Review

. 2020 Aug;22(8):1338-1347.

doi: 10.1038/s41436-020-0811-8. Epub 2020 May 19.

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

Li Xin Zhang^#¹, Gabrielle Lemire^#², Claudia Gonzaga-Jauregui³, Sirinart Molidperee¹, Carolina Galaz-Montoya³, David S Liu³, Alain Verloes⁴, Amelle G Shillington⁵, Kosuke Izumi⁶, Alyssa L Ritter⁷, Beth Keena⁶, Elaine Zackai^{7

8}, Dong Li⁹, Elizabeth Bhoj⁷, Jennifer M Tarpinian¹⁰, Emma Bedoukian¹⁰, Mary K Kukolich¹¹, A Micheil Innes¹², Grace U Ediae¹³, Sarah L Sawyer¹⁴, Karippoth Mohandas Nair¹⁵, Para Chottil Soumya¹⁵, Kinattinkara R Subbaraman¹⁵, Frank J Probst^{3

16}, Jennifer A Bassetti^{3

16}, Reid V Sutton^{3

16}, Richard A Gibbs³, Chester Brown¹⁷, Philip M Boone¹⁸, Ingrid A Holm¹⁸, Marco Tartaglia¹⁹, Giovanni Battista Ferrero²⁰, Marcello Niceta¹⁹, Maria Lisa Dentici¹⁹, Francesca Clementina Radio¹⁹, Boris Keren²¹, Constance F Wells²², Christine Coubes²², Annie Laquerrière²³, Jacqueline Aziza²⁴, Charlotte Dubucs²⁴, Sheela Nampoothiri²⁵, David Mowat²⁶, Millan S Patel²⁷, Ana Bracho²⁸, Francisco Cammarata-Scalisi²⁹, Alper Gezdirici³⁰, Alberto Fernandez-Jaen³¹, Natalie Hauser³², Yuri A Zarate³³, Katherine A Bosanko³³, Klaus Dieterich³⁴, John C Carey³⁵, Jessica X Chong^{36

37}, Deborah A Nickerson^{37

38}, Michael J Bamshad^{36

37}, Brendan H Lee³, Xiang-Jiao Yang³⁹, James R Lupski^{3

16}, Philippe M Campeau⁴⁰

Affiliations

¹ Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC, Canada.
² Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Genetics and INSERM UMR1141, APHP-Nord Université de Paris, Robert DEBRE Hospital, Paris and ERN-ITHACA, Paris, France.
⁵ Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Cook Children's Health Care System, Fort Worth, TX, USA.
¹² Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
¹³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
¹⁵ Department of Pediatrics, Government Medical College, Kozhikode, Kerala, India.
¹⁶ Texas Children's Hospital, Houston, TX, USA.
¹⁷ University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, TN, USA.
¹⁸ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
²⁰ Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy.
²¹ Genetic department, AP-HP, Sorbonne Université, Paris, France.
²² Service de Génétique Clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France.
²³ Department of Pathology, Centre for Genomic and Personalized Medicine, UNIROUEN Normandie University, Inserm U1245, Normandy, Rouen, France.
²⁴ Département anatomie et cytologie pathologiques, CHU Toulouse, Toulouse, France.
²⁵ Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
²⁶ Centre for Clinical Genetics, Sydney Children's Hospital Randwick, Sydney, Australia.
²⁷ BC Children's Hospital Research Institute and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
²⁸ Genetic Research Institute, University of Zulia, Maracaibo, Venezuela.
²⁹ Medical Genetics, University of Los Andes, Mérida, Venezuela.
³⁰ Department of Medical Genetics, Istanbul Health Science University, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
³¹ Department of Pediatric Neurology, Hospital Quirónsalud School of Medicine, Universidad Europea, Madrid, Spain.
³² Inova Health system, Falls Church, VA, USA.
³³ Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
³⁴ Medical Genetics, CHU Grenoble Alpes, Université Grenoble Alpes, Inserm, U1216, GIN, Grenoble, France.
³⁵ Division of Medical Genetics, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, USA.
³⁶ Department of Pediatrics, University of Washington, Seattle, WA, USA.
³⁷ Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA.
³⁸ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
³⁹ Goodman Cancer Center, Department of Medicine, McGill University, Montreal, QC, Canada.
⁴⁰ Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada. p.campeau@umontreal.ca.

^# Contributed equally.

PMID: 32424177
PMCID: PMC7737399
DOI: 10.1038/s41436-020-0811-8

Review

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

Li Xin Zhang et al. Genet Med. 2020 Aug.

. 2020 Aug;22(8):1338-1347.

doi: 10.1038/s41436-020-0811-8. Epub 2020 May 19.

Authors

Affiliations

¹ Sainte-Justine Hospital Research Center, University of Montreal, Montreal, QC, Canada.
² Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada.
³ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Genetics and INSERM UMR1141, APHP-Nord Université de Paris, Robert DEBRE Hospital, Paris and ERN-ITHACA, Paris, France.
⁵ Department of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
⁶ Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁷ Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁸ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹⁰ Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹¹ Cook Children's Health Care System, Fort Worth, TX, USA.
¹² Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada.
¹³ Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
¹⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
¹⁵ Department of Pediatrics, Government Medical College, Kozhikode, Kerala, India.
¹⁶ Texas Children's Hospital, Houston, TX, USA.
¹⁷ University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, TN, USA.
¹⁸ Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
¹⁹ Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
²⁰ Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy.
²¹ Genetic department, AP-HP, Sorbonne Université, Paris, France.
²² Service de Génétique Clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU de Montpellier, Montpellier, France.
²³ Department of Pathology, Centre for Genomic and Personalized Medicine, UNIROUEN Normandie University, Inserm U1245, Normandy, Rouen, France.
²⁴ Département anatomie et cytologie pathologiques, CHU Toulouse, Toulouse, France.
²⁵ Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.
²⁶ Centre for Clinical Genetics, Sydney Children's Hospital Randwick, Sydney, Australia.
²⁷ BC Children's Hospital Research Institute and Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
²⁸ Genetic Research Institute, University of Zulia, Maracaibo, Venezuela.
²⁹ Medical Genetics, University of Los Andes, Mérida, Venezuela.
³⁰ Department of Medical Genetics, Istanbul Health Science University, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey.
³¹ Department of Pediatric Neurology, Hospital Quirónsalud School of Medicine, Universidad Europea, Madrid, Spain.
³² Inova Health system, Falls Church, VA, USA.
³³ Department of Pediatrics, Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
³⁴ Medical Genetics, CHU Grenoble Alpes, Université Grenoble Alpes, Inserm, U1216, GIN, Grenoble, France.
³⁵ Division of Medical Genetics, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, USA.
³⁶ Department of Pediatrics, University of Washington, Seattle, WA, USA.
³⁷ Brotman-Baty Institute for Precision Medicine, Seattle, WA, USA.
³⁸ Department of Genome Sciences, University of Washington, Seattle, WA, USA.
³⁹ Goodman Cancer Center, Department of Medicine, McGill University, Montreal, QC, Canada.
⁴⁰ Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, University of Montreal, Montreal, QC, Canada. p.campeau@umontreal.ca.

^# Contributed equally.

PMID: 32424177
PMCID: PMC7737399
DOI: 10.1038/s41436-020-0811-8

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.

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Conflict of interest statement

CONFLICT OF INTEREST

Baylor College of Medicine (BCM) and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), which performs clinical microarray analysis and clinical exome sequencing. J.R.L. serves on the Scientific Advisory Board of BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Baylor Genetics Laboratories.

Figures

**Figure 1:**
Clinical photographs of 20 newly reported individuals with *KAT6B* disorders (GPS: Genitopatellar Syndrome/SBBYSS: Say-Barber-Biesecker-Young-Simpson Syndrome/ NOS: not otherwise specified) showing: a) Facial features of affected individuals. Note the blepharophimosis, ptosis and mask-like facies in individuals with SBBYSS and the intermediate phenotype. b) Long thumbs and/or long great toes (upper left: individual 13; upper right: individual 15; lower left and lower right: individual 29). c) Flexion contractures and club feet (left: individual 24; right: individual 5). d) Absent patella in individual 5. e) Pre-axial polydactyly of the right hand in individual 25. f) Overlapping toes in individual 21. g) A newborn with GPS who died after birth at 28 weeks of gestation (Individual 8). Note the high forehead, blepharophimosis, small palpebral fissures with hypertelorism, sparse eyebrows and eyelashes, small simplified ears with bilateral pits, proximal/distal arthrogryposis and contractures of the hip/knees.

**Figure 2:**
Distribution of all pathogenic variants in *KAT6B* reported in literature (upper panel) and 23 new variants reported in this article (lower panel) with the associated phenotype(s). GPS: Genitopatellar Syndrome/SSBYSS: Say-Barber-Biesecker-Young-Simpson Syndrome. NOS: not otherwise specified. The variant c.5624_5625del/p.Ala1876Leufs*3 reported by Gannon *et al* in 2015 has not been included in this figure, because of discordance between the reported cDNA and protein change.

See this image and copyright information in PMC

References

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

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

Authors

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Abstract

Conflict of interest statement

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