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Title: KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.
Authors: Kennedy, Joanna
Goudie, David
Blair, Edward
Chandler, Kate
Joss, Shelagh
McKay, Victoria
Green, Andrew
Armstrong, Ruth
Lees, Melissa
Kamien, Benjamin
Hopper, Bruce
Tan, Tiong Yang
Yap, Patrick
Stark, Zornitza
Okamoto, Nobuhiko
Miyake, Noriko
Matsumoto, Naomichi
Macnamara, Ellen
Murphy, Jennifer L
McCormick, Elizabeth
Hakonarson, Hakon
Falk, Marni J
Li, Dong
Blackburn, Patrick
Klee, Eric
Babovic-Vuksanovic, Dusica
Schelley, Susan
Hudgins, Louanne
Kant, Sarina
Isidor, Bertrand
Cogne, Benjamin
Bradbury, Kimberley
Williams, Mark
Patel, Chirag
Heussler, Helen
Duff-Farrier, Celia
Lakeman, Phillis
Scurr, Ingrid
Kini, Usha
Elting, Mariet
Reijnders, Margot
Schuurs-Hoeijmakers, Janneke
Wafik, Mohamed
Blomhoff, Anne
Ruivenkamp, Claudia A L
Nibbeling, Esther
Dingemans, Alexander J M
Douine, Emilie D
Nelson, Stanley F
Arboleda, Valerie A
Newbury-Ecob, Ruth
Citation: Genetics in medicine : official journal of the American College of Medical Genetics 2018-09-24
Abstract: Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
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Journal title: Genetics in medicine : official journal of the American College of Medical Genetics
Publication Date: 2018-09-24
Type: Journal Article
DOI: 10.1038/s41436-018-0259-2
Appears in Collections:(a) NT Health Research Collection

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