title: Whole exome sequencing reveals de novo pathogenic variants in KAT6A as a cause of a neurodevelopmental disorder.
abstract: Neurodevelopmental disorders (NDD) are common, with 1-3% of general population being affected, but the etiology is unknown in most individuals. Clinical whole-exome sequencing (WES) has proven to be a powerful tool for the identification of pathogenic variants leading to Mendelian disorders, among which NDD represent a significant percentage. Performing WES with a trio-approach has proven to be extremely effective in identifying de novo pathogenic variants as a common cause of NDD. Here we report six unrelated individuals with a common phenotype consisting of NDD with severe speech delay, hypotonia, and facial dysmorphism. These patients underwent WES with a trio approach and de novo heterozygous predicted pathogenic novel variants in the KAT6A gene were identified. The KAT6A gene encodes a histone acetyltransfrease protein and it has long been known for its structural involvement in acute myeloid leukemia; however, it has not previously been associated with any congenital disorder. In animal models the KAT6A ortholog is involved in transcriptional regulation during development. Given the similar findings in animal models and our patient's phenotypes, we hypothesize that KAT6A could play a role in development of the brain, face, and heart in humans. © 2016 Wiley Periodicals, Inc.
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Francisca
authors.initials: F
authors.lastname: Millan
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Megan T
authors.initials: MT
authors.lastname: Cho
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Kyle
authors.initials: K
authors.lastname: Retterer
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Monaghan
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Renkui
authors.initials: R
authors.lastname: Bai
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Patrik
authors.initials: P
authors.lastname: Vitazka
authors.affiliation: Greenwood Genetic Center, Greenville, South Carolina.
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.affiliation: Greenwood Genetic Center, Greenville, South Carolina.
authors.forename: Brooke
authors.initials: B
authors.lastname: Smith
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Brad
authors.initials: B
authors.lastname: Angle
authors.affiliation: Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.
authors.forename: Victoria
authors.initials: V
authors.lastname: Roberts
authors.affiliation: Specially For Children Genetics, Austin, Texas.
authors.forename: LaDonna
authors.initials: L
authors.lastname: Immken
authors.affiliation: Specially For Children Genetics, Austin, Texas.
authors.forename: Honey
authors.initials: H
authors.lastname: Nagakura
authors.affiliation: Children's Outpatient Center of Montgomery County, Rockville, Maryland.
authors.forename: Marc
authors.initials: M
authors.lastname: DiFazio
authors.affiliation: Institute of Human Genetics, University of California, San Francisco, California.
authors.forename: Elliott
authors.initials: E
authors.lastname: Sherr
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Eden
authors.initials: E
authors.lastname: Haverfield
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Bethany
authors.initials: B
authors.lastname: Friedman
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Aida
authors.initials: A
authors.lastname: Telegrafi
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: GeneDx, Gaithersburg, Maryland.
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D059472:Exome / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D059014:High-Throughput Nucleotide Sequencing; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000503:physiopathology; D017422:Sequence Analysis, DNA
chemical_list: D051548:Histone Acetyltransferases; C108712:KAT6A protein, human
keywords: intellectual disability; neurodevelopmental disorder; whole exome sequencing