Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Li Xin Zhang; Gabrielle Lemire; Claudia Gonzaga-Jauregui; Sirinart Molidperee; Carolina Galaz-Montoya; David S. Liu; Alain Verloes; Amelle G. Shillington; Kosuke Izumi; Alyssa L. Ritter; Beth Keena; Elaine Zackai; Dong Li; Elizabeth Bhoj; Jennifer M. Tarpinian; Emma Bedoukian; Mary K. Kukolich; A. Micheil Innes; Grace U. Ediae; Sarah L. Sawyer; Karippoth Mohandas Nair; Para Chottil Soumya; Kinattinkara R. Subbaraman; Frank J. Probst; Jennifer A. Bassetti; Reid V. Sutton; Richard A. Gibbs; Chester Brown; Philip M. Boone; Ingrid A. Holm; Marco Tartaglia; Giovanni Battista Ferrero; Marcello Niceta; Maria Lisa Dentici; Francesca Clementina Radio; Boris Keren; Constance F. Wells; Christine Coubes; Annie Laquerrière; Jacqueline Aziza; Charlotte Dubucs; Sheela Nampoothiri; David Mowat; Millan S. Patel; Ana Bracho; Francisco Cammarata-Scalisi; Alper Gezdirici; Alberto Fernandez-Jaen; Natalie Hauser; Yuri A. Zarate; Katherine A. Bosanko; Klaus Dieterich; John C. Carey; Jessica X. Chong; Deborah A. Nickerson; Michael J. Bamshad; Brendan H. Lee; Xiang Jiao Yang; James R. Lupski; Philippe M. Campeau

doi:10.1038/s41436-020-0811-8

Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Li Xin Zhang, Gabrielle Lemire, Claudia Gonzaga-Jauregui, Sirinart Molidperee, Carolina Galaz-Montoya, David S. Liu, Alain Verloes, Amelle G. Shillington, Kosuke Izumi, Alyssa L. Ritter, Beth Keena, Elaine Zackai, Dong Li, Elizabeth Bhoj, Jennifer M. Tarpinian, Emma Bedoukian, Mary K. Kukolich, A. Micheil Innes, Grace U. Ediae, Sarah L. SawyerKarippoth Mohandas Nair, Para Chottil Soumya, Kinattinkara R. Subbaraman, Frank J. Probst, Jennifer A. Bassetti, Reid V. Sutton, Richard A. Gibbs, Chester Brown, Philip M. Boone, Ingrid A. Holm, Marco Tartaglia, Giovanni Battista Ferrero, Marcello Niceta, Maria Lisa Dentici, Francesca Clementina Radio, Boris Keren, Constance F. Wells, Christine Coubes, Annie Laquerrière, Jacqueline Aziza, Charlotte Dubucs, Sheela Nampoothiri, David Mowat, Millan S. Patel, Ana Bracho, Francisco Cammarata-Scalisi, Alper Gezdirici, Alberto Fernandez-Jaen, Natalie Hauser, Yuri A. Zarate, Katherine A. Bosanko, Klaus Dieterich, John C. Carey, Jessica X. Chong, Deborah A. Nickerson, Michael J. Bamshad, Brendan H. Lee, Xiang Jiao Yang, James R. Lupski, Philippe M. Campeau

Pediatrics

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Purpose: Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusion: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

Original language	English
Pages (from-to)	1338-1347
Number of pages	10
Journal	Genetics in Medicine
Volume	22
Issue number	8
DOIs	https://doi.org/10.1038/s41436-020-0811-8
State	Published - Aug 1 2020

Bibliographical note

Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.

Funding

The authors thank the families for their participation and Natascia Anastasio for revision of the manuscript. We thank the Canadian Institutes of Health Research and Fonds de la recherche en santé du Québec for clinician-scientist awards to P.M.C. G.L. is supported by a Children’s Hospital Academic Medical Organization clinical fellowship award through the Children’s Hospital of Eastern Ontario. This work was partly supported by the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Alberta, Genome Quebec, Genome British Columbia, and CHEO Foundation. Sequencing and analysis was partly provided by the University of Washington Center for Mendelian Genomics (funded by grants UM1 HG006493 and U24 HG008956), the Roberts Individualized Medical Genetics Center of the Children’s Hospital of Philadelphia, and the Baylor-Hopkins Center for Mendelian Genomics (grants UM1 HG006542, R01NS058529, and R35NS105078) to J.R.L. We thank the European Reference Network for Developmental Anomalies and Intellectual Disability for its contribution.

Funders	Funder number
Care4Rare Canada Consortium
Children’s Hospital Academic Medical Organization
Children’s Hospital of Eastern Ontario
The Children’s Hospital of Philadelphia
Canada Fund for Innovation and Genome Quebec Innovation Center
Ontario Research Fund
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS058529
Genome Canada
Children's Hospital of Eastern Ontario Foundation
Baylor-Hopkins Center for Mendelian Genomics	UM1 HG006542, UM1 HG006493, U24 HG008956, R35NS105078
Canadian Institutes of Health Research
Ontario Genomics Institute
Fonds de Recherche du Québec-Santé
Genome British Columbia
Genome Alberta

Keywords

KAT6B
KAT6B disorders
SBBYSS
Say–Barber–Biesecker–Young–Simpson syndrome
genitopatellar syndrome

ASJC Scopus subject areas

Genetics(clinical)

Access to Document

10.1038/s41436-020-0811-8

Cite this

Zhang, L. X., Lemire, G., Gonzaga-Jauregui, C., Molidperee, S., Galaz-Montoya, C., Liu, D. S., Verloes, A., Shillington, A. G., Izumi, K., Ritter, A. L., Keena, B., Zackai, E., Li, D., Bhoj, E., Tarpinian, J. M., Bedoukian, E., Kukolich, M. K., Innes, A. M., Ediae, G. U., ... Campeau, P. M. (2020). Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants. Genetics in Medicine, 22(8), 1338-1347. https://doi.org/10.1038/s41436-020-0811-8

@article{39ab1b9eb80147daad66b354fb02298f,

title = "Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants",

abstract = "Purpose: Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusion: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.",

keywords = "KAT6B, KAT6B disorders, SBBYSS, Say–Barber–Biesecker–Young–Simpson syndrome, genitopatellar syndrome",

author = "Zhang, \{Li Xin\} and Gabrielle Lemire and Claudia Gonzaga-Jauregui and Sirinart Molidperee and Carolina Galaz-Montoya and Liu, \{David S.\} and Alain Verloes and Shillington, \{Amelle G.\} and Kosuke Izumi and Ritter, \{Alyssa L.\} and Beth Keena and Elaine Zackai and Dong Li and Elizabeth Bhoj and Tarpinian, \{Jennifer M.\} and Emma Bedoukian and Kukolich, \{Mary K.\} and Innes, \{A. Micheil\} and Ediae, \{Grace U.\} and Sawyer, \{Sarah L.\} and Nair, \{Karippoth Mohandas\} and Soumya, \{Para Chottil\} and Subbaraman, \{Kinattinkara R.\} and Probst, \{Frank J.\} and Bassetti, \{Jennifer A.\} and Sutton, \{Reid V.\} and Gibbs, \{Richard A.\} and Chester Brown and Boone, \{Philip M.\} and Holm, \{Ingrid A.\} and Marco Tartaglia and Ferrero, \{Giovanni Battista\} and Marcello Niceta and Dentici, \{Maria Lisa\} and Radio, \{Francesca Clementina\} and Boris Keren and Wells, \{Constance F.\} and Christine Coubes and Annie Laquerri{\`e}re and Jacqueline Aziza and Charlotte Dubucs and Sheela Nampoothiri and David Mowat and Patel, \{Millan S.\} and Ana Bracho and Francisco Cammarata-Scalisi and Alper Gezdirici and Alberto Fernandez-Jaen and Natalie Hauser and Zarate, \{Yuri A.\} and Bosanko, \{Katherine A.\} and Klaus Dieterich and Carey, \{John C.\} and Chong, \{Jessica X.\} and Nickerson, \{Deborah A.\} and Bamshad, \{Michael J.\} and Lee, \{Brendan H.\} and Yang, \{Xiang Jiao\} and Lupski, \{James R.\} and Campeau, \{Philippe M.\}",

note = "Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",

year = "2020",

month = aug,

day = "1",

doi = "10.1038/s41436-020-0811-8",

language = "English",

volume = "22",

pages = "1338--1347",

number = "8",

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Zhang, LX, Lemire, G, Gonzaga-Jauregui, C, Molidperee, S, Galaz-Montoya, C, Liu, DS, Verloes, A, Shillington, AG, Izumi, K, Ritter, AL, Keena, B, Zackai, E, Li, D, Bhoj, E, Tarpinian, JM, Bedoukian, E, Kukolich, MK, Innes, AM, Ediae, GU, Sawyer, SL, Nair, KM, Soumya, PC, Subbaraman, KR, Probst, FJ, Bassetti, JA, Sutton, RV, Gibbs, RA, Brown, C, Boone, PM, Holm, IA, Tartaglia, M, Ferrero, GB, Niceta, M, Dentici, ML, Radio, FC, Keren, B, Wells, CF, Coubes, C, Laquerrière, A, Aziza, J, Dubucs, C, Nampoothiri, S, Mowat, D, Patel, MS, Bracho, A, Cammarata-Scalisi, F, Gezdirici, A, Fernandez-Jaen, A, Hauser, N, Zarate, YA, Bosanko, KA, Dieterich, K, Carey, JC, Chong, JX, Nickerson, DA, Bamshad, MJ, Lee, BH, Yang, XJ, Lupski, JR & Campeau, PM 2020, 'Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants', Genetics in Medicine, vol. 22, no. 8, pp. 1338-1347. https://doi.org/10.1038/s41436-020-0811-8

TY - JOUR

T1 - Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

AU - Zhang, Li Xin

AU - Lemire, Gabrielle

AU - Gonzaga-Jauregui, Claudia

AU - Molidperee, Sirinart

AU - Galaz-Montoya, Carolina

AU - Liu, David S.

AU - Verloes, Alain

AU - Shillington, Amelle G.

AU - Izumi, Kosuke

AU - Ritter, Alyssa L.

AU - Keena, Beth

AU - Zackai, Elaine

AU - Li, Dong

AU - Bhoj, Elizabeth

AU - Tarpinian, Jennifer M.

AU - Bedoukian, Emma

AU - Kukolich, Mary K.

AU - Innes, A. Micheil

AU - Ediae, Grace U.

AU - Sawyer, Sarah L.

AU - Nair, Karippoth Mohandas

AU - Soumya, Para Chottil

AU - Subbaraman, Kinattinkara R.

AU - Probst, Frank J.

AU - Bassetti, Jennifer A.

AU - Sutton, Reid V.

AU - Gibbs, Richard A.

AU - Brown, Chester

AU - Boone, Philip M.

AU - Holm, Ingrid A.

AU - Tartaglia, Marco

AU - Ferrero, Giovanni Battista

AU - Niceta, Marcello

AU - Dentici, Maria Lisa

AU - Radio, Francesca Clementina

AU - Keren, Boris

AU - Wells, Constance F.

AU - Coubes, Christine

AU - Laquerrière, Annie

AU - Aziza, Jacqueline

AU - Dubucs, Charlotte

AU - Nampoothiri, Sheela

AU - Mowat, David

AU - Patel, Millan S.

AU - Bracho, Ana

AU - Cammarata-Scalisi, Francisco

AU - Gezdirici, Alper

AU - Fernandez-Jaen, Alberto

AU - Hauser, Natalie

AU - Zarate, Yuri A.

AU - Bosanko, Katherine A.

AU - Dieterich, Klaus

AU - Carey, John C.

AU - Chong, Jessica X.

AU - Nickerson, Deborah A.

AU - Bamshad, Michael J.

AU - Lee, Brendan H.

AU - Yang, Xiang Jiao

AU - Lupski, James R.

AU - Campeau, Philippe M.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - Purpose: Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusion: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

AB - Purpose: Genitopatellar syndrome and Say–Barber–Biesecker–Young–Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized. Methods: We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum. Results: We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent. Conclusion: Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.

KW - KAT6B

KW - KAT6B disorders

KW - SBBYSS

KW - Say–Barber–Biesecker–Young–Simpson syndrome

KW - genitopatellar syndrome

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U2 - 10.1038/s41436-020-0811-8

DO - 10.1038/s41436-020-0811-8

M3 - Article

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AN - SCOPUS:85085029448

SN - 1098-3600

VL - 22

SP - 1338

EP - 1347

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 8

ER -

Further delineation of the clinical spectrum of KAT6B disorders and allelic series of pathogenic variants

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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