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Further delineation of the KAT6B molecular and phenotypic spectrum

Tamsin Gannon 1 Rahat Perveen 1 Hélene Schlecht 1 Simon Ramsden 1 Beverley Anderson 1 Bronwyn Kerr 1 Ruth Day 1 Siddharth Banka 1 Mohnish Suri 2 Siren Berland 3 Michael Gabbett 4 Alan Ma 5 Stan Lyonnet 6 Valérie Cormier-Daire 6 Rüstem Yilmaz 7 Guntram Borck 7 Dagmar Wieczorek 8 Britt-Marie Anderlid 9 Sarah Smithson 10 Julie Vogt 11 Heather Moore-Barton 5 Pelin Ozlem Simsek-Kiper 12 Isabelle Maystadt 13 Anne Destrée 13 Jessica Bucher 14 Brad Angle 14 Shehla Mohammed 15 Emma Wakeling 16 Sue Price 17 Amihood Singer 18 Yves Sznajer 19 Annick Toutain 20 Damien Haye 20 Ruth Newbury-Ecob 10 Mélanie Fradin 21, 22 Julie Mcgaughran 4 Beyhan Tuysuz 23 Mark Tein 24 Katelijne Bouman 25 Tabib Dabir 26 Jenneke Ende 27 Ho Ming Luk 28 Daniela T. Pilz 29 Jacqueline Eason 2 Sally Davies 29 Willie Reardon 30 Livia Garavelli 31 Orsetta Zuffardi 32 Koen Devriendt 33 Ruth Armstrong 34 Diana Johnson 35 Martine Doco-Fenzy 36 Emilia Bijlsma 37 Sheila Unger 38 Hermine E. Veenstra-Knol 25 Jürgen Kohlhase 3 Ivan Fm Lo 28 Janine Smith 5 Jill Clayton-Smith 1, *
* Corresponding author
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.
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Submitted on : Thursday, November 5, 2015 - 3:23:25 PM
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Tamsin Gannon, Rahat Perveen, Hélene Schlecht, Simon Ramsden, Beverley Anderson, et al.. Further delineation of the KAT6B molecular and phenotypic spectrum. European Journal of Human Genetics, Nature Publishing Group, 2015, 23 (9), pp.1165--1170. ⟨10.1038/ejhg.2014.248⟩. ⟨hal-01195741⟩

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