Further delineation of the KAT6B molecular and phenotypic spectrum.

Hdl Handle:
http://hdl.handle.net/10147/620599
Title:
Further delineation of the KAT6B molecular and phenotypic spectrum.
Authors:
Gannon, Tamsin; Perveen, Rahat; Schlecht, Hélene; Ramsden, Simon; Anderson, Beverley; Kerr, Bronwyn; Day, Ruth; Banka, Siddharth; Suri, Mohnish; Berland, Siren; Gabbett, Michael; Ma, Alan; Lyonnet, Stan; Cormier-Daire, Valerie; Yilmaz, Rüstem; Borck, Guntram; Wieczorek, Dagmar; Anderlid, Britt-Marie; Smithson, Sarah; Vogt, Julie; Moore-Barton, Heather; Simsek-Kiper, Pelin Ozlem; Maystadt, Isabelle; Destrée, Anne; Bucher, Jessica; Angle, Brad; Mohammed, Shehla; Wakeling, Emma; Price, Sue; Singer, Amihood; Sznajer, Yves; Toutain, Annick; Haye, Damien; Newbury-Ecob, Ruth; Fradin, Melanie; McGaughran, Julie; Tuysuz, Beyhan; Tein, Mark; Bouman, Katelijne; Dabir, Tabib; Van den Ende, Jenneke; Luk, Ho Ming; Pilz, Daniela T; Eason, Jacqueline; Davies, Sally; Reardon, Willie; Garavelli, Livia; Zuffardi, Orsetta; Devriendt, Koen; Armstrong, Ruth; Johnson, Diana; Doco-Fenzy, Martine; Bijlsma, Emilia; Unger, Sheila; Veenstra-Knol, Hermine E; Kohlhase, Jürgen; Lo, Ivan F M; Smith, Janine; Clayton-Smith, Jill
Citation:
Further delineation of the KAT6B molecular and phenotypic spectrum. 2015, 23 (9):1165-70 Eur. J. Hum. Genet.
Publisher:
Nature Publishing Group
Journal:
European journal of human genetics : EJHG
Issue Date:
Sep-2015
URI:
http://hdl.handle.net/10147/620599
DOI:
10.1038/ejhg.2014.248
PubMed ID:
25424711
Additional Links:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351891/
Abstract:
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.
Item Type:
Article
Language:
en
Keywords:
GENETICS; INTELLECTUAL DISABILITIES; DEVELOPMENTAL DISABILITIES
MeSH:
Blepharophimosis; Child, Preschool; Congenital Hypothyroidism; Craniofacial Abnormalities; DNA Mutational Analysis; Diagnosis, Differential; Exome; Exons; Facies; Female; Gene Expression; Genetic Association Studies; Genotype; Heart Defects, Congenital; Histone Acetyltransferases; Humans; Intellectual Disability; Joint Instability; Kidney; Male; Mutation; Patella; Phenotype; Psychomotor Disorders; Scrotum; Severity of Illness Index; Urogenital Abnormalities
ISSN:
1476-5438

Full metadata record

DC FieldValue Language
dc.contributor.authorGannon, Tamsinen
dc.contributor.authorPerveen, Rahaten
dc.contributor.authorSchlecht, Héleneen
dc.contributor.authorRamsden, Simonen
dc.contributor.authorAnderson, Beverleyen
dc.contributor.authorKerr, Bronwynen
dc.contributor.authorDay, Ruthen
dc.contributor.authorBanka, Siddharthen
dc.contributor.authorSuri, Mohnishen
dc.contributor.authorBerland, Sirenen
dc.contributor.authorGabbett, Michaelen
dc.contributor.authorMa, Alanen
dc.contributor.authorLyonnet, Stanen
dc.contributor.authorCormier-Daire, Valerieen
dc.contributor.authorYilmaz, Rüstemen
dc.contributor.authorBorck, Guntramen
dc.contributor.authorWieczorek, Dagmaren
dc.contributor.authorAnderlid, Britt-Marieen
dc.contributor.authorSmithson, Sarahen
dc.contributor.authorVogt, Julieen
dc.contributor.authorMoore-Barton, Heatheren
dc.contributor.authorSimsek-Kiper, Pelin Ozlemen
dc.contributor.authorMaystadt, Isabelleen
dc.contributor.authorDestrée, Anneen
dc.contributor.authorBucher, Jessicaen
dc.contributor.authorAngle, Braden
dc.contributor.authorMohammed, Shehlaen
dc.contributor.authorWakeling, Emmaen
dc.contributor.authorPrice, Sueen
dc.contributor.authorSinger, Amihooden
dc.contributor.authorSznajer, Yvesen
dc.contributor.authorToutain, Annicken
dc.contributor.authorHaye, Damienen
dc.contributor.authorNewbury-Ecob, Ruthen
dc.contributor.authorFradin, Melanieen
dc.contributor.authorMcGaughran, Julieen
dc.contributor.authorTuysuz, Beyhanen
dc.contributor.authorTein, Marken
dc.contributor.authorBouman, Katelijneen
dc.contributor.authorDabir, Tabiben
dc.contributor.authorVan den Ende, Jennekeen
dc.contributor.authorLuk, Ho Mingen
dc.contributor.authorPilz, Daniela Ten
dc.contributor.authorEason, Jacquelineen
dc.contributor.authorDavies, Sallyen
dc.contributor.authorReardon, Willieen
dc.contributor.authorGaravelli, Liviaen
dc.contributor.authorZuffardi, Orsettaen
dc.contributor.authorDevriendt, Koenen
dc.contributor.authorArmstrong, Ruthen
dc.contributor.authorJohnson, Dianaen
dc.contributor.authorDoco-Fenzy, Martineen
dc.contributor.authorBijlsma, Emiliaen
dc.contributor.authorUnger, Sheilaen
dc.contributor.authorVeenstra-Knol, Hermine Een
dc.contributor.authorKohlhase, Jürgenen
dc.contributor.authorLo, Ivan F Men
dc.contributor.authorSmith, Janineen
dc.contributor.authorClayton-Smith, Jillen
dc.date.accessioned2016-09-20T11:51:56Z-
dc.date.available2016-09-20T11:51:56Z-
dc.date.issued2015-09-
dc.identifier.citationFurther delineation of the KAT6B molecular and phenotypic spectrum. 2015, 23 (9):1165-70 Eur. J. Hum. Genet.en
dc.identifier.issn1476-5438-
dc.identifier.pmid25424711-
dc.identifier.doi10.1038/ejhg.2014.248-
dc.identifier.urihttp://hdl.handle.net/10147/620599-
dc.description.abstractKAT6B 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.en
dc.language.isoenen
dc.publisherNature Publishing Groupen
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351891/en
dc.rightsArchived with thanks to European journal of human genetics : EJHGen
dc.subjectGENETICSen
dc.subjectINTELLECTUAL DISABILITIESen
dc.subjectDEVELOPMENTAL DISABILITIESen
dc.subject.meshBlepharophimosis-
dc.subject.meshChild, Preschool-
dc.subject.meshCongenital Hypothyroidism-
dc.subject.meshCraniofacial Abnormalities-
dc.subject.meshDNA Mutational Analysis-
dc.subject.meshDiagnosis, Differential-
dc.subject.meshExome-
dc.subject.meshExons-
dc.subject.meshFacies-
dc.subject.meshFemale-
dc.subject.meshGene Expression-
dc.subject.meshGenetic Association Studies-
dc.subject.meshGenotype-
dc.subject.meshHeart Defects, Congenital-
dc.subject.meshHistone Acetyltransferases-
dc.subject.meshHumans-
dc.subject.meshIntellectual Disability-
dc.subject.meshJoint Instability-
dc.subject.meshKidney-
dc.subject.meshMale-
dc.subject.meshMutation-
dc.subject.meshPatella-
dc.subject.meshPhenotype-
dc.subject.meshPsychomotor Disorders-
dc.subject.meshScrotum-
dc.subject.meshSeverity of Illness Index-
dc.subject.meshUrogenital Abnormalities-
dc.titleFurther delineation of the KAT6B molecular and phenotypic spectrum.en
dc.typeArticleen
dc.identifier.journalEuropean journal of human genetics : EJHGen
dc.description.fundingOtheren
dc.description.provinceLeinsteren
dc.description.peer-reviewpeer-reviewen

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