De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, 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).

Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases

“…37 Similarly, sequencing analyses were able to uncover de novo, heterozygous variants in nine individuals with neurodevelopmental delay and other multisystem anomalies in CDH2, a gene previously unassociated with a Mendelian neurodevelopmental condition. 38 Indeed, divergent aspects of UDN pipelines reflect promising avenues for case reanalysis and reveal areas where technical developments would be most impactful. Improving SV detection specificity would aid in cases with nondiagnostic microarrays, gene panels, and GS.…”

Non-junctional role of Cadherin3 in cell migration and contact inhibition of locomotion via domain-dependent, opposing regulation of Rac1

“…Many additional cadherin mutations have been identified from their role in inheritable genetic disorders (e.g. 61 ) and human disease 62 . In light of our results, we suggest a re-evaluation of cadherin mutants, including truncation, domain-swapped, and single-point mutants for their potential non-junctional roles; in cases where defects in collective cell migration or tissue-morphogenesis are observed we strongly encourage the use of model systems where studies of both collective and single-cell behaviors can be compared to help resolve non-junctional roles.…”

Stick around: Cell–Cell Adhesion Molecules during Neocortical Development

“…These authors used dominant-negative strategies [ 19 , 22 , 127 , 128 ], perturbing the function of all classical cadherins, in layer II/III projection neurons, by in utero electroporation and observed that barrel nets were disrupted, whereas no defects in callosal projections were found. Nonetheless, de novo pathogenic variants in Cdh2, targeting EC4 and EC5 domains, cause neurodevelopmental disorders with defects in callosal projections from mild hypoplasia to complete agenesis, suggesting the implication of Cdh2 in the control of this type of axonal projections [ 143 ].…”

“…Hence, their disfunctions have dramatic consequences and have been found to be responsible for several neurodevelopmental disorders [ 6 , 180 , 181 ]. Mutations in several C-CAMs have been detected in humans and associated mostly with Autism-Spectrum Disorder (ASD) [ 182 , 183 , 184 , 185 , 186 , 187 ], Attention-Deficit/Hyperactivity Disorder (ADHD) [ 184 , 188 , 189 , 190 ], Bipolar disorder (BD) [ 191 ], schizophrenia (SCZ) [ 192 ], learning disability (LD) [ 186 ], intellectual disability (ID) [ 143 , 193 , 194 ], obsessive-compulsive disorder (OCD), and Tourette Disorder (TD) [ 195 ], among others ( Table 3 ). Nevertheless, to date, very few studies have been able to link these mutations in humans and the neurological disorders caused by them with specific neocortical malfunctions, given the difficulty to identify alterations in particular brain regions as responsible for concrete neuropsychiatric symptoms.…”

“…Nevertheless, to date, very few studies have been able to link these mutations in humans and the neurological disorders caused by them with specific neocortical malfunctions, given the difficulty to identify alterations in particular brain regions as responsible for concrete neuropsychiatric symptoms. Recently and as previously mentioned, in the case of the Cdh2 gene, seven missense substitutions affecting highly conserved residues in EC4/5 crucial for Ca 2+ -binding and impairing correct trans-interactions, together with two frameshift variations leading to a truncated cytoplasmic domain, have been described to cause corpus callosum agenesis or hypoplasia as well as intellectual disability in heterozygosity [ 143 ]. Substitutions in the Cdh4 gene have also been reported to entail corpus callosum dysgenesis, as well as microcephalia, in heterozygosity [ 196 ].…”