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Further delineation of the KAT6B molecular and phenotypic spectrum

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Gannon, Tamsin Perveen, Rahat Schlecht, Hélene Ramsden, Simon Anderson, Beverley Sznajer, Yves [UCL] Clayton-Smith, Jill

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2015
Language Anglais
Journal information "European Journal of Human Genetics" - Vol. 23, no. 9, p. 1165-1170 (2015)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
issn 1018-4813
e-issn 1476-5438
Publication status Publié
Affiliations UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - (SLuc) Centre de génétique médicale UCL
MESH Subject Blepharophimosis ; Female ; Gene Expression ; Genetic Association Studies ; Genotype ; Heart Defects, Congenital ; Histone Acetyltransferases ; Humans ; Intellectual Disability ; Joint Instability ; Kidney ; Child, Preschool ; Male ; Mutation ; Patella ; Phenotype ; Psychomotor Disorders ; Scrotum ; Severity of Illness Index ; Urogenital Abnormalities ; Congenital Hypothyroidism ; Craniofacial Abnormalities ; DNA Mutational Analysis ; Diagnosis, Differential ; Exome ; Exons ; Facies
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  1. Verloes Alain, Bremond-Gignac Dominique, Isidor Bertrand, David Albert, Baumann Clarisse, Leroy Marie-Anne, Stevens René, Gillerot Yves, Héron Delphine, Héron Bénédicte, Benzacken Brigitte, Lacombe Didier, Brunner Han, Bitoun Pierre, Blepharophimosis-mental retardation (BMR) syndromes: A proposed clinical classification of the so-called Ohdo syndrome, and delineation of two new BMR syndromes, one X-linked and one autosomal recessive, 10.1002/ajmg.a.31270
  2. Day R, Beckett B, Donnai D, Fryer A, Heidenblad M, Howard P, Kerr B, Mansour S, Maye U, McKee S, Mohammed S, Sweeney E, Tassabehji M, De Vries BBA, Clayton-Smith J, A clinical and genetic study of the Say/Barber/Biesecker/Young-Simpson type of Ohdo syndrome, 10.1111/j.1399-0004.2008.01087.x
  3. Young I D, Simpson K, Unknown syndrome: abnormal facies, congenital heart defects, hypothyroidism, and severe retardation., 10.1136/jmg.24.11.715
  4. Clayton-Smith Jill, O'Sullivan James, Daly Sarah, Bhaskar Sanjeev, Day Ruth, Anderson Beverley, Voss Anne K., Thomas Tim, Biesecker Leslie G., Smith Philip, Fryer Alan, Chandler Kate E., Kerr Bronwyn, Tassabehji May, Lynch Sally-Ann, Krajewska-Walasek Malgorzata, McKee Shane, Smith Janine, Sweeney Elizabeth, Mansour Sahar, Mohammed Shehla, Donnai Dian, Black Graeme, Whole-Exome-Sequencing Identifies Mutations in Histone Acetyltransferase Gene KAT6B in Individuals with the Say-Barber-Biesecker Variant of Ohdo Syndrome, 10.1016/j.ajhg.2011.10.008
  5. Szakszon Katalin, Salpietro Carmelo, Kakar Naseebullah, Knegt Alida C., Oláh Éva, Dallapiccola Bruno, Borck Guntram, De novo mutations of the gene encoding the histone acetyltransferase KAT6B in two patients with Say-Barber/Biesecker/Young-Simpson syndrome, 10.1002/ajmg.a.35848
  6. Yu HC, Am J Med Genet, 164A, 950 (2014)
  7. Campeau Philippe M., Kim Jaeseung C., Lu James T., Schwartzentruber Jeremy A., Abdul-Rahman Omar A., Schlaubitz Silke, Murdock David M., Jiang Ming-Ming, Lammer Edward J., Enns Gregory M., Rhead William J., Rowland Jon, Robertson Stephen P., Cormier-Daire Valérie, Bainbridge Matthew N., Yang Xiang-Jiao, Gingras Marie-Claude, Gibbs Richard A., Rosenblatt David S., Majewski Jacek, Lee Brendan H., Mutations in KAT6B, Encoding a Histone Acetyltransferase, Cause Genitopatellar Syndrome, 10.1016/j.ajhg.2011.11.023
  8. Simpson Michael A., Deshpande Charu, Dafou Dimitra, Vissers Lisenka E.L.M., Woollard Wesley J., Holder Susan E., Gillessen-Kaesbach Gabriele, Derks Ronny, White Susan M., Cohen-Snuijf Ruthy, Kant Sarina G., Hoefsloot Lies H., Reardon Willie, Brunner Han G., Bongers Ernie M.H.F., Trembath Richard C., De Novo Mutations of the Gene Encoding the Histone Acetyltransferase KAT6B Cause Genitopatellar Syndrome, 10.1016/j.ajhg.2011.11.024
  9. Cormier-Daire V., Genitopatellar syndrome: a new condition comprising absent patellae, scrotal hypoplasia, renal anomalies, facial dysmorphism, and mental retardation, 10.1136/jmg.37.7.520
  10. Basel-Vanagaite Lina, Dallapiccola Bruno, Ramirez-Solis Ramiro, Segref Alexandra, Thiele Holger, Edwards Andrew, Arends Mark J., Miró Xavier, White Jacqueline K., Désir Julie, Abramowicz Marc, Dentici Maria Lisa, Lepri Francesca, Hofmann Kay, Har-Zahav Adi, Ryder Edward, Karp Natasha A., Estabel Jeanne, Gerdin Anna-Karin B., Podrini Christine, Ingham Neil J., Altmüller Janine, Nürnberg Gudrun, Frommolt Peter, Abdelhak Sonia, Pasmanik-Chor Metsada, Konen Osnat, Kelley Richard I., Shohat Mordechai, Nürnberg Peter, Flint Jonathan, Steel Karen P., Hoppe Thorsten, Kubisch Christian, Adams David J., Borck Guntram, Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome, 10.1016/j.ajhg.2012.10.011
  11. Campeau Philippe M., Lu James T., Dawson Brian C., Fokkema Ivo F. A. C., Robertson Stephen P., Gibbs Richard A., Lee Brendan H., TheKAT6B-related disorders genitopatellar syndrome and Ohdo/SBBYS syndrome have distinct clinical features reflecting distinct molecular mechanisms, 10.1002/humu.22141
  12. Tzschach Andreas, Bisgaard Anne-Marie, Kirchhoff Maria, Graul-Neumann Luitgard M, Neitzel Heidemarie, Page Stephanie, Ahmed Alischo, Müller Ines, Erdogan Fikret, Ropers Hans-Hilger, Kalscheuer Vera M, Ullmann Reinhard, Chromosome aberrations involving 10q22: report of three overlapping interstitial deletions and a balanced translocation disrupting C10orf11, 10.1038/ejhg.2009.163
  13. FIRTH HELEN V, WRIGHT CAROLINE F, , The Deciphering Developmental Disorders (DDD) study, 10.1111/j.1469-8749.2011.04032.x
  14. Kraft Michael, Cirstea Ion Cristian, Voss Anne Kathrin, Thomas Tim, Goehring Ina, Sheikh Bilal N., Gordon Lavinia, Scott Hamish, Smyth Gordon K., Ahmadian Mohammad Reza, Trautmann Udo, Zenker Martin, Tartaglia Marco, Ekici Arif, Reis André, Dörr Helmuth-Guenther, Rauch Anita, Thiel Christian Thomas, Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome–like phenotype and hyperactivated MAPK signaling in humans and mice, 10.1172/jci43428
  15. Ohdo S, Madokoro H, Sonoda T, Hayakawa K, Mental retardation associated with congenital heart disease, blepharophimosis, blepharoptosis, and hypoplastic teeth., 10.1136/jmg.23.3.242
  16. Maat-Kievit JA, Clin Dysmorphol, 3, 125 (1994)
  17. Vulto-van Silfhout Anneke T., de Vries Bert B.A., van Bon Bregje W.M., Hoischen Alexander, Ruiterkamp-Versteeg Martina, Gilissen Christian, Gao Fangjian, van Zwam Marloes, Harteveld Cornelis L., van Essen Anthonie J., Hamel Ben C.J., Kleefstra Tjitske, Willemsen Michèl A.A.P., Yntema Helger G., van Bokhoven Hans, Brunner Han G., Boyer Thomas G., de Brouwer Arjan P.M., Mutations in MED12 Cause X-Linked Ohdo Syndrome, 10.1016/j.ajhg.2013.01.007
Bibliographic reference Gannon, Tamsin ; Perveen, Rahat ; Schlecht, Hélene ; Ramsden, Simon ; Anderson, Beverley ; et. al. Further delineation of the KAT6B molecular and phenotypic spectrum. In: European Journal of Human Genetics, Vol. 23, no. 9, p. 1165-1170 (2015)
Permanent URL http://hdl.handle.net/2078.1/175963