Further delineation of the KAT6B molecular and phenotypic spectrum

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...

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Main 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 FM, Smith, Janine, Clayton-Smith, Jill
Format:	Online
Language:	English
Published:	Nature Publishing Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351891/

id	pubmed-4351891
recordtype	oai_dc
spelling	pubmed-43518912015-12-03 Further delineation of the KAT6B molecular and phenotypic spectrum 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 FM Smith, Janine Clayton-Smith, Jill Article 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. Nature Publishing Group 2015-09 2014-11-26 /pmc/articles/PMC4351891/ /pubmed/25424711 http://dx.doi.org/10.1038/ejhg.2014.248 Text en Copyright © 2015 Macmillan Publishers Limited
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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 FM Smith, Janine Clayton-Smith, Jill
spellingShingle	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 FM Smith, Janine Clayton-Smith, Jill Further delineation of the KAT6B molecular and phenotypic spectrum
author_facet	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 FM Smith, Janine Clayton-Smith, Jill
author_sort	Gannon, Tamsin
title	Further delineation of the KAT6B molecular and phenotypic spectrum
title_short	Further delineation of the KAT6B molecular and phenotypic spectrum
title_full	Further delineation of the KAT6B molecular and phenotypic spectrum
title_fullStr	Further delineation of the KAT6B molecular and phenotypic spectrum
title_full_unstemmed	Further delineation of the KAT6B molecular and phenotypic spectrum
title_sort	further delineation of the kat6b molecular and phenotypic spectrum
description	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.
publisher	Nature Publishing Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351891/
_version_	1613195970061795328

Further delineation of the KAT6B molecular and phenotypic spectrum

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