De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects
Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to...
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| Published in | American journal of human genetics Vol. 105; no. 4; p. 854 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
03.10.2019
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs
4]; c.2564_2567dupTGTT [p.Leu856Phefs
5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects). |
|---|---|
| AbstractList | Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects). Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs 4]; c.2564_2567dupTGTT [p.Leu856Phefs 5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects). |
| Author | Accogli, Andrea Delphine, Heron McDonald, Marie Azzarello-Burri, Silvia Argilli, Emanuela McConkie-Rosell, Allyn Yam, Patricia T Lafond-Lapalme, Joël Charron, Frédéric Srour, Myriam Trimouille, Aurélien Genevieve, David Begtrup, Amber Keren, Boris Rivière, Jean-Baptiste Dionne-Laporte, Alexandre St-Onge, Judith Calabretta, Sara Rauch, Anita Krier, Joel Pallais, Juan C Van-Gils, Julien Fieg, Elizabeth McWalter, Kirsty Joset, Pascal Rouleau, Guy A Severino, Mariasavina Simpson, Brittany N Boudrahem-Addour, Nassima Sherr, Elliott H Freedman, Sharon F Hopkin, Robert J |
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Electronic address: frederic.charron@ircm.qc.ca – sequence: 32 givenname: Myriam surname: Srour fullname: Srour, Myriam email: myriam.srour@mcgill.ca organization: Department of Pediatrics, Division of Pediatric Neurology, McGill University, H4A 3J1, Montreal, QC, Canada; McGill University Health Center Research Institute, H4A 3J1, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, H3A 2B4, Montreal, QC, Canada. Electronic address: myriam.srour@mcgill.ca |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/31585109$$D View this record in MEDLINE/PubMed |
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| ContentType | Journal Article |
| Contributor | Bonner, Devon Bivona, Stephanie Cooper, Cynthia M Brush, Matthew Forghani, Irman Bale, Jim Cope, Heidi Beggs, Alan H Burke, Elizabeth A Carrasquillo, Olveen Jones, Angela L Esteves, Cecilia Baker, Eva Colley, Heather A Adams, David R Bayrak-Toydemir, Pinar Clark, Gary D Goldman, Alica M Gourdine, Jean-Philippe F Botto, Lorenzo Ferreira, Carlos Fisher, Paul G Chang, Ta Chen Peter Eng, Christine M Dhar, Shweta U Fieg, Elizabeth L Fernandez, Liliana Karaviti, Lefkothea Brokamp, Elly Briere, Lauren C Balasubramanyam, Ashok Cogan, Joy D Andrews, Ashley Groden, Catherine A Kelley, Emily G Hayes, Nichole Isasi, Rosario Baldridge, Dustin Agrawal, Pankaj Jamal, Fariha Brown, Donna M Draper, David D Godfrey, Rena A Batzli, Gabriel F Bernstein, Jonathan A Butte, Manish J Duncan, Laura Estwick, Tyra Bohnsack, John Bick, David P Jiang, Yong-Hui Bacino, Carlos A Hanchard, Neil A Cobban, Laurel A Dell'Angelica, Esteban C Gropman, Andrea L Fogel, Brent L Alvey, Justin Huang, Alden Burrage, Lindsay C Davids, Mariska Huang, Yong Chao, Hsiao-Tuan Barbouth, Deborah Co |
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| Copyright | Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
| Copyright_xml | – notice: Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
| CorporateAuthor | Undiagnosed Diseases Network |
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| DOI | 10.1016/j.ajhg.2019.09.005 |
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| Discipline | Biology |
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| Issue | 4 |
| Keywords | cell-cell adhesion ACOG CDH2 N-cadherin eye defects genital defects cardiac defects corpus callosum intellectual disability |
| Language | English |
| License | Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
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| SubjectTerms | Axons - pathology Cadherins - genetics Corpus Callosum - pathology Eye - pathology Frameshift Mutation Genitalia - pathology Heart Defects, Congenital - genetics Heterozygote Humans Neurodevelopmental Disorders - genetics Neurodevelopmental Disorders - pathology |
| Title | De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects |
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