title: De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females.
abstract: Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.
authors: Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors: R
authors: R
authors: Webster
authors: GeneDx, Gaithersburg, MD, USA.
authors: M T
authors: MT
authors: Cho
authors: GeneDx, Gaithersburg, MD, USA.
authors: K
authors: K
authors: Retterer
authors: GeneDx, Gaithersburg, MD, USA.
authors: F
authors: F
authors: Millan
authors: Boston Children's Hospital, Boston, MA, USA.
authors: C
authors: C
authors: Nowak
authors: Boston Children's Hospital, Boston, MA, USA.
authors: J
authors: J
authors: Douglas
authors: University of Michigan, Ann Arbor, MI, USA.
authors: A
authors: A
authors: Ahmad
authors: Department of Neurology and Pediatrics, University of Minnesota Medical Center, Minneapolis, MN, USA.
authors: G V
authors: GV
authors: Raymond
authors: Department of Neurology and Pediatrics, University of Minnesota Medical Center, Minneapolis, MN, USA.
authors: M R
authors: MR
authors: Johnson
authors: Neurometabolic Diseases Laboratory, ICREA/IDIBELL and CIBERER U759, Barcelona, Spain.
authors: A
authors: A
authors: Pujol
authors: GeneDx, Gaithersburg, MD, USA.
authors: A
authors: A
authors: Begtrup
authors: GeneDx, Gaithersburg, MD, USA.
authors: D
authors: D
authors: McKnight
authors: New York University School of Medicine, New York, NY, USA.
authors: O
authors: O
authors: Devinsky
authors: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA.
authors: W K
authors: WK
authors: Chung
mesh_terms: D004827:Epilepsy / Q000235:genetics; D059472:Exome; D005260:Female; D050172:Genes, X-Linked; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D000073658:Loss of Function Mutation; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics; D010641:Phenotype
chemical_list: C000598871:NEXMIF protein, human; D009419:Nerve Tissue Proteins
keywords: KIAA2022; autism; intellectual disability; seizures; whole-exome sequencing