title: Deficiency of the cyclin-dependent kinase inhibitor, CDKN1B, results in overgrowth and neurodevelopmental delay.
abstract: Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay.
authors.affiliation: Department of Medical & Molecular Genetics, King's College London School of Medicine, Guy's Hospital, Great Maze Pond, London, United Kingdom.
authors.forename: William
authors.initials: W
authors.lastname: Grey
authors.forename: Louise
authors.initials: L
authors.lastname: Izatt
authors.forename: Wafa
authors.initials: W
authors.lastname: Sahraoui
authors.forename: Yiu-Ming
authors.initials: YM
authors.lastname: Ng
authors.forename: Caroline
authors.initials: C
authors.lastname: Ogilvie
authors.forename: Anthony
authors.initials: A
authors.lastname: Hulse
authors.forename: Eric
authors.initials: E
authors.lastname: Tse
authors.forename: Roman
authors.initials: R
authors.lastname: Holic
authors.forename: Veronica
authors.initials: V
authors.lastname: Yu
mesh_terms: D001321:Autistic Disorder / Q000235:genetics; D002675:Child, Preschool; D055028:Comparative Genomic Hybridization; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27