title: POGZ truncating alleles cause syndromic intellectual disability.
abstract: BACKGROUND
  Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.
  
  
  METHODS
  Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.
  
  
  RESULTS
  We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.
  
  
  CONCLUSIONS
  While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: Janson
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: Christine R
authors.initials: CR
authors.lastname: Beck
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Harel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Posey
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656, USA.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Farwell
authors.affiliation: Ambry Genetics, Aliso Viejo, CA, 92656, USA.
authors.forename: Zöe
authors.initials: Z
authors.lastname: Powis
authors.affiliation: Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55102, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Mendelsohn
authors.affiliation: Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, 55102, USA.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Baker
authors.affiliation: Arnold Palmer Medical Center, Division of Genetics, Orlando, FL, 32806, USA.
authors.forename: Lynda
authors.initials: L
authors.lastname: Pollack
authors.affiliation: Arnold Palmer Medical Center, Division of Genetics, Orlando, FL, 32806, USA.
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Mason
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Klaas J
authors.initials: KJ
authors.lastname: Wierenga
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Arrington
authors.affiliation: University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hall
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37212, USA.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Psychogios
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, 37212, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Fairbrother
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Walkiewicz
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Person
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Zhiyv
authors.initials: Z
authors.lastname: Niu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.|Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.|University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA.|Exome Laboratory, Baylor Miraca Genetics Laboratory, Houston, TX, 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA. vrsutton@texaschildrens.org.
authors.forename: V Reid
authors.initials: VR
authors.lastname: Sutton
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA / Q000379:methods*; D019895:Transposases / Q000235:genetics*; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins
chemical_list: D019895:Transposases; C541037:POGZ protein, human; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins