@article {717, title = {De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Oct 03}, pages = {854-868}, 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).

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.09.005}, author = {Accogli, Andrea and Calabretta, Sara and St-Onge, Judith and Boudrahem-Addour, Nassima and Dionne-Laporte, Alexandre and Joset, Pascal and Azzarello-Burri, Silvia and Rauch, Anita and Krier, Joel and Fieg, Elizabeth and Pallais, Juan C and McConkie-Rosell, Allyn and McDonald, Marie and Freedman, Sharon F and Rivi{\`e}re, Jean-Baptiste and Lafond-Lapalme, Jo{\"e}l and Simpson, Brittany N and Hopkin, Robert J and Trimouille, Aur{\'e}lien and Van-Gils, Julien and Begtrup, Amber and McWalter, Kirsty and Delphine, Heron and Keren, Boris and Genevi{\`e}ve, David and Argilli, Emanuela and Sherr, Elliott H and Severino, Mariasavina and Rouleau, Guy A and Yam, Patricia T and Charron, Fr{\'e}d{\'e}ric and Srour, Myriam} } @article {678, title = {Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 Jun 06}, pages = {1210-1222}, abstract = {

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70\% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.03.021}, author = {O{\textquoteright}Donnell-Luria, Anne H and Pais, Lynn S and Faundes, V{\'\i}ctor and Wood, Jordan C and Sveden, Abigail and Luria, Victor and Abou Jamra, Rami and Accogli, Andrea and Amburgey, Kimberly and Anderlid, Britt Marie and Azzarello-Burri, Silvia and Basinger, Alice A and Bianchini, Claudia and Bird, Lynne M and Buchert, Rebecca and Carr{\'e}, Wilfrid and Ceulemans, Sophia and Charles, Perrine and Cox, Helen and Culliton, Lisa and Curr{\`o}, Aurora and Demurger, Florence and Dowling, James J and Duban-Bedu, Benedicte and Dubourg, Christ{\`e}le and Eiset, Saga Elise and Escobar, Luis F and Ferrarini, Alessandra and Haack, Tobias B and Hashim, Mona and Heide, Solveig and Helbig, Katherine L and Helbig, Ingo and Heredia, Raul and H{\'e}ron, Delphine and Isidor, Bertrand and Jonasson, Amy R and Joset, Pascal and Keren, Boris and Kok, Fernando and Kroes, Hester Y and Lavillaureix, Alino{\"e} and Lu, Xin and Maas, Saskia M and Maegawa, Gustavo H B and Marcelis, Carlo L M and Mark, Paul R and Masruha, Marcelo R and McLaughlin, Heather M and McWalter, Kirsty and Melchinger, Esther U and Mercimek-Andrews, Saadet and Nava, Caroline and Pendziwiat, Manuela and Person, Richard and Ramelli, Gian Paolo and Ramos, Luiza L P and Rauch, Anita and Reavey, Caitlin and Renieri, Alessandra and Rie{\ss}, Angelika and Sanchez-Valle, Amarilis and Sattar, Shifteh and Saunders, Carol and Schwarz, Niklas and Smol, Thomas and Srour, Myriam and Steindl, Katharina and Syrbe, Steffen and Taylor, Jenny C and Telegrafi, Aida and Thiffault, Isabelle and Trauner, Doris A and van der Linden, Helio and van Koningsbruggen, Silvana and Villard, Laurent and Vogel, Ida and Vogt, Julie and Weber, Yvonne G and Wentzensen, Ingrid M and Widjaja, Elysa and Zak, Jaroslav and Baxter, Samantha and Banka, Siddharth and Rodan, Lance H} } @article {483, title = {De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {103}, year = {2018}, month = {2018 08 02}, pages = {305-316}, abstract = {

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.07.003}, author = {Gregor, Anne and Sadleir, Lynette G and Asadollahi, Reza and Azzarello-Burri, Silvia and Battaglia, Agatino and Ousager, Lilian Bomme and Boonsawat, Paranchai and Bruel, Ange-Line and Buchert, Rebecca and Calpena, Eduardo and Cogn{\'e}, Benjamin and Dallapiccola, Bruno and Distelmaier, Felix and Elmslie, Frances and Faivre, Laurence and Haack, Tobias B and Harrison, Victoria and Henderson, Alex and Hunt, David and Isidor, Bertrand and Joset, Pascal and Kumada, Satoko and Lachmeijer, Augusta M A and Lees, Melissa and Lynch, Sally Ann and Martinez, Francisco and Matsumoto, Naomichi and McDougall, Carey and Mefford, Heather C and Miyake, Noriko and Myers, Candace T and Moutton, S{\'e}bastien and Nesbitt, Addie and Novelli, Antonio and Orellana, Carmen and Rauch, Anita and Rosello, Monica and Saida, Ken and Santani, Avni B and Sarkar, Ajoy and Scheffer, Ingrid E and Shinawi, Marwan and Steindl, Katharina and Symonds, Joseph D and Zackai, Elaine H and Reis, Andr{\'e} and Sticht, Heinrich and Zweier, Christiane} }