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Human Genetics

, Volume 131, Issue 1, pp 145–156 | Cite as

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

  • Blake C. Ballif
  • Jill A. Rosenfeld
  • Ryan Traylor
  • Aaron Theisen
  • Patricia I. Bader
  • Roger L. Ladda
  • Susan L. Sell
  • Michelle Steinraths
  • Urvashi Surti
  • Marianne McGuire
  • Shelley Williams
  • Sandra A. Farrell
  • James Filiano
  • Rhonda E. Schnur
  • Lauren B. Coffey
  • Raymond C. Tervo
  • Tracy Stroud
  • Michael Marble
  • Michael Netzloff
  • Kristen Hanson
  • Arthur S. Aylsworth
  • J. S. Bamforth
  • Deepti Babu
  • Dmitriy M. Niyazov
  • J. Britt  Ravnan
  • Roger A. Schultz
  • Allen N. Lamb
  • Beth S. Torchia
  • Bassem A. Bejjani
  • Lisa G. Shaffer
Original Investigation

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.

Keywords

Bacterial Artificial Chromosome Critical Region Intellectual Disability Microcephaly Terminal Deletion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We are grateful to many clinicians, counselors, and laboratory directors for their assistance with collecting the information in this report, including Dr. Miriam Kalichman and Dr. David Aughton. We are also very grateful to the patients and their families for supporting this research.

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Blake C. Ballif
    • 1
  • Jill A. Rosenfeld
    • 1
  • Ryan Traylor
    • 1
  • Aaron Theisen
    • 1
  • Patricia I. Bader
    • 2
  • Roger L. Ladda
    • 3
  • Susan L. Sell
    • 3
  • Michelle Steinraths
    • 4
  • Urvashi Surti
    • 5
  • Marianne McGuire
    • 6
  • Shelley Williams
    • 6
  • Sandra A. Farrell
    • 7
  • James Filiano
    • 8
  • Rhonda E. Schnur
    • 9
  • Lauren B. Coffey
    • 9
  • Raymond C. Tervo
    • 10
  • Tracy Stroud
    • 11
  • Michael Marble
    • 12
  • Michael Netzloff
    • 13
  • Kristen Hanson
    • 13
  • Arthur S. Aylsworth
    • 14
  • J. S. Bamforth
    • 15
  • Deepti Babu
    • 15
  • Dmitriy M. Niyazov
    • 16
  • J. Britt  Ravnan
    • 1
  • Roger A. Schultz
    • 1
  • Allen N. Lamb
    • 1
  • Beth S. Torchia
    • 1
  • Bassem A. Bejjani
    • 1
  • Lisa G. Shaffer
    • 1
  1. 1.Signature Genomic LaboratoriesSpokaneUSA
  2. 2.Northeast Indiana Genetic CounselingFt. WayneUSA
  3. 3.Penn State Hershey Medical CenterHersheyUSA
  4. 4.Victoria General HospitalVictoriaCanada
  5. 5.Pittsburgh Cytogenetics Laboratory, Magee-Womens Hospital of UPMCUniversity of PittsburghPittsburghUSA
  6. 6.Children’s Hospital of PittsburghPittsburghUSA
  7. 7.Credit Valley HospitalMississaugaCanada
  8. 8.Dartmouth-Hitchcock Medical CenterLebanonUSA
  9. 9.Cooper University Hospital/Robert Wood Johnson Medical SchoolCamdenUSA
  10. 10.Gillette Children’s Specialty HealthcareSt. PaulUSA
  11. 11.University of MissouriColumbiaUSA
  12. 12.Louisiana State University Health Sciences Center/Children’s Hospital of New OrleansNew OrleansUSA
  13. 13.Michigan State UniversityEast LansingUSA
  14. 14.Departments of Pediatrics and GeneticsUniversity of North Carolina-Chapel HillChapel HillUSA
  15. 15.University of AlbertaEdmontonCanada
  16. 16.Ochsner Clinic FoundationNew OrleansUSA

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