title: Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.
abstract: Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
authors.affiliation: Sektion für Funktionelle Genetik am Institut für Humangenetik, Universität zu Lübeck, Lübeck 23538, Germany.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Kaiser
authors.forename: Morad
authors.initials: M
authors.lastname: Ansari
authors.forename: Diana
authors.initials: D
authors.lastname: Braunholz
authors.forename: María
authors.initials: M
authors.lastname: Concepción Gil-Rodríguez
authors.forename: Christophe
authors.initials: C
authors.lastname: Decroos
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Wilde
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Fincher
authors.forename: Maninder
authors.initials: M
authors.lastname: Kaur
authors.forename: Masashige
authors.initials: M
authors.lastname: Bando
authors.forename: David J
authors.initials: DJ
authors.lastname: Amor
authors.forename: Paldeep S
authors.initials: PS
authors.lastname: Atwal
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Christine M
authors.initials: CM
authors.lastname: Bowman
authors.forename: Jacquelyn J
authors.initials: JJ
authors.lastname: Bradley
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.forename: Dinah
authors.initials: D
authors.lastname: Clark
authors.forename: Miguel
authors.initials: M
authors.lastname: Del Campo
authors.forename: Nataliya
authors.initials: N
authors.lastname: Di Donato
authors.forename: Peter
authors.initials: P
authors.lastname: Diakumis
authors.forename: Holly
authors.initials: H
authors.lastname: Dubbs
authors.forename: David A
authors.initials: DA
authors.lastname: Dyment
authors.forename: Juliane
authors.initials: J
authors.lastname: Eckhold
authors.forename: Sarah
authors.initials: S
authors.lastname: Ernst
authors.forename: Jose C
authors.initials: JC
authors.lastname: Ferreira
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Francey
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gehlken
authors.forename: Encarna
authors.initials: E
authors.lastname: Guillén-Navarro
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gyftodimou
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Hall
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.forename: Louanne
authors.initials: L
authors.lastname: Hudgins
authors.forename: Melanie
authors.initials: M
authors.lastname: Hullings
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Hunter
authors.forename: Helger
authors.initials: H
authors.lastname: Yntema
authors.forename: A Micheil
authors.initials: AM
authors.lastname: Innes
authors.forename: Antonie D
authors.initials: AD
authors.lastname: Kline
authors.forename: Zita
authors.initials: Z
authors.lastname: Krumina
authors.forename: Hane
authors.initials: H
authors.lastname: Lee
authors.forename: Kathleen
authors.initials: K
authors.lastname: Leppig
authors.forename: Sally Ann
authors.initials: SA
authors.lastname: Lynch
authors.forename: Mark B
authors.initials: MB
authors.lastname: Mallozzi
authors.forename: Linda
authors.initials: L
authors.lastname: Mannini
authors.forename: Shane
authors.initials: S
authors.lastname: McKee
authors.forename: Sarju G
authors.initials: SG
authors.lastname: Mehta
authors.forename: Ieva
authors.initials: I
authors.lastname: Micule
authors.forename: Shehla
authors.initials: S
authors.lastname: Mohammed
authors.forename: Ellen
authors.initials: E
authors.lastname: Moran
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Joe-Ann S
authors.initials: JA
authors.lastname: Moser
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Noon
authors.forename: Naohito
authors.initials: N
authors.lastname: Nozaki
authors.forename: Luis
authors.initials: L
authors.lastname: Nunes
authors.forename: John G
authors.initials: JG
authors.lastname: Pappas
authors.forename: Lynette S
authors.initials: LS
authors.lastname: Penney
authors.forename: Antonio
authors.initials: A
authors.lastname: Pérez-Aytés
authors.forename: Michael B
authors.initials: MB
authors.lastname: Petersen
authors.forename: Beatriz
authors.initials: B
authors.lastname: Puisac
authors.forename: Nicole
authors.initials: N
authors.lastname: Revencu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Roeder
authors.forename: Sulagna
authors.initials: S
authors.lastname: Saitta
authors.forename: Angela E
authors.initials: AE
authors.lastname: Scheuerle
authors.forename: Karen L
authors.initials: KL
authors.lastname: Schindeler
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Siu
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Strom
authors.forename: Heidi
authors.initials: H
authors.lastname: Thiese
authors.forename: Inga
authors.initials: I
authors.lastname: Vater
authors.forename: Patrick
authors.initials: P
authors.lastname: Willems
authors.forename: Kathleen
authors.initials: K
authors.lastname: Williamson
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Fabiola
authors.initials: F
authors.lastname: Quintero-Rivera
authors.forename: Jolanta
authors.initials: J
authors.lastname: Wierzba
authors.forename: Antonio
authors.initials: A
authors.lastname: Musio
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.forename: Laird G
authors.initials: LG
authors.lastname: Jackson
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shirahige
authors.forename: Juan
authors.initials: J
authors.lastname: Pié
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
authors.forename: Ian D
authors.initials: ID
authors.lastname: Krantz
authors.forename: David R
authors.initials: DR
authors.lastname: Fitzpatrick
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Deardorff
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D055762:Cranial Fontanelles / Q000002:abnormalities* / Q000201:enzymology; D003635:De Lange Syndrome / Q000201:enzymology* / Q000235:genetics; D005124:Eye Abnormalities / Q000201:enzymology* / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006972:Hypertelorism / Q000201:enzymology* / Q000235:genetics; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D012097:Repressor Proteins; C409470:HDAC8 protein, human; D006655:Histone Deacetylases