Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2.
Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up-to-date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well-defined X-linked KS type 2, and comment on phenotype-genotype correlations as well as sex-specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki-like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients.
Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
Nina
N
Bögershausen
Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier, France.|University of Montpellier, Montpellier, France.|INSERM UMR1183, Montpellier, France.
Vincent
V
Gatinois
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Vera
V
Riehmer
Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey.
Hülya
H
Kayserili
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Jutta
J
Becker
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Michaela
M
Thoenes
Pediatric Genetics Unit, Department of Pediatrics, Hacettepe University Medical Faculty, Ankara, Turkey.
Pelin Özlem
PÖ
Simsek-Kiper
Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier, France.|INSERM UMR1183, Montpellier, France.
Mouna
M
Barat-Houari
Department of Pediatric Genetics, Marmara University Medical Faculty, Istanbul, Turkey.
Nursel H
NH
Elcioglu
Institute of Human Genetics, University of Duesseldorf, Duesseldorf, Germany.
Dagmar
D
Wieczorek
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.|Zentrum für Humangenetik, Medizinische Universität, Innsbruck, Austria.
Sigrid
S
Tinschert
Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier, France.|University of Montpellier, Montpellier, France.|INSERM UMR1183, Montpellier, France.
Guillaume
G
Sarrabay
Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Tim M
TM
Strom
Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier, France.
Aurélie
A
Fabre
Genetic Services of Western Australia, Princess Margaret and King Edward Memorial Hospitals, Perth, Australia.|Western Australian Register of Developmental Anomalies, Perth, Australia.|Telethon Kids Institute, Perth, Australia.|School of Paediatrics and Child Health, University of Western Australia, Perth, Australia.
Gareth
G
Baynam
INSERM UMR1183, Montpellier, France.
Elodie
E
Sanchez
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Gudrun
G
Nürnberg
Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
Umut
U
Altunoglu
Department of Genetics, APHP-Robert DEBRE University Hospital, Paris VII University, Denis Diderot Medical School, Paris, France.
Yline
Y
Capri
Department of Genetics, Nantes University Hospital, Nantes, France.
Bertrand
B
Isidor
Department of Medical Genetics, Bordeaux University, CHU Bordeaux, INSERM U1211, Bordeaux, France.
Didier
D
Lacombe
University of Montpellier, Montpellier, France.|INSERM UMR1183, Montpellier, France.|Department of Medical Genetics, Reference Center for Developmental Abnormalities, CHU, Montpellier, France.
Carole
C
Corsini
Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, INSERM U1163, Paris, France.|Service de Génétique, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris, France.
Valérie
V
Cormier-Daire
HCL Genetic Department, INSERM U1028 CNRS UMR 5292, UCBL1, CRNL, GENDEV Team, Lyon, France.
Damien
D
Sanlaville
Department of Medical Genetics, l'Archet II Hospital, Nice, France.
Fabienne
F
Giuliano
Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, INSERM U1163, Paris, France.
Kim-Hanh
KH
Le Quan Sang
Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, INSERM U1163, Paris, France.
Honorine
H
Kayirangwa
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Peter
P
Nürnberg
Institute of Human Genetics, Technische Universität München, Munich, Germany.|Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Thomas
T
Meitinger
Pediatric Genetics Unit, Department of Pediatrics, Hacettepe University Medical Faculty, Ankara, Turkey.
Koray
K
Boduroglu
Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
Barbara
B
Zoll
Institut Imagine, Paris Descartes-Sorbonne Paris Cité University, INSERM U1163, Paris, France.|Service de Génétique, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris, France.
Stanislas
S
Lyonnet
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.
Andreas
A
Tzschach
Department of Genetics, APHP-Robert DEBRE University Hospital, Paris VII University, Denis Diderot Medical School, Paris, France.
Alain
A
Verloes
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Germany.
Nataliya
N
Di Donato
Laboratory of Rare and Autoinflammatory Diseases, CHU Montpellier, Montpellier, France.|University of Montpellier, Montpellier, France.|INSERM UMR1183, Montpellier, France.
Isabelle
I
Touitou
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Christian
C
Netzer
Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
Yun
Y
Li
University of Montpellier, Montpellier, France.|INSERM UMR1183, Montpellier, France.|Department of Medical Genetics, Reference Center for Developmental Abnormalities, CHU, Montpellier, France.
David
D
Geneviève
Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
Gökhan
G
Yigit
Institute of Human Genetics, University Medical Center Goettingen, Goettingen, Germany.
Bernd
B
Wollnik
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities* / Q000473:pathology; D005260:Female; D050172:Genes, X-Linked; D020022:Genetic Predisposition to Disease; D006402:Hematologic Diseases / Q000235:genetics* / Q000473:pathology; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D008297:Male; D000072741:Maternal Inheritance; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009634:Noonan Syndrome / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015837:Vestibular Diseases / Q000235:genetics* / Q000473:pathology
D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human
KDM6A; KDM6C; KMT2D; Kabuki syndrome; MLL2; UTY