Journal Article

Further delineation of the KAT6B molecular and phenotypic spectrum

Price, Sue, Newbury-Ecob, Ruth, Lo, Ivan FM, Wieczorek, Dagmar, Tein, Mark, Suri, Mohnish, Dabir, Tabib, Reardon, Willie, Clayton-Smith, Jill, Anderson, Beverley, Garavelli, Livia, Kerr, Bronwyn, Ma, Alan, Angle, Brad, Singer, Amihood, Anderlid, Britt-Marie, Bucher, Jessica, Fradin, Melanie, Simsek-Kiper, Pelin Ozlem, Pilz, Daniela T, Smith, Janine, Unger, Sheila, Vogt, Julie, Doco-Fenzy, Martine, McGaughran, Julie, Mohammed, Shehla, Gannon, Tamsin, Cormier-Daire, Valerie, Borck, Guntram, Van den Ende, Jenneke, Smithson, Sarah, Yilmaz, Rüstem, Veenstra-Knol, Hermine E, Moore-Barton, Heather, Sznajer, Yves, Berland, Siren, Toutain, Annick, Johnson, Diana, Lyonnet, Stan, Day, Ruth, Gabbett, Michael, Luk, Ho Ming, Haye, Damien, Ramsden, Simon, Destrée, Anne, Perveen, Rahat, Banka, Siddharth, Maystadt, Isabelle, Tuysuz, Beyhan, Schlecht, Hélene, Bijlsma, Emilia, Zuffardi, Orsetta, Wakeling, Emma, Davies, Sally, Eason, Jacqueline, Armstrong, Ruth, Bouman, Katelijne, Kohlhase, Jürgen, Devriendt, Koen

2015

Overview

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
• Subject: Blepharophimosis / Blepharophimosis - diagnosis / Blepharophimosis - genetics / Blepharophimosis - pathology / Child, Preschool / Clonal deletion / Congenital diseases / Congenital Hypothyroidism - diagnosis / Congenital Hypothyroidism - genetics / Congenital Hypothyroidism - pathology / Craniofacial Abnormalities - diagnosis / Craniofacial Abnormalities - genetics / Craniofacial Abnormalities - pathology / Defects / Diagnosis, Differential / DNA Mutational Analysis / Exome / Exons / Facies / Female / Gene deletion / Gene Expression / Genetic Association Studies / Genetics / Genotype / Genotype & phenotype / Genotypes / Haploinsufficiency / Heart Defects, Congenital - diagnosis / Heart Defects, Congenital - genetics / Heart Defects, Congenital - pathology / Histone Acetyltransferases - genetics / Hospitals / Human genetics / Humans / Intellectual disabilities / Intellectual Disability - diagnosis / Intellectual Disability - genetics / Intellectual Disability - pathology / Joint Instability - diagnosis / Joint Instability - genetics / Joint Instability - pathology / Kidney - abnormalities / Kidney - pathology / Life Sciences / Male / Medicine / Molecular modelling / Mutation / Patella - abnormalities / Patella - pathology / Pediatrics / Phenotype / Phenotypes / Psychomotor Disorders - diagnosis / Psychomotor Disorders - genetics / Psychomotor Disorders - pathology / Scrotum - abnormalities / Scrotum - pathology / Severity of Illness Index / Splicing / Statistical analysis / Thyroid / Thyroid gland / Urogenital Abnormalities - diagnosis / Urogenital Abnormalities - genetics / Urogenital Abnormalities - pathology