@article {923, title = {Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome.}, journal = {Am J Med Genet A}, volume = {185}, year = {2021}, month = {2021 01}, pages = {119-133}, abstract = {

Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a "Dubowitz-like" condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48\%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26\%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61926}, author = {Dyment, David A and O{\textquoteright}Donnell-Luria, Anne and Agrawal, Pankaj B and Coban Akdemir, Zeynep and Aleck, Kyrieckos A and Antaki, Danny and Al Sharhan, Hind and Au, Ping-Yee B and Aydin, Hatip and Beggs, Alan H and Bilguvar, Kaya and Boerwinkle, Eric and Brand, Harrison and Brownstein, Catherine A and Buyske, Steve and Chodirker, Bernard and Choi, Jungmin and Chudley, Albert E and Clericuzio, Carol L and Cox, Gerald F and Curry, Cynthia and de Boer, Elke and de Vries, Bert B A and Dunn, Kathryn and Dutmer, Cullen M and England, Eleina M and Fahrner, Jill A and Geckinli, Bilgen B and Genetti, Casie A and Gezdirici, Alper and Gibson, William T and Gleeson, Joseph G and Greenberg, Cheryl R and Hall, April and Hamosh, Ada and Hartley, Taila and Jhangiani, Shalini N and Karaca, Ender and Kernohan, Kristin and Lauzon, Julie L and Lewis, M E Suzanne and Lowry, R Brian and L{\'o}pez-Gir{\'a}ldez, Francesc and Matise, Tara C and McEvoy-Venneri, Jennifer and McInnes, Brenda and Mhanni, Aziz and Garcia Minaur, Sixto and Moilanen, Jukka and Nguyen, An and Nowaczyk, Malgorzata J M and Posey, Jennifer E and {\~O}unap, Katrin and Pehlivan, Davut and Pajusalu, Sander and Penney, Lynette S and Poterba, Timothy and Prontera, Paolo and Doriqui, Maria Juliana Rodovalho and Sawyer, Sarah L and Sobreira, Nara and Stanley, Valentina and Torun, Deniz and Wargowski, David and Witmer, P Dane and Wong, Isaac and Xing, Jinchuan and Zaki, MAH S and Zhang, Yeting and Boycott, Kym M and Bamshad, Michael J and Nickerson, Deborah A and Blue, Elizabeth E and Innes, A Micheil} } @article {206, title = {Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype.}, journal = {Cancer Discov}, volume = {5}, year = {2015}, month = {2015 Feb}, pages = {135-42}, abstract = {

UNLABELLED: Deficiency in BRCA-dependent DNA interstrand crosslink (ICL) repair is intimately connected to breast cancer susceptibility and to the rare developmental syndrome Fanconi anemia. Bona fide Fanconi anemia proteins, BRCA2 (FANCD1), PALB2 (FANCN), and BRIP1 (FANCJ), interact with BRCA1 during ICL repair. However, the lack of detailed phenotypic and cellular characterization of a patient with biallelic BRCA1 mutations has precluded assignment of BRCA1 as a definitive Fanconi anemia susceptibility gene. Here, we report the presence of biallelic BRCA1 mutations in a woman with multiple congenital anomalies consistent with a Fanconi anemia-like disorder and breast cancer at age 23. Patient cells exhibited deficiency in BRCA1 and RAD51 localization to DNA-damage sites, combined with radial chromosome formation and hypersensitivity to ICL-inducing agents. Restoration of these functions was achieved by ectopic introduction of a BRCA1 transgene. These observations provide evidence in support of BRCA1 as a new Fanconi anemia gene (FANCS).

SIGNIFICANCE: We establish that biallelic BRCA1 mutations cause a distinct FA-S, which has implications for risk counselling in families where both parents harbor BRCA1 mutations. The genetic basis of hereditary cancer susceptibility syndromes provides diagnostic information, insights into treatment strategies, and more accurate recurrence risk counseling to families.

}, keywords = {Adult, Alleles, Base Sequence, BRCA1 Protein, Breast Neoplasms, Fanconi Anemia, Fanconi Anemia Complementation Group Proteins, Female, Genes, BRCA1, Genetic Predisposition to Disease, Humans, Mutation, Young Adult}, issn = {2159-8290}, doi = {10.1158/2159-8290.CD-14-1156}, author = {Sawyer, Sarah L and Tian, Lei and K{\"a}hk{\"o}nen, Marketta and Schwartzentruber, Jeremy and Kircher, Martin and Majewski, Jacek and Dyment, David A and Innes, A Micheil and Boycott, Kym M and Moreau, Lisa A and Moilanen, Jukka S and Greenberg, Roger A} } @article {273, title = {Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 01}, pages = {2888-900}, abstract = {

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80\% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for \~{}5\% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Cohort Studies, Cranial Fontanelles, De Lange Syndrome, Eye Abnormalities, Female, Genes, X-Linked, Histone Deacetylases, Humans, Hypertelorism, Infant, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Repressor Proteins, Sequence Alignment}, issn = {1460-2083}, doi = {10.1093/hmg/ddu002}, author = {Kaiser, Frank J and Ansari, Morad and Braunholz, Diana and Concepci{\'o}n Gil-Rodr{\'\i}guez, Mar{\'\i}a and Decroos, Christophe and Wilde, Jonathan J and Fincher, Christopher T and Kaur, Maninder and Bando, Masashige and Amor, David J and Atwal, Paldeep S and Bahlo, Melanie and Bowman, Christine M and Bradley, Jacquelyn J and Brunner, Han G and Clark, Dinah and Del Campo, Miguel and Di Donato, Nataliya and Diakumis, Peter and Dubbs, Holly and Dyment, David A and Eckhold, Juliane and Ernst, Sarah and Ferreira, Jose C and Francey, Lauren J and Gehlken, Ulrike and Guill{\'e}n-Navarro, Encarna and Gyftodimou, Yolanda and Hall, Bryan D and Hennekam, Raoul and Hudgins, Louanne and Hullings, Melanie and Hunter, Jennifer M and Yntema, Helger and Innes, A Micheil and Kline, Antonie D and Krumina, Zita and Lee, Hane and Leppig, Kathleen and Lynch, Sally Ann and Mallozzi, Mark B and Mannini, Linda and McKee, Shane and Mehta, Sarju G and Micule, Ieva and Mohammed, Shehla and Moran, Ellen and Mortier, Geert R and Moser, Joe-Ann S and Noon, Sarah E and Nozaki, Naohito and Nunes, Luis and Pappas, John G and Penney, Lynette S and P{\'e}rez-Ayt{\'e}s, Antonio and Petersen, Michael B and Puisac, Beatriz and Revencu, Nicole and Roeder, Elizabeth and Saitta, Sulagna and Scheuerle, Angela E and Schindeler, Karen L and Siu, Victoria M and Stark, Zornitza and Strom, Samuel P and Thiese, Heidi and Vater, Inga and Willems, Patrick and Williamson, Kathleen and Wilson, Louise C and Hakonarson, Hakon and Quintero-Rivera, Fabiola and Wierzba, Jolanta and Musio, Antonio and Gillessen-Kaesbach, Gabriele and Ramos, Feliciano J and Jackson, Laird G and Shirahige, Katsuhiko and Pi{\'e}, Juan and Christianson, David W and Krantz, Ian D and FitzPatrick, David R and Deardorff, Matthew A} }