@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 {786, title = {Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 08}, pages = {1338-1347}, abstract = {

PURPOSE: Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized.

METHODS: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum.

RESULTS: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent.

CONCLUSION: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

}, keywords = {Blepharophimosis, Exons, Histone Acetyltransferases, Humans, Intellectual Disability, Mutation}, issn = {1530-0366}, doi = {10.1038/s41436-020-0811-8}, author = {Zhang, Li Xin and Lemire, Gabrielle and Gonzaga-Jauregui, Claudia and Molidperee, Sirinart and Galaz-Montoya, Carolina and Liu, David S and Verloes, Alain and Shillington, Amelle G and Izumi, Kosuke and Ritter, Alyssa L and Keena, Beth and Zackai, Elaine and Li, Dong and Bhoj, Elizabeth and Tarpinian, Jennifer M and Bedoukian, Emma and Kukolich, Mary K and Innes, A Micheil and Ediae, Grace U and Sawyer, Sarah L and Nair, Karippoth Mohandas and Soumya, Para Chottil and Subbaraman, Kinattinkara R and Probst, Frank J and Bassetti, Jennifer A and Sutton, Reid V and Gibbs, Richard A and Brown, Chester and Boone, Philip M and Holm, Ingrid A and Tartaglia, Marco and Ferrero, Giovanni Battista and Niceta, Marcello and Dentici, Maria Lisa and Radio, Francesca Clementina and Keren, Boris and Wells, Constance F and Coubes, Christine and Laquerri{\`e}re, Annie and Aziza, Jacqueline and Dubucs, Charlotte and Nampoothiri, Sheela and Mowat, David and Patel, Millan S and Bracho, Ana and Cammarata-Scalisi, Francisco and Gezdirici, Alper and Fern{\'a}ndez-Ja{\'e}n, Alberto and Hauser, Natalie and Zarate, Yuri A and Bosanko, Katherine A and Dieterich, Klaus and Carey, John C and Chong, Jessica X and Nickerson, Deborah A and Bamshad, Michael J and Lee, Brendan H and Yang, Xiang-Jiao and Lupski, James R and Campeau, Philippe M} }