@article {1000, title = {A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 04 01}, pages = {749-756}, abstract = {

The DNA damage-binding protein 1 (DDB1) is part of the CUL4-DDB1 ubiquitin E3 ligase complex (CRL4), which is essential for DNA repair, chromatin remodeling, DNA replication, and signal transduction. Loss-of-function variants in genes encoding the complex components CUL4 and PHIP have been reported to cause syndromic intellectual disability with hypotonia and obesity, but no phenotype has been reported in association with DDB1 variants. Here, we report eight unrelated individuals, identified through Matchmaker Exchange, with de novo monoallelic variants in DDB1, including one recurrent variant in four individuals. The affected individuals have a consistent phenotype of hypotonia, mild to moderate intellectual disability, and similar facies, including horizontal or slightly bowed eyebrows, deep-set eyes, full cheeks, a short nose, and large, fleshy and forward-facing earlobes, demonstrated in the composite face generated from the cohort. Digital anomalies, including brachydactyly and syndactyly, were common. Three older individuals have obesity. We show that cells derived from affected individuals have altered DDB1 function resulting in abnormal DNA damage signatures and histone methylation following UV-induced DNA damage. Overall, our study adds to the growing family of neurodevelopmental phenotypes mediated by disruption of the CRL4 ubiquitin ligase pathway and begins to delineate the phenotypic and molecular effects of DDB1 misregulation.

}, keywords = {Adolescent, Alleles, Child, Child, Preschool, DNA Repair, DNA-Binding Proteins, Female, Humans, Male, Mutation, Neurodevelopmental Disorders, Phenotype, Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.03.007}, author = {White, Susan M and Bhoj, Elizabeth and Nellaker, Christoffer and Lachmeijer, Augusta M A and Marshall, Aren E and Boycott, Kym M and Li, Dong and Smith, Wendy and Hartley, Taila and McBride, Arran and Ernst, Michelle E and May, Alison S and Wieczorek, Dagmar and Abou Jamra, Rami and Koch-Hogrebe, Margarete and {\~O}unap, Katrin and Pajusalu, Sander and van Gassen, K L I and Sadedin, Simon and Ellingwood, Sara and Tan, Tiong Yang and Christodoulou, John and Barea, Jaime and Lockhart, Paul J and Nezarati, Marjan M and Kernohan, Kristin D} } @article {912, title = {Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 07}, pages = {1215-1226}, abstract = {

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.

METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.

RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.

CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.

}, keywords = {Exome, Germ Cells, Humans, Intellectual Disability, Mutation, Missense, Phenotype, Transcriptome, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins}, issn = {1530-0366}, doi = {10.1038/s41436-020-0792-7}, author = {Castilla-Vallmanya, Laura and Selmer, Kaja K and Dimartino, Cl{\'e}mantine and Rabionet, Raquel and Blanco-S{\'a}nchez, Bernardo and Yang, Sandra and Reijnders, Margot R F and van Essen, Antonie J and Oufadem, Myriam and Vigeland, Magnus D and Stadheim, Barbro and Houge, Gunnar and Cox, Helen and Kingston, Helen and Clayton-Smith, Jill and Innis, Jeffrey W and Iascone, Maria and Cereda, Anna and Gabbiadini, Sara and Chung, Wendy K and Sanders, Victoria and Charrow, Joel and Bryant, Emily and Millichap, John and Vitobello, Antonio and Thauvin, Christel and Mau-Them, Frederic Tran and Faivre, Laurence and Lesca, Gaetan and Labalme, Audrey and Rougeot, Christelle and Chatron, Nicolas and Sanlaville, Damien and Christensen, Katherine M and Kirby, Amelia and Lewandowski, Raymond and Gannaway, Rachel and Aly, MAH and Lehman, Anna and Clarke, Lorne and Graul-Neumann, Luitgard and Zweier, Christiane and Lessel, Davor and Lozic, Bernarda and Aukrust, Ingvild and Peretz, Ryan and Stratton, Robert and Smol, Thomas and Dieux-Co{\"e}slier, Anne and Meira, Joanna and Wohler, Elizabeth and Sobreira, Nara and Beaver, Erin M and Heeley, Jennifer and Briere, Lauren C and High, Frances A and Sweetser, David A and Walker, Melissa A and Keegan, Catherine E and Jayakar, Parul and Shinawi, Marwan and Kerstjens-Frederikse, Wilhelmina S and Earl, Dawn L and Siu, Victoria M and Reesor, Emma and Yao, Tony and Hegele, Robert A and Vaske, Olena M and Rego, Shannon and Shapiro, Kevin A and Wong, Brian and Gambello, Michael J and McDonald, Marie and Karlowicz, Danielle and Colombo, Roberto and Serretti, Alessandro and Pais, Lynn and O{\textquoteright}Donnell-Luria, Anne and Wray, Alison and Sadedin, Simon and Chong, Belinda and Tan, Tiong Y and Christodoulou, John and White, Susan M and Slavotinek, Anne and Barbouth, Deborah and Morel Swols, Dayna and Parisot, M{\'e}lanie and Bole-Feysot, Christine and Nitschk{\'e}, Patrick and Pingault, V{\'e}ronique and Munnich, Arnold and Cho, Megan T and Cormier-Daire, Val{\'e}rie and Balcells, Susanna and Lyonnet, Stanislas and Grinberg, Daniel and Amiel, Jeanne and Urreizti, Roser and Gordon, Christopher T} }