauen, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D'Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell'Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Madison P. Goldrich, Alana Grajewski, Irma Gutierrez, Don Hadley, Sihoun Hahn, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Jennifer Kennedy, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Kimberly LeBlanc, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Mariko Nakano-Okuno, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Anna Raper, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, K.-G. Queenie, Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz-Hubshman, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Diane B. Zastrow, Zhe Zhang, Chunli Zhao, Stephan Zuchner, Hugo Bellen, and Rachel Mahoney
Subjects: Adenosine Diphosphate, Mice, Inbred C57BL, Mice, Saccharomyces cerevisiae Proteins, Neurodevelopmental Disorders, Animals, Humans, Histidine, Methyltransferases, Saccharomyces cerevisiae, Syndrome, Genetics (clinical), Article
Abstract: Diphthamide is a post-translationally modified histidine essential for messenger RNA translation and ribosomal protein synthesis. We present evidence for DPH5 as a novel cause of embryonic lethality and profound neurodevelopmental delays (NDDs).Molecular testing was performed using exome or genome sequencing. A targeted Dph5 knockin mouse (C57BL/6Ncrl-Dph5DPH5 variants p.His260Arg (homozygous), p.Asn110Ser and p.Arg207Ter (heterozygous), and p.Asn174LysfsTer10 (homozygous) were identified in 3 unrelated families with distinct overlapping craniofacial features, profound NDDs, multisystem abnormalities, and miscarriages. Dph5 p.His260Arg homozygous knockin was embryonically lethal with only 1 subviable mouse exhibiting impaired growth, craniofacial dysmorphology, and multisystem dysfunction recapitulating the human phenotype. Adenosine diphosphate-ribosylation assays showed absent to decreased function in DPH5-knockout human and yeast cells. In silico modeling of the variants showed altered DPH5 structure and disruption of its interaction with eEF2.We provide strong clinical, biochemical, and functional evidence for DPH5 as a novel cause of embryonic lethality or profound NDDs with multisystem involvement and expand diphthamide-deficiency syndromes and ribosomopathies.
Published: 2022

28. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Author: Felix Marbach, Georgi Stoyanov, Florian Erger, Constantine A. Stratakis, Nikolaos Settas, Edra London, Jill A. Rosenfeld, Erin Torti, Chad Haldeman-Englert, Evgenia Sklirou, Elena Kessler, Sophia Ceulemans, Stanley F. Nelson, Julian A. Martinez-Agosto, Christina G.S. Palmer, Rebecca H. Signer, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Joel B. Krier, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Marisa V. Andrews, Dorothy K. Grange, Rebecca Willaert, Richard Person, Aida Telegrafi, Aaron Sievers, Magdalena Laugsch, Susanne Theiß, YuZhu Cheng, Olivier Lichtarge, Panagiotis Katsonis, Amber Stocco, and Christian P. Schaaf
Subjects: 0301 basic medicine, Apraxias, Autism Spectrum Disorder, Pain, Biology, Apraxia, Article, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Pregnancy, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Global developmental delay, Genetics (clinical), Genetics, medicine.disease, Phenotype, Human genetics, 030104 developmental biology, Neurodevelopmental Disorders, Autism spectrum disorder, Cyclic AMP-Dependent Protein Kinase RIbeta Subunit, Female, 030217 neurology & neurosurgery
Abstract: Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.
Published: 2021

29. Effective variant filtering and expected candidate variant yield in studies of rare human disease

Author: Rong Mao, Joseph Brown, Brent S. Pedersen, Harriet Dashnow, Amelia D. Wallace, Joshua D. Schiffman, Pinar Bayrak-Toydemir, Aaron R. Quinlan, D. Hunter Best, Tatiana Tvrdik, Martin Tristani-Firouzi, and Matt Velinder
Subjects: Population, Biology, QH426-470, Compound heterozygosity, Article, Deep sequencing, 03 medical and health sciences, 0302 clinical medicine, Genetics research, Genetics, SNP, Allele, education, Indel, Molecular Biology, Allele frequency, Exome, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Sequence annotation, Medicine, 030217 neurology & neurosurgery
Abstract: In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.
Published: 2021

30. The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change

Author: Heidi L Rehm, Joseph T Alaimo, Swaroop Aradhya, Pinar Bayrak-Toydemir, Hunter Best, Rhonda Brandon, Jillian G Buchan, Elizabeth C Chao, Elaine Chen, Jacob Clifford, Ana S Cohen, Laura K Conlin, Soma Das, Kyle W Davis, Daniela del Gaudio, Florencia Del Viso, Christina DiVincenzo, Marcia Eisenberg, Lucia Guidugli, Monia B Hammer, Steven M Harrison, Kathryn E Hatchell, Lindsay Havens Dyer, Lily U Hoang, James M Holt, Vaidehi Jobanputra, Izabela D Karbassi, Hutton M Kearney, Melissa A Kelly, Jacob M Kelly, Michelle L Kluge, Timothy Komala, Paul Kruszka, Lynette Lau, Matthew S Lebo, Christian R Marshall, Dianalee McKnight, Kirsty McWalter, Yan Meng, Narasimhan Nagan, Christian S Neckelmann, Nir Neerman, Zhiyv Niu, Vitoria K Paolillo, Sarah A Paolucci, Denise Perry, Tina Pesaran, Kelly Radtke, Kristen J Rasmussen, Kyle Retterer, Carol J Saunders, Elizabeth Spiteri, Christine M Stanley, Anna Szuto, Ryan J Taft, Isabelle Thiffault, Brittany C Thomas, Amanda Thomas-Wilson, Erin Thorpe, Timothy J Tidwell, Meghan C Towne, and Hana Zouk
Abstract: Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact. We collected data from over 1.5 million genetic tests from 19 clinical laboratories across the United States and Canada from during 2020-2021. We found a lower rate of inconclusive results due to VUS on ES/GS tests compared to MGPs (22.5% vs. 32.6%; p
Published: 2022

31. Rapid genome sequencing identifies a novel de novo

Author: Hayley M, Reynolds, Ting, Wen, Andrew, Farrell, Rong, Mao, Barry, Moore, Steven E, Boyden, Pinar, Bayrak-Toydemir, Thomas J, Nicholas, Shawn, Rynearson, Carson, Holt, Christine, Miller, Katherine, Noble, Dawn, Bentley, Rachel, Palmquist, Betsy, Ostrander, Stephanie, Manberg, Joshua L, Bonkowsky, Brian J, Shayota, and Sabrina Malone, Jenkins
Subjects: Myasthenic Syndromes, Congenital, Phenotype, Synaptosomal-Associated Protein 25, Whole Genome Sequencing, Humans, Chromosome Mapping, Pedigree
Abstract: Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al.
Published: 2022

32. A concurrent dual analysis of genomic data augments diagnoses: Experiences of 2 clinical sites in the Undiagnosed Diseases Network

Author: Rebecca C. Spillmann, Queenie K.-G. Tan, Chloe Reuter, Kelly Schoch, Jennefer Kohler, Devon Bonner, Diane Zastrow, Anna Alkelai, Evan Baugh, Heidi Cope, Shruti Marwaha, Matthew T. Wheeler, Jonathan A. Bernstein, Vandana Shashi, Maria T. Acosta, Margaret Adam, David R. Adams, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Hugo J. Bellen, Jimmy Bennet, Beverly Berg-Rood, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Thomas Cassini, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Madison P. Goldrich, Alana Grajewski, Irma Gutierrez, Don Hadley, Sihoun Hahn, Rizwan Hamid, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Wendy Introne, Rosario Isasi, Kosuke Izumi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Orpa Jean-Marie, Vaidehi Jobanputra, Lefkothea Karaviti, Jennifer Kennedy, Shamika Ketkar, Dana Kiley, Gonench Kilich, Shilpa N. Kobren, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Kimberly LeBlanc, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Rachel Mahoney, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Mariko Nakano-Okuno, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Anna Raper, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Mario Saporta, Judy Schaechter, Timothy Schedl, C. Ron Scott, Daryl A. Scott, Jimann Shin, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Monika Weisz-Hubshman, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Jordan Whitlock, Lynne A. Wolfe, Kim Worley, Changrui Xiao, Shinya Yamamoto, John Yang, Diane B. Zastrow, Zhe Zhang, Chunli Zhao, and Stephan Zuchner
Subjects: Genetics (clinical)
Published: 2023

33. Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases

Author: Shilpa Nadimpalli Kobren, Dustin Baldridge, Matt Velinder, Joel B. Krier, Kimberly LeBlanc, Cecilia Esteves, Barbara N. Pusey, Stephan Züchner, Elizabeth Blue, Hane Lee, Alden Huang, Lisa Bastarache, Anna Bican, Joy Cogan, Shruti Marwaha, Anna Alkelai, David R. Murdock, Pengfei Liu, Daniel J. Wegner, Alexander J. Paul, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennett, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Daya, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Susan Korrick, Mary Kozuira, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Grace L. LaMoure, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Brendan H. Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Calum A. MacRae, Ellen F. Macnamara, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martinez-Agosto, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo M. Moretti, Paolo Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stanley F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Aaron Quinlan, Archana N. Raja, Deepak A. Rao, Wendy Raskind, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, C. Ron Scott, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca H. Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, null Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Melissa Walker, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, and Shamil R. Sunyaev
Subjects: Prioritization, Genome, medicine.diagnostic_test, Genomic sequencing, Multimodal data, Computational Biology, Structural variant, Genomics, Undiagnosed Diseases, Data science, Shruti, Article, Workflow, Biomedical data, medicine, Humans, Genetic Testing, Psychology, Software, Genetics (clinical), Genetic testing
Abstract: Author(s): Kobren, Shilpa Nadimpalli; Baldridge, Dustin; Velinder, Matt; Krier, Joel B; LeBlanc, Kimberly; Esteves, Cecilia; Pusey, Barbara N; Zuchner, Stephan; Blue, Elizabeth; Lee, Hane; Huang, Alden; Bastarache, Lisa; Bican, Anna; Cogan, Joy; Marwaha, Shruti; Alkelai, Anna; Murdock, David R; Liu, Pengfei; Wegner, Daniel J; Paul, Alexander J; Undiagnosed Diseases Network; Sunyaev, Shamil R; Kohane, Isaac S | Abstract: PurposeGenomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.MethodsWe collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.ResultsWe found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.ConclusionThe largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.
Published: 2021

34. One is the loneliest number: genotypic matchmaking using the electronic health record

Author: Nichole Hayes, Euan A. Ashley, Laura A. Mamounas, Allyn McConkie-Rosell, Shirley Sutton, John J.E. Mulvihill, John H. Postlethwait, Richard L. Maas, Jennefer N. Kohler, Dana Kiley, Joel B. Krier, Pankaj B. Agrawal, Xue Zhong Liu, Josh F. Peterson, Jill A. Rosenfeld, Thomas May, Jennifer E. Kyle, David A. Sweetser, Neil H. Parker, Jeanette C. Papp, Manish J. Butte, Calum A. MacRae, Rong Mao, Vandana Shashi, Christopher A. Walsh, Alica M. Goldman, Gabor T. Marth, Sharyn A. Lincoln, David Goldstein, Colleen E. McCormack, Byron L. Lam, Elly Brokamp, Lynette Rives, Lee-kai Wang, Lorraine Potocki, Mary Koziura, Matthew T. Wheeler, Teri A. Manolio, Camille L. Birch, Moretti Paolo, Willa Thorson, Fariha Jamal, Cynthia M. Cooper, Yong Huang, Matt Velinder, Catherine H. Sillari, Archana Raja, Andrea L. Gropman, J. Carl Pallais, Amy K. Robertson, Dave Viskochil, William J. Craigen, Thomas C. Markello, Devin Oglesbee, Olveen Carrasquillo, Precilla D'Souza, Lorenzo D. Botto, Hugo J. Bellen, Susan L. Samson, Jim Bale, Lisa Shakachite, Catherine Groden, Kathleen Shields, Jimann Shin, Carlos Ferreira, Lynne A. Wolfe, Melissa A. Haendel, Brent L. Fogel, Joan M. Stoler, Rebecca C. Spillmann, Roy C. Levitt, Gary D. Clark, Daniel J. Wegner, Gill Bejerano, Deborah Krakow, Ashok Balasubramanyam, J. Scott Newberry, Heidi Cope, Jijun Wan, Sandra K. Loo, Laura Duncan, Elizabeth A. Worthey, Leigh Anne Tang, Mercedes E. Alejandro, Matthew Might, Cecelia P. Tamburro, Patrick Allard, Joseph Loscalzo, Bret L. Bostwick, Lisa Emrick, Sarah K. Nicholas, David R. Murdock, Jeremy D. Woods, Alana L. Grajewski, Eva H. Baker, Lindsay C. Burrage, Stephen Pak, Camilo Toro, Ashley Andrews, James P. Orengo, Shawn Levy, Lance H. Rodan, Kelly Schoch, Jyoti G. Dayal, Thomas O. Metz, Kathy Sisco, Stephanie Bivona, Paolo Moretti, Braden E. Boone, Mahshid S. Azamian, Nicole M. Walley, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, F. Sessions Cole, Guoyun Yu, Rena A. Godfrey, John F. Bohnsack, Elizabeth A. Burke, John H. Newman, Alden Y. Huang, Patricia A. Ward, Barbara N. Pusey, Maria T. Acosta, Alan H. Beggs, Melissa A. Walker, Shweta U. Dhar, Edwin K. Silverman, Stephan Züchner, Ian R. Lanza, Bobbie-Jo M. Webb-Robertson, Anastasia L. Wise, Angela Jones, Nicholas Stong, Irman Forghani, Matthew H. Brush, Michael F. Wangler, Jonathan A. Bernstein, Aaron R. Quinlan, David D. Draper, Pinar Bayrak-Toydemir, Diane B. Zastrow, Daniel C. Dorset, Anna Bican, David J. Eckstein, Janet S. Sinsheimer, Isaac S. Kohane, Hsiao-Tuan Chao, May Christine V. Malicdan, C. Christopher Lau, Mariska Davids, Eva Morava-Kozicz, Beth A. Martin, Daryl A. Scott, Prashant Sharma, Elizabeth L. Fieg, Lauren C. Briere, Shinya Yamamoto, Devon Bonner, Ralph L. Sacco, Amanda J. Yoon, John Yang, Katrina M. Waters, Carlos A. Bacino, Pengfei Liu, Brendan Lee, Lisa Bastarache, Emily G. Kelley, Tiphanie P. Vogel, Jason Hom, Marta M. Majcherska, Robb Rowley, Liliana Fernandez, Carsten Bonnenmann, Stanley F. Nelson, Colleen E. Wahl, Guney Bademci, Justin Alvey, Naghmeh Dorrani, Hane Lee, Lefkothea P. Karaviti, Monte Westerfield, John A. Phillips, Laurel A. Cobban, Chunli Zhao, Nicola Longo, Donna M. Krasnewich, Ta Chen Peter Chang, Tiina K. Urv, Christine M. Eng, Chloe M. Reuter, Ingrid A. Holm, Jozef Lazar, Emilie D. Douine, Susan A. Korrick, Alexa T. McCray, Richard A. Lewis, Ronit Marom, Kimberly LeBlanc, Cynthia J. Tifft, Cecilia Esteves, David R. Adams, Donna M. Brown, Avi Nath, Rebecca Signer, Martin G. Martin, Julian A. Martinez-Agosto, Jacob L. McCauley, Alyssa A. Tran, Jennifer A. Sullivan, William A. Gahl, Brendan C. Lanpher, Marie Morimoto, Donna Novacic, Jean-Philippe F. Gourdine, Paul G. Fisher, Fred F. Telischi, Shruti Marwaha, Heather A. Colley, Queenie K.-G. Tan, Seema R. Lalani, Deborah Barbouth, Jennifer E. Posey, Yong-hui Jiang, Jennifer Wambach, Mario Saporta, Jean M. Johnston, Dustin Baldridge, Timothy Schedl, Pace Laura, Ellen Macnamara, Joy D. Cogan, Kevin S. Smith, David M. Koeller, Genecee Renteria, Maura R.Z. Ruzhnikov, Christina G.S. Palmer, Valerie Maduro, Frances A. High, Gerard T. Berry, Holly K. Tabor, Terra R. Coakley, Surendra Dasari, Neil A. Hanchard, David P. Bick, Laure Fresard, Rizwan Hamid, Lilianna Solnica-Krezel, Gabriel F. Batzli, Judy Schaechter, John C. Carey, Tyra Estwick, and Mustafa Tekin
Subjects: World Wide Web, Electronic health record, Biology, Genetics (clinical)
Published: 2021

35. Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science

Author: Kelly Schoch, Cecilia Esteves, Anna Bican, Rebecca Spillmann, Heidi Cope, Allyn McConkie-Rosell, Nicole Walley, Liliana Fernandez, Jennefer N. Kohler, Devon Bonner, Chloe Reuter, Nicholas Stong, John J. Mulvihill, Donna Novacic, Lynne Wolfe, Ayat Abdelbaki, Camilo Toro, Cyndi Tifft, May Malicdan, William Gahl, Pengfei Liu, John Newman, David B. Goldstein, Jason Hom, Jacinda Sampson, Matthew T. Wheeler, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J.Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J.Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C.Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Terra R. Coakley, Paul G. Fisher, Laure Fresard, Yong Huang, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, and Joy Cogan
Subjects: Exome sequencing, 0301 basic medicine, Computational biology, 030105 genetics & heredity, Genome sequencing, Article, DNA sequencing, Retrospective data, 03 medical and health sciences, Rare Diseases, Animals, Humans, Genomic medicine, Medicine, Medical diagnosis, Exome, Genetics (clinical), Retrospective Studies, Disease gene, business.industry, Genomics, 030104 developmental biology, Phenotyping, New disease, Undiagnosed diseases, Ultra-rare diseases, business
Abstract: Purpose The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices. Methods We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods. Results Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling. Conclusion Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.
Published: 2021

36. Characterization of Reference Materials for Spinal Muscular Atrophy Genetic Testing

Author: Pinar Bayrak-Toydemir, Junqing Shen, Rong Mao, James D. Metcalf, Victoria M. Pratt, Aiko Iwata-Otsubo, Thomas W. Prior, Ty C. Lynnes, Shumaila Qureshi, Ha T. Pham, Francesco Vetrini, Kasinathan Muralidharan, Lisa V. Kalman, and Deborah Requesens
Subjects: 0301 basic medicine, Newborn screening, medicine.diagnostic_test, business.industry, Computational biology, Spinal muscular atrophy, SMN1, medicine.disease, SMA, nervous system diseases, Pathology and Forensic Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, medicine, Molecular Medicine, Copy-number variation, Allele, business, Genotyping, Genetic testing
Abstract: Spinal muscular atrophy (SMA) is an autosomal recessive disorder predominately caused by bi-allelic loss of the SMN1 gene. Increased copies of SMN2, a low functioning nearly identical paralog, are associated with a less severe phenotype. SMA was recently recommended for inclusion in newborn screening. Clinical laboratories must accurately measure SMN1 and SMN2 copy number to identify SMA patients and carriers, and to identify individuals likely to benefit from therapeutic interventions. Having publicly available and appropriately characterized reference materials with various combinations of SMN1 and SMN2 copy number variants is critical to assure accurate SMA clinical testing. To address this need, the CDC-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and the Coriell Institute for Medical Research, has characterized 15 SMA reference materials derived from publicly available cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using three different methods. The characterized samples had zero to four copies of SMN1 and zero to five copies SMN2. The samples also contained clinically important allele combinations (eg, zero copies SMN1, three copies SMN2), and several had markers indicative of an SMA carrier. These and other reference materials characterized by the Genetic Testing Reference Materials Coordination Program are available from the Coriell Institute and are proposed to support the quality of clinical laboratory testing.
Published: 2021

37. De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations

Author: Kerith-Rae Dias, Colleen M. Carlston, Laura E.R. Blok, Lachlan De Hayr, Urwah Nawaz, Carey-Anne Evans, Pinar Bayrak-Toydemir, Stephanie Htun, Ying Zhu, Alan Ma, Sally Ann Lynch, Catherine Moorwood, Karen Stals, Sian Ellard, Matthew N. Bainbridge, Jennifer Friedman, John G. Pappas, Rachel Rabin, Catherine B. Nowak, Jessica Douglas, Theodore E. Wilson, Maria J. Guillen Sacoto, Sureni V. Mullegama, Timothy Blake Palculict, Edwin P. Kirk, Jason R. Pinner, Matthew Edwards, Francesca Montanari, Claudio Graziano, Tommaso Pippucci, Bri Dingmann, Ian Glass, Heather C. Mefford, Takeyoshi Shimoji, Toshimitsu Suzuki, Kazuhiro Yamakawa, Haley Streff, Christian P. Schaaf, Anne M. Slavotinek, Irina Voineagu, John C. Carey, Michael F. Buckley, Annette Schenck, Robert J. Harvey, and Tony Roscioli
Subjects: All institutes and research themes of the Radboud University Medical Center, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Gene Expression Regulation, Protein Domains, Neurodevelopmental Disorders, Intellectual Disability, Exome Sequencing, Brain, Humans, Genetics (clinical)
Abstract: ZMYND8 encodes a multidomain protein that serves as a central interactive hub for coordinating critical roles in transcription regulation, chromatin remodeling, regulation of super-enhancers, DNA damage response and tumor suppression. We delineate a novel neurocognitive disorder caused by variants in the ZMYND8 gene.An international collaboration, exome sequencing, molecular modeling, yeast two-hybrid assays, analysis of available transcriptomic data and a knockdown Drosophila model were used to characterize the ZMYND8 variants.ZMYND8 variants were identified in 11 unrelated individuals; 10 occurred de novo and one suspected de novo; 2 were truncating, 9 were missense, of which one was recurrent. The disorder is characterized by intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies. Missense variants in the PWWP domain of ZMYND8 abolish the interaction with Drebrin and missense variants in the MYND domain disrupt the interaction with GATAD2A. ZMYND8 is broadly expressed across cell types in all brain regions and shows highest expression in the early stages of brain development. Neuronal knockdown of the DrosophilaZMYND8 ortholog results in decreased habituation learning, consistent with a role in cognitive function.We present genomic and functional evidence for disruption of ZMYND8 as a novel etiology of syndromic intellectual disability.
Published: 2022

38. Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder

Author: Katherine Wesseling Perry, Archana Raja, Emilie D. Douine, Xue Zhong Liu, Brent L. Fogel, Stan F. Nelson, Kenneth R. Maravilla, Eva H. Baker, Dave Viskochil, Kerstin Kutsche, Jordan H. Whitlock, Susan L. Samson, Christine M. Eng, Chloe M. Reuter, Suman Jayadev, David R. Adams, Sihoun Hahn, Rebecca C. Spillmann, Margaret Adam, Heather C Mefford, John C. Carey, Ehsan Ghayoor Karimiani, Donna M. Krasnewich, David Goldstein, Susan A. Korrick, Guoyun Yu, Tomas Honzik, Henry Houlden, Andrea L. Gropman, David A. Sweetser, Anna Bican, Carlos A. Bacino, Liliana Fernandez, Gabrielle Brown, Justin Alvey, Hane Lee, Emanuele G. Coci, Hongzheng Dai, Mario Saporta, Laurel A. Cobban, John F. Bohnsack, Stephanie Fox, Heidi Cope, Tyra Estwick, Lorraine Potocki, Nichole Hayes, Elizabeth A. Burke, Rizwan Hamid, Aaron R. Quinlan, Kelly Hassey, Lindsay C. Burrage, Jane Juusola, Adeline Vanderver, Malik Alawi, Teri A. Manolio, Maja Hempel, Esther M. Maier, Jennifer Kennedy, Bruce D. Gelb, Martha Horike-Pyne, Amarilis Sanchez-Valle, Euan A. Ashley, Surendra Dasari, Elizabeth Blue, Eva Morava-Kozicz, Natalie Rosenwasser, Alan H. Beggs, Bryn D. Webb, Isaac S. Kohane, Kelly Schoch, C. Christopher Lau, Nicole M. Walley, Laura M. Amendola, Genecee Renteria, Catherine H. Sillari, Jonathan A. Bernstein, Pinar Bayrak-Toydemir, R. Frank Kooy, Mariko Nakano-Okuno, Manuela Siekmeyer, Marije E. C. Meuwissen, Stephanie Bivona, Mark Wener, Precilla D'Souza, Olveen Carrasquillo, Paolo Moretti, Diane B. Zastrow, David J. Eckstein, Janet S. Sinsheimer, Kathy Sisco, Holly K. Tabor, William E. Byrd, Esteban C. Dell'Angelica, Rosario Isasi, Jacinda B. Sampson, Carsten Bonnenmann, J. Lawrence Merritt, Joan M. Stoler, Richard L. Maas, Paul G. Fisher, Jeanette C. Papp, Kimberly LeBlanc, Lilianna Solnica-Krezel, Mustafa Tekin, Mathias Woidy, Andrew B. Crouse, Katleen Ballon, David Murphy, Matthew T. Wheeler, Joseph Loscalzo, Ellen Macnamara, Cecelia P. Tamburro, Lefkothea P. Karaviti, Chunli Zhao, Ingrid A. Holm, Pankaj B. Agrawal, Alana L. Grajewski, Stephen C. Pak, Ian R. Lanza, Mohammad Doosti, Jennifer E. Posey, Rebecca Signer, Katie Golden-Grant, Christopher A. Walsh, Alica M. Goldman, Jyoti G. Dayal, Queenie K.-G. Tan, Martin G. Martin, Joy D. Cogan, Kevin S. Smith, Deborah A. Nickerson, Elisabeth McGee, Laure Fresard, Rena A. Godfrey, Sharyn A. Lincoln, Kathleen E. Sullivan, Mariska Davids, Melissa A. Walker, Prashant Sharma, Maria Iascone, Neil H. Parker, Carlos Ferreira, Elizabeth L. Fieg, Edwin K. Silverman, Michael L. Cunningham, Pengfei Liu, Edward M. Behrens, Sandra K. Loo, David R. Murdock, F. Sessions Cole, C. Ron Scott, Dan Doherty, Elly Brokamp, John H. Newman, Alden Y. Huang, Laura A. Pace, Avi Nath, Jimmy Bennet, Georg Christoph Korenke, Alyssa A. Tran, Gabriel F. Batzli, Jimann Shin, Matthew A. Deardorff, Naghmeh Dorrani, Diane Beysen, Irma Gutierrez, Stanislav Kmoch, Majid Alfadhel, Fred F. Telischi, Jennifer A. Sullivan, William A. Gahl, María Palomares-Bralo, Gerard T. Berry, Colleen E. McCormack, Lance H. Rodan, Reza Maroofian, Lenka Nosková, Judy Schaechter, Lynne A. Wolfe, Deborah Krakow, Daryl A. Scott, Tara Wenger, Jason Hom, Dustin Baldridge, Lynette Rives, Lee-kai Wang, Dawn L. Earl, Ralph L. Sacco, Fernando Santos-Simarro, Irman Forghani, Fuki M. Hisama, Terra R. Coakley, Hsiao-Tuan Chao, Jeremy D. Woods, Emily G. Kelley, Jean M. Johnston, Neil A. Hanchard, Amy K. Robertson, Matt Velinder, Byron L. Lam, Wendy H. Raskind, William J. Craigen, Stephan Züchner, Guney Bademci, Julian A. Martinez-Agosto, Mary Koziura, Beth A. Martin, Angela Sun, John A. Phillips, Seema R. Lalani, Daniela Buhas, Emily Solem, Gary D. Clark, Gill Bejerano, Ingo Kurth, Deborah Barbouth, Tiina K. Urv, Fanny Kortüm, Ian A. Glass, Ta Chen Peter Chang, Yong Huang, Roy C. Levitt, Paola Francesca Ajmone, Brenna Boyd, René Santer, Tim Schedl, David D. Draper, Ghayda M. Mirzaa, Aroa Rodríguez Alonso, Stephanie Wallace, Colleen E. Wahl, Calum A. MacRae, Gail P. Jarvik, Jacob L. McCauley, Jill A. Rosenfeld, Ronit Marom, Monte Westerfield, Matthew Might, Poupak Javaher-Haghighi, Brendan C. Lanpher, Devon Bonner, Cynthia J. Tifft, Cecilia Esteves, May Christine V. Malicdan, Jim Bale, Fariha Jamal, Nicola Longo, Christina G.S. Palmer, Lisa Emrick, Peter H. Byers, Vandana Shashi, Tiphanie P. Vogel, Richard A. Lewis, Jijun Wan, Barbara N. Pusey, Maria T. Acosta, Jaak Jaeken, Allyn McConkie-Rosell, Shirley Sutton, John Yang, Lorenzo D. Botto, Hilde Peeters, Rong Mao, Catherine Groden, Brendan Lee, Marta M. Majcherska, Rami Abou Jamra, Ashok Balasubramanyam, Joel B. Krier, Majid Mojarrad, Maria Francesca Bedeschi, Mahshid S. Azamian, Shruti Marwaha, Heather A. Colley, Katrina M. Dipple, Sirisak Chanprasert, Alexa T. McCray, Nicholas Stong, Anne V. Hing, Laura A. Mamounas, Edward C. Smith, Lauren C. Briere, John J.E. Mulvihill, Virginia P. Sybert, Maura R.Z. Ruzhnikov, Valerie Maduro, Frances A. High, Manish J. Butte, Willa Thorson, J. Carl Pallais, Jennefer N. Kohler, Dana Kiley, Raphael Bernier, Christina Lam, Michael J. Bamshad, Patricia A. Ward, Michael F. Wangler, Anita E. Beck, Shinya Yamamoto, Beverly Berg-Rood, Robb Rowley, Gabor T. Marth, Cynthia M. Cooper, Jeffrey G. Jarvik, Thomas C. Markello, Saskia Biskup, Devin Oglesbee, Laura Duncan, Elijah Kravets, Daniel J. Wegner, Mercedes E. Alejandro, Sarah K. Nicholas, Jennifer A. Wambach, Marni J. Falk, Brianna M. Tucker, Marie Morimoto, Corina Heller, Donna Novacic, Camilo Toro, Ashley Andrews, James P. Orengo, Shweta U. Dhar, and Pauline E. Schneeberger
Subjects: 0301 basic medicine, MAPK/ERK pathway, Death Domain Receptor Signaling Adaptor Proteins, Programmed cell death, Developmental Disabilities, Biology, 03 medical and health sciences, 0302 clinical medicine, Epidermal growth factor, medicine, Guanine Nucleotide Exchange Factors, Humans, Death domain, Kinase, Original Articles, Phenotype, Hypotonia, Protein Transport, 030104 developmental biology, Mutation, Cancer research, Human medicine, Neurology (clinical), Nervous System Diseases, Signal transduction, medicine.symptom, 030217 neurology & neurosurgery, Signal Transduction
Abstract: In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.
Published: 2020

39. Curaçao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2)

Author: Desiree DeMille, Pinar Bayrak-Toydemir, Kevin J. Whitehead, Whitney Wooderchak-Donahue, and Jamie McDonald
Subjects: 0301 basic medicine, Proband, medicine.medical_specialty, business.industry, Consensus criteria, ACVRL1, 030105 genetics & heredity, Confidence interval, Molecular analysis, 03 medical and health sciences, 030104 developmental biology, Clinical diagnosis, Internal medicine, Medicine, In patient, medicine.symptom, business, Telangiectasia, Genetics (clinical)
Abstract: Determine the variant detection rate for ENG, ACVRL1, and SMAD4 in individuals who meet consensus (Curacao) criteria for the clinical diagnosis of hereditary hemorrhagic telangiectasia. Review of HHT center database for individuals with three or more HHT diagnostic criteria, in whom molecular genetic analysis for ENG, ACVRL1, and SMAD4 had been performed. A variant known or suspected to be causal was detected in ENG in 67/152 (44.1%; 95% confidence interval [CI], 36.0–52.4%), ACVRL1 in 79/152 (52.0%; 95% CI, 43.7–60.1%), and SMAD4 in 2/152 (1.3%; 95% CI, 0.2–4.7%) family probands with definite HHT. Only 4/152 (2.6%; 95% CI, 0.7–6.6%) family probands did not have a variant in one of these genes. Previous reports of the variant detection rate for ENG and ACVRL1 in HHT patients have come from laboratories, which receive samples from clinicians with a wide range of expertise in recognizing clinical manifestations of HHT. These studies suggest a significantly lower detection rate (~75–85%) than we have found in patients who meet strictly applied consensus criteria (96.1%). Analysis of SMAD4 adds an additional detection rate of 1.3%. HHT as defined by the Curacao criteria is highly predictive of a causative variant in either ENG or ACVRL1.
Published: 2020

40. De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation

Author: Dongxue Mao, Chloe M. Reuter, Maura R.Z. Ruzhnikov, Anita E. Beck, Emily G. Farrow, Lisa T. Emrick, Jill A. Rosenfeld, Katherine M. Mackenzie, Laurie Robak, Matthew T. Wheeler, Lindsay C. Burrage, Mahim Jain, Pengfei Liu, Daniel Calame, Sébastien Küry, Martin Sillesen, Klaus Schmitz-Abe, Davide Tonduti, Luigina Spaccini, Maria Iascone, Casie A. Genetti, Mary K. Koenig, Madeline Graf, Alyssa Tran, Mercedes Alejandro, Brendan H. Lee, Isabelle Thiffault, Pankaj B. Agrawal, Jonathan A. Bernstein, Hugo J. Bellen, Hsiao-Tuan Chao, Maria T. Acosta, Margaret Adam, David R. Adams, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Raphael Bernier, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Elizabeth A. Burke, Manish J. Butte, Peter Byers, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Yong-hui Jiang, Jean M. Johnston, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Kimberly LeBlanc, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Genecee Renteria, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Monte Westerfield, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Proband, Ataxia, Adolescent, Developmental Disabilities, Nervous System Malformations, Leukoencephalopathy, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Leukoencephalopathies, Report, Genetics, medicine, Humans, Missense mutation, Kinase activity, Child, Genetics (clinical), biology, Leukodystrophy, Genetic Variation, Infant, medicine.disease, White Matter, Hypotonia, Hereditary Central Nervous System Demyelinating Diseases, 030104 developmental biology, Child, Preschool, eIF2B, Immunology, biology.protein, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract: EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2α), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.
Published: 2020

41. Diagnostic gene sequencing panels: from design to report—a technical standard of the American College of Medical Genetics and Genomics (ACMG)

Author: Pinar Bayrak-Toydemir, Jennifer L. Gannon, Sibel Kantarci, Bryan L. Krock, Colleen Carlston, Shulin Zhang, Lora J. H. Bean, and Birgit Funke
Subjects: medicine.medical_specialty, medicine.diagnostic_test, Computer science, Pseudogene, Technical standard, Context (language use), Genomics, Computational biology, medicine, Medical genetics, Gene family, Predictive testing, Genetics (clinical), Genetic testing
Abstract: Gene sequencing panels are a powerful diagnostic tool for many clinical presentations associated with genetic disorders. Advances in DNA sequencing technology have made gene panels more economical, flexible, and efficient. Because the genes included on gene panels vary widely between laboratories in gene content (e.g., number, reason for inclusion, evidence level for gene–disease association) and technical completeness (e.g., depth of coverage), standards that address technical and clinical aspects of gene panels are needed. This document serves as a technical standard for laboratories designing, offering, and reporting gene panel testing. Although these principles can apply to multiple indications for genetic testing, the primary focus is on diagnostic gene panels (as opposed to carrier screening or predictive testing) with emphasis on technical considerations for the specific genes being tested. This technical standard specifically addresses the impact of gene panel content on clinical sensitivity, specificity, and validity—in the context of gene evidence for contribution to and strength of evidence for gene–disease association—as well as technical considerations such as sequencing limitations, presence of pseudogenes/gene families, mosaicism, transcript choice, detection of copy-number variants, reporting, and disclosure of assay limitations.
Published: 2020

42. Magnetic Resonance Imaging characteristics in case of TOR1AIP1 muscular dystrophy

Author: Aashim Bhatia, Bret C. Mobley, Joy Cogan, Mary E. Koziura, Elly Brokamp, John Phillips, John Newman, Steven A. Moore, Rizwan Hamid, Maria T. Acosta, David R. Adams, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Mariska Davids, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Sandra K. Loo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: medicine.medical_specialty, Adolescent, Gene mutation, Article, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Muscular dystrophy, Muscle, Skeletal, Gluteal muscles, Muscle Weakness, Muscle biopsy, medicine.diagnostic_test, business.industry, Muscle weakness, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, Muscular Atrophy, medicine.anatomical_structure, Lower Extremity, Muscular Dystrophies, Limb-Girdle, 030220 oncology & carcinogenesis, Female, Radiology, Iliopsoas, medicine.symptom, business, Molecular Chaperones
Abstract: Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.
Published: 2019

43. A Comprehensive Triple-Repeat Primed PCR and a Long-Range PCR Agarose-Based Assay for Improved Genotyping of Guanine-Adenine-Adenine Repeats in Friedreich Ataxia

Author: Mohamed Jama, Rebecca L. Margraf, Ping Yu, N. Scott Reading, and Pinar Bayrak-Toydemir
Subjects: Guanine, Genotype, Trinucleotide Repeats, Friedreich Ataxia, Adenine, Iron-Binding Proteins, Sepharose, Molecular Medicine, Humans, Trinucleotide Repeat Expansion, Polymerase Chain Reaction, Pathology and Forensic Medicine
Abstract: Friedreich ataxia is a rare autosomal recessive, neuromuscular degenerative disease caused by an expansion of a trinucleotide [guanine-adenine-adenine (GAA)] repeat in intron 1 of the FXN gene. It is common in the White population, characterized by progressive gait and limb ataxia, lack of tendon reflexes in the legs, loss of position sense, and hypertrophic cardiomyopathy. Detection and genotyping of the trinucleotide repeat length is important for the diagnosis and prognosis of the disease. A two-tier genotyping assay with an improved triple-repeat primed PCR (TR-PCR) for alleles200 GAA repeats (±1 to 5 repeats) and an agarose gel-based, long-range PCR (LR-PCR) assay to genotype expanded alleles200 GAA repeats (±50 repeats) is described. Of the 1236 DNA samples tested using TR-PCR, 31 were identified to have expanded alleles200 repeats and were reflexed to the LR-PCR procedure for confirmation and quantification. The TR-PCR assay described herein is a diagnostic genotyping assay that reduces the need for further testing. The LR-PCR component is a confirmatory test for true homozygous and heterozygous samples with normal and expanded alleles, as indicated by the TR-PCR assay. The use of this two-tier method offers a comprehensive evaluation to detect and genotype the smallest and largest number of GAA repeats, improving the classification of FXN alleles as normal, mutable normal, borderline, and expanded alleles.
Published: 2021

44. Homozygous GDF2 nonsense mutations result in a loss of circulating BMP9 and BMP10 and are associated with either PAH or an 'HHT‐like' syndrome in children

Author: Pinar Bayrak-Toydemir, Lidia Ruiz-Llorente, Oliver Quarrell, Katie Bergstrom, Jamie McDonald, Robin Condliffe, Nicholas W. Morrell, Kelechi Ugonna, Rebecca Mason, Jennifer M. Martin, David Moore, Carmelo Bernabeu, Paul D. Upton, Whitney Wooderchak-Donahue, Joshua Hodgson, James R. Bentham, Hodgson, Joshua [0000-0001-8423-0935], Ruiz-Llorente, Lidia [0000-0003-1430-9618], McDonald, Jamie [0000-0001-9939-7922], Quarrell, Oliver [0000-0002-3818-9051], Martin, Jennifer [0000-0002-7697-7438], Moore, David [0000-0001-9308-5741], Bergstrom, Katie [0000-0002-0353-2278], Bayrak-Toydemir, Pinar [0000-0001-9381-2478], Wooderchak-Donahue, Whitney [0000-0002-9358-7466], Morrell, Nicholas W [0000-0001-5700-9792], Condliffe, Robin [0000-0002-3492-4143], Bernabeu, Carmelo [0000-0002-1563-6162], Upton, Paul D [0000-0003-2716-4921], Apollo - University of Cambridge Repository, British Heart Foundation, Consejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Hodgson, Joshua, Ruiz-Llorente, Lidia, McDonald, Jamie, Quarrell, Oliver, Martin, Jennifer, Moore, David, Bergstrom, Katie, Bayrak-Toydemir, Pinar, Wooderchak-Donahue, Whitney, Morrell, Nicholas W., Condliffe, Robin, Bernabéu, Carmelo, Upton, Paul D., Morrell, Nicholas W. [0000-0001-5700-9792], Bernabéu, Carmelo [0000-0002-1563-6162], Upton, Paul D. [0000-0003-2716-4921], Morrell, Nicholas [0000-0001-5700-9792], and Upton, Paul [0000-0003-2716-4921]
Subjects: 0301 basic medicine, medicine.medical_specialty, Mutant, Nonsense mutation, GDF2, Enzyme-Linked Immunosorbent Assay, Pulmonary arteriovenous malformations, Telangiectases, 030105 genetics & heredity, QH426-470, Pulmonary arterial hypertension, Asymptomatic, Cell Line, 03 medical and health sciences, Bone morphogenetic proteins, Internal medicine, bone morphogenetic protein, pulmonary arterial hypertension, Growth Differentiation Factor 2, medicine, Genetics, Humans, hereditary hemorrhagic telangiectasia, Genetic Predisposition to Disease, Child, Telangiectasia, Molecular Biology, Gene, Alleles, Genetic Association Studies, Genetics (clinical), business.industry, Homozygote, Angiography, Original Articles, Syndrome, Pathophysiology, Phenotype, 030104 developmental biology, Endocrinology, Hereditary hemorrhagic telangiectasia, Codon, Nonsense, pulmonary arteriovenous malformations, Bone Morphogenetic Proteins, Original Article, Telangiectasia, Hereditary Hemorrhagic, medicine.symptom, business
Abstract: 13 p.-3 fig.-1 tab., Background: Disrupted endothelial BMP9/10 signaling may contribute to the pathophysiology of both hereditary hemorrhagic telangiectasia (HHT) and pulmonary arterial hypertension (PAH), yet loss of circulating BMP9 has not been confirmed in individuals with ultra-rare homozygous GDF2 (BMP9 gene) nonsense mutations. We studied two pediatric patients homozygous for GDF2 (BMP9 gene) nonsense mutations: one with PAH (c.[76C>T];[76C>T] or p.[Gln26Ter];[Gln26Ter] and a new individual with pulmonary arteriovenous malformations (PAVMs; c.[835G>T];[835G>T] or p.[Glu279Ter];[Glu279Ter]); both with facial telangiectases., Methods: Plasma samples were assayed for BMP9 and BMP10 by ELISA. In parallel, serum BMP activity was assayed using an endothelial BRE-luciferase reporter cell line (HMEC1-BRE). Proteins were expressed for assessment of secretion and processing., Results: Plasma levels of both BMP9 and BMP10 were undetectable in the two homozygous index cases and this corresponded to low serum-derived endothelial BMP activity in the patients. Measured BMP9 and BMP10 levels were reduced in the asymptomatic heterozygous p.[Glu279Ter] parents, but serum activity was normal. Although expression studies suggested alternate translation can be initiated at Met57 in the p.[Gln26Ter] mutant, this does not result in secretion of functional BMP9., Conclusion: Collectively, these data show that homozygous GDF2 mutations, leading to a loss of circulating BMP9 and BMP10, can cause either pediatric PAH and/or "HHT-like" telangiectases and PAVMs. Although patients reported to date have manifestations that overlap with those of HHT, none meet the Curaçao criteria for HHT and seem distinct from HHT in terms of the location and appearance of telangiectases, and a tendency for tiny, diffuse PAVMs., This study was supported by British Heart Foundation Grant/Award Numbers: FS/15/62/323032, RG/13/4/30107, and RG/19/3/34265; Consejo Superior de Investigaciones Científicas (CSIC) Grant/Award Number: 201920E022; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) Grant/ Award Numbers: ISCIII-CB06/07/0038 and CNV-234-PRF-360.
Published: 2021

45. An autosomal dominant neurological disorder caused by de novo variants in FAR1 resulting in uncontrolled synthesis of ether lipids

Author: Sacha Ferdinandusse, Kirsty McWalter, Heleen te Brinke, Lodewijk IJlst, Petra M. Mooijer, Jos P.N. Ruiter, Alida E.M. van Lint, Mia Pras-Raves, Eric Wever, Francisca Millan, Maria J. Guillen Sacoto, Amber Begtrup, Mark Tarnopolsky, Lauren Brady, Roger L. Ladda, Susan L. Sell, Catherine B. Nowak, Jessica Douglas, Cuixia Tian, Elizabeth Ulm, Seth Perlman, Arlene V. Drack, Karen Chong, Nicole Martin, Jennifer Brault, Elly Brokamp, Camilo Toro, William A. Gahl, Ellen F. Macnamara, Lynne Wolfe, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Lindsay C. Burrage, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Jill A. Rosenfeld, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Rebecca C. Spillmann, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Lance H. Rodan, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. Phillips, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Quinten Waisfisz, Petra J.G. Zwijnenburg, Alban Ziegler, Magalie Barth, Rosemarie Smith, Sara Ellingwood, Deborah Gaebler-Spira, Somayeh Bakhtiari, Michael C. Kruer, Antoine H.C. van Kampen, Ronald J.A. Wanders, Hans R. Waterham, David Cassiman, Frédéric M. Vaz, Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Methodology, Epidemiology and Data Science, APH - Personalized Medicine, Laboratory for General Clinical Chemistry, ARD - Amsterdam Reproduction and Development, Human genetics, ACS - Atherosclerosis & ischemic syndromes, and Amsterdam Reproduction & Development (AR&D)
Subjects: Candidate gene, Hereditary spastic paraplegia, Undiagnosed Diseases Network, Neurological disorder, Biology, medicine.disease, Molecular biology, Article, Biochemical phenotype, Bilateral Cataracts, Gene panel, medicine, Ether lipid synthesis, In patient, Genetics (clinical)
Abstract: Author(s): Ferdinandusse, Sacha; McWalter, Kirsty; Te Brinke, Heleen; IJlst, Lodewijk; Mooijer, Petra M; Ruiter, Jos PN; van Lint, Alida EM; Pras-Raves, Mia; Wever, Eric; Millan, Francisca; Guillen Sacoto, Maria J; Begtrup, Amber; Tarnopolsky, Mark; Brady, Lauren; Ladda, Roger L; Sell, Susan L; Nowak, Catherine B; Douglas, Jessica; Tian, Cuixia; Ulm, Elizabeth; Perlman, Seth; Drack, Arlene V; Chong, Karen; Martin, Nicole; Brault, Jennifer; Brokamp, Elly; Toro, Camilo; Gahl, William A; Macnamara, Ellen F; Wolfe, Lynne; Undiagnosed Diseases Network; Waisfisz, Quinten; Zwijnenburg, Petra JG; Ziegler, Alban; Barth, Magalie; Smith, Rosemarie; Ellingwood, Sara; Gaebler-Spira, Deborah; Bakhtiari, Somayeh; Kruer, Michael C; van Kampen, Antoine HC; Wanders, Ronald JA; Waterham, Hans R; Cassiman, David; Vaz, Frederic M | Abstract: PurposeIn this study we investigate the disease etiology in 12 patients with de novo variants in FAR1 all resulting in an amino acid change at position 480 (p.Arg480Cys/His/Leu).MethodsFollowing next-generation sequencing and clinical phenotyping, functional characterization was performed in patients' fibroblasts using FAR1 enzyme analysis, FAR1 immunoblotting/immunofluorescence, and lipidomics.ResultsAll patients had spastic paraparesis and bilateral congenital/juvenile cataracts, in most combined with speech and gross motor developmental delay and truncal hypotonia. FAR1 deficiency caused by biallelic variants results in defective ether lipid synthesis and plasmalogen deficiency. In contrast, patients' fibroblasts with the de novo FAR1 variants showed elevated plasmalogen levels. Further functional studies in fibroblasts showed that these variants cause a disruption of the plasmalogen-dependent feedback regulation of FAR1 protein levels leading to uncontrolled ether lipid production.ConclusionHeterozygous de novo variants affecting the Arg480 residue of FAR1 lead to an autosomal dominant disorder with a different disease mechanism than that of recessive FAR1 deficiency and a diametrically opposed biochemical phenotype. Our findings show that for patients with spastic paraparesis and bilateral cataracts, FAR1 should be considered as a candidate gene and added to gene panels for hereditary spastic paraplegia, cerebral palsy, and juvenile cataracts.
Published: 2021

46. Lysosomal Storage and Albinism Due to Effects of a De Novo CLCN7 Variant on Lysosomal Acidification

Author: Elena-Raluca Nicoli, Mary R. Weston, Mary Hackbarth, Alissa Becerril, Austin Larson, Wadih M. Zein, Peter R. Baker, John Douglas Burke, Heidi Dorward, Mariska Davids, Yan Huang, David R. Adams, Patricia M. Zerfas, Dong Chen, Thomas C. Markello, Camilo Toro, Tim Wood, Gene Elliott, Mylinh Vu, Wei Zheng, Lisa J. Garrett, Cynthia J. Tifft, William A. Gahl, Debra L. Day-Salvatore, Joseph A. Mindell, May Christine V. Malicdan, Maria T. Acosta, Pankaj Agrawal, Mercedes E. Alejandro, Patrick Allard, Justin Alvey, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanyam, Dustin Baldridge, Jim Bale, Deborah Barbouth, Gabriel F. Batzli, Pinar Bayrak-Toydemir, Alan H. Beggs, Gill Bejerano, Hugo J. Bellen, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, David P. Bick, Camille L. Birch, Stephanie Bivona, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Braden E. Boone, Bret L. Bostwick, Lorenzo Botto, Lauren C. Briere, Elly Brokamp, Donna M. Brown, Matthew Brush, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Precilla D'Souza, Surendra Dasari, Jyoti G. Dayal, Esteban C. Dell'Angelica, Shweta U. Dhar, Naghmeh Dorrani, Daniel C. Dorset, Emilie D. Douine, David D. Draper, Laura Duncan, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Tyra Estwick, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, Rena A. Godfrey, Alica M. Goldman, David B. Goldstein, Jean-Philippe F. Gourdine, Alana Grajewski, Catherine A. Groden, Andrea L. Gropman, Melissa Haendel, Rizwan Hamid, Neil A. Hanchard, Nichole Hayes, Frances High, Ingrid A. Holm, Jason Hom, Alden Huang, Yong Huang, Rosario Isasi, Fariha Jamal, Yong-hui Jiang, Jean M. Johnston, Angela L. Jones, Lefkothea Karaviti, Emily G. Kelley, Dana Kiley, David M. Koeller, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Susan Korrick, Mary Koziura, Joel B. Krier, Jennifer E. Kyle, Seema R. Lalani, Byron Lam, Brendan C. Lanpher, Ian R. Lanza, C. Christopher Lau, Jozef Lazar, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Shawn E. Levy, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Thomas May, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Thomas O. Metz, Matthew Might, Eva Morava-Kozicz, Paolo M. Moretti, Marie Morimoto, John J. Mulvihill, David R. Murdock, Avi Nath, Stan F. Nelson, J. Scott Newberry, John H. Newman, Sarah K. Nicholas, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, John H. Postlethwait, Lorraine Potocki, Barbara N. Pusey, Aaron Quinlan, Archana N. Raja, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Jill A. Rosenfeld, Robb K. Rowley, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Lisa Shakachite, Prashant Sharma, Vandana Shashi, Kathleen Shields, Jimann Shin, Rebecca Signer, Catherine H. Sillari, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Kevin S. Smith, Lilianna Solnica-Krezel, Rebecca C. Spillmann, Joan M. Stoler, Nicholas Stong, Jennifer A. Sullivan, Shirley Sutton, David A. Sweetser, Holly K. Tabor, Cecelia P. Tamburro, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Alyssa A. Tran, Tiina K. Urv, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Katrina M. Waters, Bobbie-Jo M. Webb-Robertson, Daniel Wegner, Monte Westerfield, Matthew T. Wheeler, Anastasia L. Wise, Lynne A. Wolfe, Jeremy D. Woods, Elizabeth A. Worthey, Shinya Yamamoto, John Yang, Amanda J. Yoon, Guoyun Yu, Diane B. Zastrow, Chunli Zhao, and Stephan Zuchner
Subjects: Male, 0301 basic medicine, Albinism, Antiporter, Vacuole, Article, Organomegaly, Mice, Xenopus laevis, 03 medical and health sciences, 0302 clinical medicine, Chloride Channels, Lysosome, Genetics, medicine, Lysosomal storage disease, Animals, Humans, Genetics (clinical), Hypopigmentation, biology, Chemistry, Genetic Variation, Infant, Fibroblasts, Hydrogen-Ion Concentration, medicine.disease, Molecular biology, Lysosomal Storage Diseases, 030104 developmental biology, medicine.anatomical_structure, Oocytes, biology.protein, Female, CLCN7, medicine.symptom, Lysosomes, Acids, 030217 neurology & neurosurgery, Intracellular
Abstract: Optimal lysosome function requires maintenance of an acidic pH maintained by proton pumps in combination with a counterion transporter such as the Cl(−)/H(+) exchanger, CLCN7 (ClC-7), encoded by CLCN7. The role of ClC-7 in maintaining lysosomal pH has been controversial. In this paper, we performed clinical and genetic evaluations of two children of different ethnicities. Both children had delayed myelination and development, organomegaly, and hypopigmentation, but neither had osteopetrosis. Whole-exome and -genome sequencing revealed a de novo c.2144A>G variant in CLCN7 in both affected children. This p.Tyr715Cys variant, located in the C-terminal domain of ClC-7, resulted in increased outward currents when it was heterologously expressed in Xenopus oocytes. Fibroblasts from probands displayed a lysosomal pH approximately 0.2 units lower than that of control cells, and treatment with chloroquine normalized the pH. Primary fibroblasts from both probands also exhibited markedly enlarged intracellular vacuoles; this finding was recapitulated by the overexpression of human p.Tyr715Cys CLCN7 in control fibroblasts, reflecting the dominant, gain-of-function nature of the variant. A mouse harboring the knock-in Clcn7 variant exhibited hypopigmentation, hepatomegaly resulting from abnormal storage, and enlarged vacuoles in cultured fibroblasts. Our results show that p.Tyr715Cys is a gain-of-function CLCN7 variant associated with developmental delay, organomegaly, and hypopigmentation resulting from lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles. Our data supports the hypothesis that the ClC-7 antiporter plays a critical role in maintaining lysosomal pH.
Published: 2019

47. Characterization of a mutation in the zona pellucida module of Endoglin that causes Hereditary Hemorrhagic Telangiectasia

Author: Fabio Pagella, Carmelo Bernabeu, Lidia Ruiz-Llorente, Sara Plumitallo, Elisa Chiapparino, Luca Jovine, Pinar Bayrak-Toydemir, Carla Olivieri, Cesare Danesino, Guido Manfredi, Ministerio de Economía, Industria y Competitividad (España), Consejo Superior de Investigaciones Científicas (España), Centro de Investigación Biomédica en Red Enfermedades Raras (España), Instituto de Salud Carlos III, Ruiz-Llorente, Lidia, Plumitallo, Sara, Danesino, Cesare, Bayrak-Toydemir, Pinar, Bernabéu, Carmelo, Jovine, Luca, Olivieri, Carla, Ruiz-Llorente, Lidia [0000-0003-1430-9618], Plumitallo, Sara [0000-0003-2998-777X], Danesino, Cesare [0000-0002-8400-5671], Bayrak-Toydemir, Pinar [0000-0001-9381-2478], Bernabéu, Carmelo [0000-0002-1563-6162], Jovine, Luca [0000-0002-2679-6946], and Olivieri, Carla [0000-0001-5812-3175]
Subjects: Adult, Male, Protein Folding, Haploinsufficiency, Biology, medicine.disease_cause, HHT, Young Adult, Exon, Protein Domains, hemic and lymphatic diseases, otorhinolaryngologic diseases, Genetics, medicine, Humans, Cysteine, Child, Zona pellucida, ZP-domain, Mutation, Expression vector, Endoglin, ACVRL1, Exons, General Medicine, Transfection, Middle Aged, Molecular biology, Pedigree, ENG, medicine.anatomical_structure, Italy, Membrane protein, Female, Telangiectasia, Hereditary Hemorrhagic, Signal Transduction
Abstract: 7 p.-4 fig., Hereditary hemorrhagic telangiectasia (HHT) is a vascular rare disease characterized by nose and gastrointestinal bleeding, skin and mucosa telangiectasias, and arteriovenous malformations in internal organs. HHT shows an autosomal dominant inheritance and a worldwide prevalence of approximately 1:5000 individuals. In >80% of patients, HHT is caused by mutations in either ENG (HHT1) or ACVRL1 (HHT2) genes, which code for the membrane proteins Endoglin and Activin A Receptor Type II-Like Kinase 1 (ALK1), respectively, both belonging to the TGF-β/BMP signaling pathway. In this work, we describe a novel mutation in exon 9 of ENG (c.1145 G > A) found in five affected members of a family, all of them with characteristic symptoms of HHT. This mutation involves Cys382 residue of the Endoglin protein (p.Cys382 > Tyr) in the zona pellucida (ZP) module of its extracellular region. This is a critical residue involved in a conserved intrachain disulphide bond and in the correct folding of the protein. In fact, transfection studies in human cells using Endoglin expression vectors demonstrated that the p.Cys382 > Tyr mutation results in a marked reduction in the levels of the Endoglin protein. These results demonstrate the pathogenic role for this variant in HHT1 and confirm the key function of Cys382 in Endoglin expression., This work was supported by the Ministerio de Economía, Industria y Competitividad (Grant SAF2013-43421-R to CB); the Consejo Superior de Investigaciones Científicas (Grant 201420E039 and 201920E022 to CB); and the Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER; Grant ISCIII-CB06/07/0038 to CB and contract to LR-L) of Spain. CIBERER is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain supported by FEDER funds.
Published: 2019

48. Misattributed parentage as an unanticipated finding during exome/genome sequencing: current clinical laboratory practices and an opportunity for standardization

Author: Patricia A. Ward, Lindsey Mighion, Jerry Machado, Rong Mao, Celeste Eno, Kelly D. Farwell Hagman, Dima El-Khechen, Jane Juusola, Lora J. H. Bean, Alicia Braxton, Pinar Bayrak-Toydemir, Heidi L. Rehm, Amy Lovelette Hernandez, Gina Londre, Bethany Friedman, Elizabeth C. Chao, Edward D. Esplin, Joshua L. Deignan, and Tina Hambuch
Subjects: Male, Parents, 0301 basic medicine, medicine.medical_specialty, Standardization, Genetics, Medical, Genomics, 030105 genetics & heredity, Genome, DNA sequencing, 03 medical and health sciences, Surveys and Questionnaires, Exome Sequencing, medicine, Humans, Relevance (law), Exome, Genetic Testing, Genetics (clinical), Incidental Findings, Informed Consent, Whole Genome Sequencing, Genome, Human, Clinical Laboratory Services, 030104 developmental biology, Family medicine, Medical genetics, Female, Genetic relatedness, Psychology
Abstract: Clinical laboratories performing exome or genome sequencing (ES/GS) are familiar with the challenges associated with proper consenting for and reporting of medically actionable secondary findings based on recommendations from the American College of Medical Genetics and Genomics (ACMG). Misattributed parentage is another type of unanticipated finding a laboratory may encounter during family-based ES/GS; however, there are currently no professional recommendations related to the proper consenting for and reporting of misattributed parentage encountered during ES/GS. We surveyed 10 clinical laboratories offering family-based ES/GS regarding their consent language, discovery, and reporting of misattributed parentage. Many laboratories have already developed their own practices/policies for these issues, which do not necessarily agree with those from other labs. There are several other possibilities besides true misattributed parentage that could result in similar laboratory findings, and laboratories often feel they lack sufficient information to make formal conclusions on a report regarding the true genetic relatedness of the submitted samples. However, understanding the genetic relatedness (or lack thereof) of the samples submitted for family-based ES/GS has medical relevance. Therefore, professional recommendations for the appropriate handling of suspected misattributed parentage encountered during ES/GS are needed to help standardize current clinical laboratory practices.
Published: 2019

49. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author: Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, Ping Yee Billie Au, Boston Children's Hospital, University of Alberta, Universität Leipzig [Leipzig], Geneva University Hospital (HUG), Tel Aviv University [Tel Aviv], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Baylor College of Medicine (BCM), Baylor University, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Lausanne University Hospital, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Children’s Hospital of Philadelphia (CHOP ), Hospital Universitario La Paz, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University [Durham], University of Kansas Medical Center [Lawrence], University of Missouri System, Children's Mercy Hospital [Kansas City], Weill Cornell Medicine [New York], University of Calgary, Research reported in this paper was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number(s) (U01HG007709 [Baylor College of Medicine] and U01HG007672 [Duke University to V.S.]). Additional funding for this project was under award number 1RO1HD090132-01A1 (Cornell University to G.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by a Canadian Institutes of Health Research Grant (MOP-97988 to H.T.K.), and a Rowland and Muriel Haryett Fellowship (University of Alberta, to S.M.L.) and a fellowship from the Ministry of Education and Research of the Community of Madrid to M.P.M. (B2017/BMD-3721), and microgrant from the Rare Disease Foundation (P.Y.B.A. and H.T.K.). Sequencing and analysis was supported by the National Human Genome Research Institute grants UM1 HG008900 and R01 HG009141. K.A.D., B.C., and E.O. were supported the National Institute of Mental Health U01 MH119689., Universität Leipzig, Columbia University Medical Center (CUMC), Columbia University [New York], Tel Aviv University (TAU), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Unité de recherche de l'institut du thorax (ITX-lab), University of Kansas Medical Center [Kansas City, KS, USA], Weill Cornell Medicine [Cornell University], and Cornell University [New York]
Subjects: Ataxia, Calcium Channels, L-Type, Long QT syndrome, Timothy syndrome, Bioinformatics, Article, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual disability, medicine, Missense mutation, Humans, Autistic Disorder, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, Long QT Syndrome, Phenotype, Autism, Syndactyly, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.
Published: 2020

50. Potential Second-Hits in Hereditary Hemorrhagic Telangiectasia

Author: Michelle Letarte, Carmelo Bernabeu, Pinar Bayrak-Toydemir, Jamie McDonald, Consejo Superior de Investigaciones Científicas (España), Bernabéu, Carmelo, Bayrak-Toydemir, Pinar, McDonald, Jamie, Letarte, Michelle, Bernabéu, Carmelo [0000-0002-1563-6162], Bayrak-Toydemir, Pinar [0000-0001-9381-2478], McDonald, Jamie [0000-0001-9939-7922], and Letarte, Michelle [ https://orcid.org/ 0000-0002-5901-7582
Subjects: Pathology, lcsh:Medicine, Telangiectases, Review, ALK1, Transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), Loss of heterozygosity, angiogenesis, 0302 clinical medicine, hemic and lymphatic diseases, somatic mutation, Second-hit, Telangiectasia, vascular injury, 0303 health sciences, endoglin, Endoglin, Genetic disorder, General Medicine, Hereditary hemorrhagic telangiectasia (HHT), medicine.symptom, medicine.medical_specialty, Vascular injury, shear stress, 03 medical and health sciences, Germline mutation, medicine, otorhinolaryngologic diseases, Allele, arteriovenous malformation (AVM), 030304 developmental biology, Inflammation, Shear stress, business.industry, Somatic mutation, lcsh:R, Cell adhesion, Vascular endothelial growth factor (VEGF), ACVRL1, cell adhesion, medicine.disease, hereditary hemorrhagic telangiectasia (HHT), second-hit, inflammation, Angiogenesis, business, Smad4, 030217 neurology & neurosurgery
Abstract: 21 p.-2 fig., Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder that presents with telangiectases in skin and mucosae, and arteriovenous malformations (AVMs) in internal organs such as lungs, liver, and brain. Mutations in ENG (endoglin), ACVRL1 (ALK1), and MADH4 (Smad4) genes account for over 95% of HHT. Localized telangiectases and AVMs are present in different organs, with frequencies which differ among affected individuals. By itself, HHT gene heterozygosity does not account for the focal nature and varying presentation of the vascular lesions leading to the hypothesis of a “second-hit” that triggers the lesions. Accumulating research has identified a variety of triggers that may synergize with HHT gene heterozygosity to generate the vascular lesions. Among the postulated second-hits are: mechanical trauma, light, inflammation, vascular injury, angiogenic stimuli, shear stress, modifier genes, and somatic mutations in the wildtype HHT gene allele. The aim of this review is to summarize these triggers, as well as the functional mechanisms involved., This research was funded by Consejo Superior de Investigaciones Científicas of Spain (CSIC; grant 201920E022 to C.B.).
Published: 2020

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