PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features

Raida Khalil, Connor Kenny, R. Sean Hill, Ganeshwaran H. Mochida, Ramzi Nasir, Jennifer N. Partlow, Brenda J. Barry, Muna Al-Saffar, Chloe Egan, Christine R. Stevens, Stacey B. Gabriel, A. James Barkovich, Jay W. Ellison, Lihadh Al-Gazali, Christopher A. Walsh, Maria Chahrour

Research output: Contribution to journalArticle

Abstract

Protein homeostasis is tightly regulated by the ubiquitin proteasome pathway. Disruption of this pathway gives rise to a host of neurological disorders. Through whole exome sequencing (WES) in families with neurodevelopmental disorders, we identified mutations in PSMD12, a core component of the proteasome, underlying a neurodevelopmental disorder with intellectual disability (ID) and features of autism spectrum disorder (ASD). We performed WES on six affected siblings from a multiplex family with ID and autistic features, the affected father, and two unaffected mothers, and a trio from a simplex family with one affected child with ID and periventricular nodular heterotopia. We identified an inherited heterozygous nonsense mutation in PSMD12 (NM_002816: c.367C>T: p.R123X) in the multiplex family and a de novo nonsense mutation in the same gene (NM_002816: c.601C>T: p.R201X) in the simplex family. PSMD12 encodes a non-ATPase regulatory subunit of the 26S proteasome. We confirm the association of PSMD12 with ID, present the first cases of inherited PSMD12 mutation, and demonstrate the heterogeneity of phenotypes associated with PSMD12 mutations.

Original languageEnglish (US)
Pages (from-to)736-745
Number of pages10
JournalAmerican Journal of Medical Genetics, Part B: Neuropsychiatric Genetics
Volume177
Issue number8
DOIs
StatePublished - Dec 1 2018

Fingerprint

Haploinsufficiency
Intellectual Disability
Exome
Nonsense Codon
Proteasome Endopeptidase Complex
Mutation
Periventricular Nodular Heterotopia
Disabled Children
Ubiquitin
Nervous System Diseases
Fathers
Siblings
Homeostasis
Mothers
Neurodevelopmental Disorders
Phenotype
Genes
Proteins

Keywords

  • autism spectrum disorder
  • intellectual disability
  • neurogenetics
  • proteasome

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. / Khalil, Raida; Kenny, Connor; Hill, R. Sean; Mochida, Ganeshwaran H.; Nasir, Ramzi; Partlow, Jennifer N.; Barry, Brenda J.; Al-Saffar, Muna; Egan, Chloe; Stevens, Christine R.; Gabriel, Stacey B.; Barkovich, A. James; Ellison, Jay W.; Al-Gazali, Lihadh; Walsh, Christopher A.; Chahrour, Maria.

In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, Vol. 177, No. 8, 01.12.2018, p. 736-745.

Research output: Contribution to journalArticle

Khalil, R, Kenny, C, Hill, RS, Mochida, GH, Nasir, R, Partlow, JN, Barry, BJ, Al-Saffar, M, Egan, C, Stevens, CR, Gabriel, SB, Barkovich, AJ, Ellison, JW, Al-Gazali, L, Walsh, CA & Chahrour, M 2018, ' PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features', American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics, vol. 177, no. 8, pp. 736-745. https://doi.org/10.1002/ajmg.b.32688
Khalil, Raida ; Kenny, Connor ; Hill, R. Sean ; Mochida, Ganeshwaran H. ; Nasir, Ramzi ; Partlow, Jennifer N. ; Barry, Brenda J. ; Al-Saffar, Muna ; Egan, Chloe ; Stevens, Christine R. ; Gabriel, Stacey B. ; Barkovich, A. James ; Ellison, Jay W. ; Al-Gazali, Lihadh ; Walsh, Christopher A. ; Chahrour, Maria. / PSMD12 haploinsufficiency in a neurodevelopmental disorder with autistic features. In: American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics. 2018 ; Vol. 177, No. 8. pp. 736-745.
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