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Genotype–phenotype correlation in interstitial 6q deletions: a report of 12 new cases

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Abstract

Interstitial deletions of 6q are associated with variable phenotypes, including growth retardation, dysmorphic features, upper limb malformations, and Prader–Willi (PW)-like features. Only a minority of cases in the literature have been characterized with high resolution techniques, making genotype–phenotype correlations difficult. We report 12 individuals with overlapping, 200-kb to 16.4-Mb interstitial deletions within 6q15q22.33 characterized by microarray-based comparative genomic hybridization to better correlate deletion regions with specific phenotypes. Four individuals have a PW-like phenotype, though only two have deletion of SIM1, the candidate gene for this feature. Therefore, other genes on 6q may contribute to this phenotype including multiple genes on 6q16 and our newly proposed candidate, the transcription cofactor gene VGLL2 on 6q22.2. Two individuals present with movement disorders as a major feature, and ataxia is present in a third. The 4.1-Mb 6q22.1q22.2 critical region for movement disorders includes the cerebellar-expressed candidate gene GOPC. Observed brain malformations include thick corpus callosum in two subjects, cerebellar vermal hypoplasia in two subjects, and cerebellar atrophy in one subject. Seven subjects' deletions overlap a ~250-kb cluster of four genes on 6q22.1 including MARCKS, HDAC2, and HS3ST5, which are involved in neural development. Two subjects have only this gene cluster deleted, and one deletion was apparently de novo, suggesting at least one of these genes plays an important role in development. Although the phenotypes associated with 6q deletions can vary, using overlapping deletions to delineate critical regions improves genotype–phenotype correlation for interstitial 6q deletions.

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Acknowledgements

We thank all of the patients and their families for their participation in this project. We thank Erin Dodge and Aaron Theisen (Signature Genomics) for their extensive editorial assistance on this manuscript. We thank Beth Torchia (Signature Genomics) for her assistance reviewing microarray data. Finally, we thank Shannon Jeddi (Genetic Medicine Central California) for her assistance gathering clinical information.

Conflict of interest

JAR, JWE, BCB, and LGS are employees of Signature Genomic Laboratories, PerkinElmer, Inc.

Author information

Author notes

  1. Kandamurugu Manickam

    Present address: Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH, 43205, USA

  2. Bryce Heese

    Present address: Children’s Mercy Hospital, 2401 Gillham Rd., Kansas City, MO, 64108, USA

  3. Jay W. Ellison

    Present address: Signature Genomic Laboratories, PerkinElmer, Inc., 2820 N. Astor St., Spokane, WA, 99207, USA

  4. Trilochan Sahoo

    Present address: Quest Diagnostics Nichols Institute, 33608 Ortega Hwy., San Juan Capistrano, CA, 92675, USA

  5. Allen N. Lamb

    Present address: ARUP Laboratories, University of Utah, 500 Chipeta Way, Salt Lake City, UT, 84108, USA

Authors and Affiliations

  1. Signature Genomic Laboratories, PerkinElmer, Inc., 2820 N. Astor St., Spokane, WA, 99207, USA

    Jill A. Rosenfeld, Trilochan Sahoo, Allen N. Lamb, Blake C. Ballif & Lisa G. Shaffer

  2. Neurogenetics Unit, Montreal Neurological Hospital & Institute, 3801 University St., Montreal, Quebec, H3A 2B4, Canada

    Dina Amrom & Eva Andermann

  3. Epilepsy Service, Montreal Neurological Hospital & Institute, 3801 University St., Montreal, Quebec, H3A 2B4, Canada

    Frederick Andermann & Martin Veilleux

  4. Department of Neurology & Neurosurgery, McGill University, 3801 University St., Montreal, Quebec, H3A 2B4, Canada

    Dina Amrom, Eva Andermann, Frederick Andermann & Martin Veilleux

  5. Department of Human Genetics, McGill University, Stewart Biology Bld., 1205 Dr Penfield Ave., Rm. N5-13, Montreal, Quebec, H3A 1B1, Canada

    Eva Andermann

  6. Department of Pediatrics, McGill University, 2300 Tupper St., Rm. C-426, Montreal, Quebec, H3H 1P3, Canada

    Frederick Andermann

  7. Genetic Medicine Central California/UCSF, 155 N. Fresno St., Fresno, CA, 93701, USA

    Cynthia Curry & Jamie Fisher

  8. Children’s Hospital, New Orleans, 200 Henry Clay Avenue, New Orleans, LA, 70118, USA

    Stephen Deputy

  9. Department of Pediatrics, University of North Carolina, School of Medicine, 260 MacNider Bld., Chapel Hill, NC, 27599, USA

    Arthur S. Aylsworth, Cynthia M. Powell & Kandamurugu Manickam

  10. Department of Genetics, University of North Carolina-Chapel Hill, 120 Mason Farm Rd., Chapel Hill, NC, 27599, USA

    Arthur S. Aylsworth, Cynthia M. Powell & Kandamurugu Manickam

  11. Shands Hospital at University of Florida, 1600 S.W. Archer Rd, Gainesville, FL, 32608, USA

    Bryce Heese & Melissa Maisenbacher

  12. TC Thompson Children’s Hospital, 910 Blackford St., Chattanooga, TN, 37403, USA

    Cathy Stevens

  13. Mayo Clinic, 200 First St., S.W., Rochester, MN, 55905, USA

    Jay W. Ellison

  14. Medical Genetics, Children’s Hospital at Dartmouth, Dartmouth Hitchcock Medical Center, One Medical Center Dr., Lebanon, NH, 03756, USA

    Sheila Upton & John Moeschler

  15. Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut St., Indianapolis, IN, 46202, USA

    Wilfredo Torres-Martinez & Abby Stevens

  16. Department of Pediatrics, Division of Genetics, Children’s Hospital at Montefiore, 3415 Bainbridge Ave., Bronx, NY, 10467, USA

    Robert Marion & Elaine Maria Pereira

  17. Department of Molecular Genetics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY, 10461, USA

    Melanie Babcock & Bernice Morrow

  18. Department of Neurology, University of Washington, and Seattle Children’s Research Institute, 1900 9th Ave, Seattle, WA, 98101, USA

    Alex R. Paciorkowski

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  1. Jill A. Rosenfeld
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Correspondence to Lisa G. Shaffer.

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Rosenfeld, J.A., Amrom, D., Andermann, E. et al. Genotype–phenotype correlation in interstitial 6q deletions: a report of 12 new cases. Neurogenetics 13, 31–47 (2012). https://doi.org/10.1007/s10048-011-0306-5

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