Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate.
We describe a female subject (DGAP100) with a 46,X,t(X;5)(p11.3;q35.3)inv(5)(q35.3q35.1)dn, severe psychomotor retardation with hypotonia, global postnatal growth restriction, microcephaly, globally reduced cerebral volume, seizures, facial dysmorphia and cleft palate. Fluorescence in situ hybridization and whole-genome sequencing demonstrated that the X chromosome breakpoint disrupts KDM6A in the second intron. No genes were directly disrupted on chromosome 5. KDM6A is a histone 3 lysine 27 demethylase and a histone 3 lysine 4 methyltransferase. Expression of KDM6A is significantly reduced in DGAP100 lymphoblastoid cells compared to control samples. We identified nine additional cases with neurodevelopmental delay and various other features consistent with the DGAP100 phenotype with copy number variation encompassing KDM6A from microarray databases. We evaluated haploinsufficiency of kdm6a in a zebrafish model. kdm6a is expressed in the pharyngeal arches and ethmoid plate of the developing zebrafish, while a kdm6a morpholino knockdown exhibited craniofacial defects. We conclude KDM6A dosage regulation is associated with severe and diverse structural defects and developmental abnormalities.
Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital, Boston, MA, USA.
Amelia M
AM
Lindgren
Tatiana
T
Hoyos
Michael E
ME
Talkowski
Carrie
C
Hanscom
Ian
I
Blumenthal
Colby
C
Chiang
Carl
C
Ernst
Shahrin
S
Pereira
Zehra
Z
Ordulu
Carol
C
Clericuzio
Joanne M
JM
Drautz
Jill A
JA
Rosenfeld
Lisa G
LG
Shaffer
Lea
L
Velsher
Tania
T
Pynn
Joris
J
Vermeesch
David J
DJ
Harris
James F
JF
Gusella
Eric C
EC
Liao
Cynthia C
CC
Morton
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001934:Branchial Region / Q000201:enzymology; D002460:Cell Line; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002972:Cleft Palate / Q000235:genetics; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D005260:Female; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency / Q000235:genetics*; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D007621:Karyotyping; D008831:Microcephaly / Q000235:genetics; D009123:Muscle Hypotonia / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011596:Psychomotor Disorders / Q000235:genetics; D012640:Seizures / Q000235:genetics; D014178:Translocation, Genetic; D014960:X Chromosome / Q000235:genetics; D055815:Young Adult; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
D009687:Nuclear Proteins; D029961:Zebrafish Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human