De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects

Undiagnosed Diseases Network

Research output: Contribution to journalArticle

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.Leu855Valfs4]; c.2564_2567dupTGTT [p.Leu856Phefs5]) 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).

Original languageEnglish (US)
Pages (from-to)854-868
Number of pages15
JournalAmerican journal of human genetics
Volume105
Issue number4
DOIs
StatePublished - Oct 3 2019

Fingerprint

Cadherins
Axons
Agenesis of Corpus Callosum
Calcium
Cell Adhesion
Duane Retraction Syndrome
Binding Sites
Developmental Disabilities
Neurodevelopmental Disorders
Intellectual Disability
Adhesives
Axon Guidance

Keywords

  • ACOG
  • cardiac defects
  • CDH2
  • cell-cell adhesion
  • corpus callosum
  • eye defects
  • genital defects
  • intellectual disability
  • N-cadherin

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects. / Undiagnosed Diseases Network.

In: American journal of human genetics, Vol. 105, No. 4, 03.10.2019, p. 854-868.

Research output: Contribution to journalArticle

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title = "De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects",
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).",
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author = "{Undiagnosed Diseases Network} and Andrea Accogli and Sara Calabretta and Judith St-Onge and Nassima Boudrahem-Addour and Alexandre Dionne-Laporte and Pascal Joset and Silvia Azzarello-Burri and Anita Rauch and Joel Krier and Elizabeth Fieg and Pallais, {Juan C.} and Acosta, {Maria T.} and Adams, {David R.} and Pankaj Agrawal and Alejandro, {Mercedes E.} and Patrick Allard and Justin Alvey and Ashley Andrews and Ashley, {Euan A.} and Azamian, {Mahshid S.} and Bacino, {Carlos A.} and Guney Bademci and Eva Baker and Ashok Balasubramanyam and Dustin Baldridge and Jim Bale and Deborah Barbouth and Batzli, {Gabriel F.} and Pinar Bayrak-Toydemir and Beggs, {Alan H.} and Gill Bejerano and Bellen, {Hugo J.} and Bernstein, {Jonathan A.} and Berry, {Gerard T.} and Anna Bican and Bick, {David P.} and Birch, {Camille L.} and Stephanie Bivona and John Bohnsack and Carsten Bonnenmann and Devon Bonner and Boone, {Braden E.} and Olveen Carrasquillo and Chang, {Ta Chen Peter} and Rosario Isasi and Byron Lam and Jacob McCauley and Ralph Sacco and Mustafa Tekin and Fred Telischi",
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T1 - De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects

AU - Undiagnosed Diseases Network

AU - Accogli, Andrea

AU - Calabretta, Sara

AU - St-Onge, Judith

AU - Boudrahem-Addour, Nassima

AU - Dionne-Laporte, Alexandre

AU - Joset, Pascal

AU - Azzarello-Burri, Silvia

AU - Rauch, Anita

AU - Krier, Joel

AU - Fieg, Elizabeth

AU - Pallais, Juan C.

AU - Acosta, Maria T.

AU - Adams, David R.

AU - Agrawal, Pankaj

AU - Alejandro, Mercedes E.

AU - Allard, Patrick

AU - Alvey, Justin

AU - Andrews, Ashley

AU - Ashley, Euan A.

AU - Azamian, Mahshid S.

AU - Bacino, Carlos A.

AU - Bademci, Guney

AU - Baker, Eva

AU - Balasubramanyam, Ashok

AU - Baldridge, Dustin

AU - Bale, Jim

AU - Barbouth, Deborah

AU - Batzli, Gabriel F.

AU - Bayrak-Toydemir, Pinar

AU - Beggs, Alan H.

AU - Bejerano, Gill

AU - Bellen, Hugo J.

AU - Bernstein, Jonathan A.

AU - Berry, Gerard T.

AU - Bican, Anna

AU - Bick, David P.

AU - Birch, Camille L.

AU - Bivona, Stephanie

AU - Bohnsack, John

AU - Bonnenmann, Carsten

AU - Bonner, Devon

AU - Boone, Braden E.

AU - Carrasquillo, Olveen

AU - Chang, Ta Chen Peter

AU - Isasi, Rosario

AU - Lam, Byron

AU - McCauley, Jacob

AU - Sacco, Ralph

AU - Tekin, Mustafa

AU - Telischi, Fred

PY - 2019/10/3

Y1 - 2019/10/3

N2 - 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).

AB - 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).

KW - ACOG

KW - cardiac defects

KW - CDH2

KW - cell-cell adhesion

KW - corpus callosum

KW - eye defects

KW - genital defects

KW - intellectual disability

KW - N-cadherin

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