title: High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44.
abstract: Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.
authors.affiliation: Signature Genomic Laboratories, Spokane, WA 99207, USA. blake.ballif@perkinelmer.com
authors.forename: Blake C
authors.initials: BC
authors.lastname: Ballif
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.forename: Ryan
authors.initials: R
authors.lastname: Traylor
authors.forename: Aaron
authors.initials: A
authors.lastname: Theisen
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Bader
authors.forename: Roger L
authors.initials: RL
authors.lastname: Ladda
authors.forename: Susan L
authors.initials: SL
authors.lastname: Sell
authors.forename: Michelle
authors.initials: M
authors.lastname: Steinraths
authors.forename: Urvashi
authors.initials: U
authors.lastname: Surti
authors.forename: Marianne
authors.initials: M
authors.lastname: McGuire
authors.forename: Shelley
authors.initials: S
authors.lastname: Williams
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Farrell
authors.forename: James
authors.initials: J
authors.lastname: Filiano
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Schnur
authors.forename: Lauren B
authors.initials: LB
authors.lastname: Coffey
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Tervo
authors.forename: Tracy
authors.initials: T
authors.lastname: Stroud
authors.forename: Michael
authors.initials: M
authors.lastname: Marble
authors.forename: Michael
authors.initials: M
authors.lastname: Netzloff
authors.forename: Kristen
authors.initials: K
authors.lastname: Hanson
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Aylsworth
authors.forename: J S
authors.initials: JS
authors.lastname: Bamforth
authors.forename: Deepti
authors.initials: D
authors.lastname: Babu
authors.forename: Dmitriy M
authors.initials: DM
authors.lastname: Niyazov
authors.forename: J Britt
authors.initials: JB
authors.lastname: Ravnan
authors.forename: Roger A
authors.initials: RA
authors.lastname: Schultz
authors.forename: Allen N
authors.initials: AN
authors.lastname: Lamb
authors.forename: Beth S
authors.initials: BS
authors.lastname: Torchia
authors.forename: Bassem A
authors.initials: BA
authors.lastname: Bejjani
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Shaffer
mesh_terms: D000015:Abnormalities, Multiple; D000293:Adolescent; D061085:Agenesis of Corpus Callosum / Q000235:genetics* / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D005260:Female; D005796:Genes / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D012640:Seizures / Q000235:genetics* / Q000473:pathology; D013577:Syndrome
chemical_list: D015415:Biomarkers