KAT6A Syndrome

genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

Deciphering Developmental Disorders (DDD) Study, Joanna Kennedy, David Goudie, Edward Blair, Kate Chandler, Shelagh Joss, Victoria McKay, Andrew Green, Ruth Armstrong, Melissa Lees, Benjamin Kamien, Bruce Hopper, Tiong Yang Tan, Patrick Yap, Zornitza Stark, Nobuhiko Okamoto, Noriko Miyake, Naomichi Matsumoto, Ellen Macnamara, Jennifer L Murphy & 32 others Elizabeth McCormick, Hakon Hakonarson, Marni J Falk, Dong Li, Patrick Blackburn, Eric Klee, Dusica Babovic-Vuksanovic, Susan Schelley, Louanne Hudgins, Sarina Kant, Bertrand Isidor, Benjamin Cogne, Kimberley Bradbury, Mark Williams, Chirag Patel, Helen Heussler, Celia Duff-Farrier, Phillis Lakeman, Ingrid Scurr, Usha Kini, Mariet Elting, Margot Reijnders, Janneke Schuurs-Hoeijmakers, Mohamed Wafik, Anne Blomhoff, Claudia A. L. Ruivenkamp, Esther Nibbeling, Alexander J. M. Dingemans, Emilie D. Douine, Stanley F. Nelson, Valerie A. Arboleda, Ruth Newbury-Ecob

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)850-860
Number of pages11
JournalGenetics in Medicine
Volume21
Early online date24 Sep 2018
DOIs
Publication statusPublished - 24 Sep 2018

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Genetic Association Studies
Social Media
Language Development Disorders
Microcephaly
Penetrance
Missense Mutation
Intellectual Disability
Exons
Phenotype
Surveys and Questionnaires

Keywords

  • KAT6A syndrome; chromatin modifiers; intellectual disability
  • genetic diagnosis
  • phenotypic spectrum

Cite this

Deciphering Developmental Disorders (DDD) Study, Kennedy, J., Goudie, D., Blair, E., Chandler, K., Joss, S., ... Newbury-Ecob, R. (2018). KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. Genetics in Medicine, 21, 850-860. https://doi.org/10.1038/s41436-018-0259-2
Deciphering Developmental Disorders (DDD) Study ; 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. / KAT6A Syndrome : genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. In: Genetics in Medicine. 2018 ; Vol. 21. pp. 850-860.
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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.",
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note = "This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. J.K. held an NIHR Academic Clinical Fellowship post during this course of this study. This work was also supported by an NIH Early Independence Award to V.A.A. (DP5OD024579), and the KAT6A Foundation.",
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Deciphering Developmental Disorders (DDD) Study, Kennedy, J, Goudie, D, Blair, E, Chandler, K, Joss, S, McKay, V, Green, A, Armstrong, R, Lees, M, Kamien, B, Hopper, B, Tan, TY, Yap, P, Stark, Z, Okamoto, N, Miyake, N, Matsumoto, N, Macnamara, E, Murphy, JL, McCormick, E, Hakonarson, H, Falk, MJ, Li, D, Blackburn, P, Klee, E, Babovic-Vuksanovic, D, Schelley, S, Hudgins, L, Kant, S, Isidor, B, Cogne, B, Bradbury, K, Williams, M, Patel, C, Heussler, H, Duff-Farrier, C, Lakeman, P, Scurr, I, Kini, U, Elting, M, Reijnders, M, Schuurs-Hoeijmakers, J, Wafik, M, Blomhoff, A, Ruivenkamp, CAL, Nibbeling, E, Dingemans, AJM, Douine, ED, Nelson, SF, Arboleda, VA & Newbury-Ecob, R 2018, 'KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants', Genetics in Medicine, vol. 21, pp. 850-860. https://doi.org/10.1038/s41436-018-0259-2

KAT6A Syndrome : genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. / Deciphering Developmental Disorders (DDD) Study; 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. (Lead / Corresponding author); Newbury-Ecob, Ruth (Lead / Corresponding author).

In: Genetics in Medicine, Vol. 21, 24.09.2018, p. 850-860.

Research output: Contribution to journalArticle

TY - JOUR

T1 - KAT6A Syndrome

T2 - genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

AU - Deciphering Developmental Disorders (DDD) Study

AU - Kennedy, Joanna

AU - Goudie, David

AU - Blair, Edward

AU - Chandler, Kate

AU - Joss, Shelagh

AU - McKay, Victoria

AU - Green, Andrew

AU - Armstrong, Ruth

AU - Lees, Melissa

AU - Kamien, Benjamin

AU - Hopper, Bruce

AU - Tan, Tiong Yang

AU - Yap, Patrick

AU - Stark, Zornitza

AU - Okamoto, Nobuhiko

AU - Miyake, Noriko

AU - Matsumoto, Naomichi

AU - Macnamara, Ellen

AU - Murphy, Jennifer L

AU - McCormick, Elizabeth

AU - Hakonarson, Hakon

AU - Falk, Marni J

AU - Li, Dong

AU - Blackburn, Patrick

AU - Klee, Eric

AU - Babovic-Vuksanovic, Dusica

AU - Schelley, Susan

AU - Hudgins, Louanne

AU - Kant, Sarina

AU - Isidor, Bertrand

AU - Cogne, Benjamin

AU - Bradbury, Kimberley

AU - Williams, Mark

AU - Patel, Chirag

AU - Heussler, Helen

AU - Duff-Farrier, Celia

AU - Lakeman, Phillis

AU - Scurr, Ingrid

AU - Kini, Usha

AU - Elting, Mariet

AU - Reijnders, Margot

AU - Schuurs-Hoeijmakers, Janneke

AU - Wafik, Mohamed

AU - Blomhoff, Anne

AU - Ruivenkamp, Claudia A. L.

AU - Nibbeling, Esther

AU - Dingemans, Alexander J. M.

AU - Douine, Emilie D.

AU - Nelson, Stanley F.

AU - Arboleda, Valerie A.

AU - Newbury-Ecob, Ruth

N1 - This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. J.K. held an NIHR Academic Clinical Fellowship post during this course of this study. This work was also supported by an NIH Early Independence Award to V.A.A. (DP5OD024579), and the KAT6A Foundation.

PY - 2018/9/24

Y1 - 2018/9/24

N2 - 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.

AB - 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.

KW - KAT6A syndrome; chromatin modifiers; intellectual disability

KW - genetic diagnosis

KW - phenotypic spectrum

UR - http://www.scopus.com/inward/record.url?scp=85053824960&partnerID=8YFLogxK

U2 - 10.1038/s41436-018-0259-2

DO - 10.1038/s41436-018-0259-2

M3 - Article

VL - 21

SP - 850

EP - 860

JO - Genetics in Medicine

JF - Genetics in Medicine

SN - 1098-3600

ER -

Deciphering Developmental Disorders (DDD) Study, Kennedy J, Goudie D, Blair E, Chandler K, Joss S et al. KAT6A Syndrome: genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants. Genetics in Medicine. 2018 Sep 24;21:850-860. https://doi.org/10.1038/s41436-018-0259-2