title: Cerebellar and posterior fossa malformations in patients with autism-associated chromosome 22q13 terminal deletion.
abstract: The 22q13.3 deletion causes a neurodevelopmental syndrome, also known as Phelan-McDermid syndrome (MIM #606232), characterized by developmental delay and severe delay or absence of expressive speech. Two patients with hemizygous chromosome 22q13.3 telomeric deletion were referred to us when brain-imaging studies revealed cerebellar vermis hypoplasia (CBVH). To determine whether developmental abnormalities of the cerebellum are a consistent feature of the 22q13.3 deletion syndrome, we examined brain-imaging studies for 10 unrelated subjects with 22q13 terminal deletion. In seven cases where the availability of DNA and array technology allowed, we mapped deletion boundaries using comparative intensity analysis with single nucleotide polymorphism (SNP) microarrays. Approximate deletion boundaries for three additional cases were derived from clinical or published molecular data. We also examined brain-imaging studies for a patient with an intragenic SHANK3 mutation. We report the first brain-imaging data showing that some patients with 22q13 deletions have severe posterior CBVH, and one individual with a SHANK3 mutation has a normal cerebellum. This genotype-phenotype study suggests that the 22q13 deletion phenotype includes abnormal posterior fossa structures that are unlikely to be attributed to SHANK3 disruption. Other genes in the region, including PLXNB2 and MAPK8IP2, display brain expression patterns and mouse mutant phenotypes critical for proper cerebellar development. Future studies of these genes may elucidate their relationship to 22q13.3 deletion phenotypes.
authors.affiliation: Committee on Neurobiology, The University of Chicago, Chicago, IL, USA.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Aldinger
authors.forename: Jillene
authors.initials: J
authors.lastname: Kogan
authors.forename: Virginia
authors.initials: V
authors.lastname: Kimonis
authors.forename: Bridget
authors.initials: B
authors.lastname: Fernandez
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.forename: Brian
authors.initials: B
authors.lastname: Chung
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Millen
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.forename: William B
authors.initials: WB
authors.lastname: Dobyns
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D001321:Autistic Disorder / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000002:abnormalities*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000175:diagnosis* / Q000235:genetics; D002874:Chromosome Mapping; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D056726:Genetic Association Studies; D056426:Genetic Loci; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C408376:MAPK8IP2 protein, human; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human