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KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants.

Kennedy, Joanna
; 
Goudie, David
; 
Blair, Edward
; 
Chandler, Kate
; 
Joss, Shelagh
; 
McKay, Victoria
; 
Green, Andrew
; 
Armstrong, Ruth
; 
Lees, Melissa
; 
Kamien, Benjamin
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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
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Date
2018-09-24
Date Submitted
Keywords
KAT6A syndrome; chromatin modifiers; intellectual disability
genetic diagnosis
phenotypic spectrum
INTELLECTUAL DISABILITIES
DEVELOPMENTAL DELAY
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Subject Mesh
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Start Date
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nihms-1040041.pdf
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URI
https://hdl.handle.net/10147/627191
Abstract
Purpose: 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. Methods: 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. Results: 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. Conclusion: Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.
Language
en
Citation
ISSN
eISSN
1530-0366
ISBN
DOI
10.1038/s41436-018-0259-2
PMID
30245513
PMCID
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