title: Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.
abstract: Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.
authors.affiliation: Centre de Génétique Humaine, Université de Franche-Comté, 25000 Besançon, France. vmald@skypro.be
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Qingming
authors.initials: Q
authors.lastname: Hou
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.forename: Martine
authors.initials: M
authors.lastname: Doco-Fenzy
authors.forename: Ana
authors.initials: A
authors.lastname: Medeira
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Christelle
authors.initials: C
authors.lastname: Cabrol
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.forename: Pierre
authors.initials: P
authors.lastname: Cacciagli
authors.forename: Sébastien
authors.initials: S
authors.lastname: Moutton
authors.forename: Emilie
authors.initials: E
authors.lastname: Landais
authors.forename: Jacques
authors.initials: J
authors.lastname: Motte
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.forename: Céline
authors.initials: C
authors.lastname: Bonnet
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.forename: Juliette
authors.initials: J
authors.lastname: Dupont
authors.forename: Heng-Ye
authors.initials: HY
authors.lastname: Man
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000378:metabolism*; D002675:Child, Preschool; D055785:Gene Knockdown Techniques; D050172:Genes, X-Linked; D008040:Genetic Linkage; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017423:Sequence Analysis, RNA; D055815:Young Adult