Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate

• Published in: Human genetics Vol. 132; no. 5; pp. 537 - 552
• Main Authors: Lindgren, Amelia M., Hoyos, Tatiana, Talkowski, Michael E., Hanscom, Carrie, Blumenthal, Ian, Chiang, Colby, Ernst, Carl, Pereira, Shahrin, Ordulu, Zehra, Clericuzio, Carol, Drautz, Joanne M., Rosenfeld, Jill A., Shaffer, Lisa G., Velsher, Lea, Pynn, Tania, Vermeesch, Joris, Harris, David J., Gusella, James F., Liao, Eric C., Morton, Cynthia C.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.05.2013; Springer; Springer Nature B.V
• Subjects: Abnormalities, Multiple - genetics; Animals; Biomedical and Life Sciences; Biomedicine; Birth defects; Branchial Region - enzymology; Cell Line; Chromosome 5; Chromosomes, Human, Pair 5 - genetics; Cleft lip/palate; Cleft palate; Cleft Palate - genetics; Comparative Genomic Hybridization; Copy number; Danio rerio; DNA Copy Number Variations; DNA sequencing; Female; Fluorescence; Fluorescence in situ hybridization; Gene Function; Gene Knockdown Techniques; Genomes; Genomics; Growth; Haploinsufficiency; Haploinsufficiency - genetics; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histone methyltransferase; Human Genetics; Humans; Hybridization; Intellectual disabilities; Intellectual Disability - genetics; Karyotyping; Lysine; Metabolic Diseases; Methyltransferase; Microcephaly; Microcephaly - genetics; Microencephaly; Molecular Medicine; Muscle Hypotonia - genetics; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleotide sequencing; Original Investigation; Pharynx; Phenotype; Phenotypes; Psychomotor Disorders - genetics; Seizures; Seizures (Medicine); Seizures - genetics; Translocation, Genetic; Whole genome sequencing; X Chromosome - genetics; Young Adult; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - growth & development; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Cleft Palate; Dysmorphic Facial Feature; Pharyngeal Arch; Translocation Breakpoint; Kabuki Syndrome
• ISSN: 0340-6717; 1432-1203; 1432-1203
• DOI: 10.1007/s00439-013-1263-x

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.