Skip to main content

Advertisement

SpringerLink
Log in

Establishing a reference group for distal 18q-: clinical description and molecular basis

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Although constitutional chromosome abnormalities have been recognized since the 1960s, clinical characterization and development of treatment options have been hampered by their obvious genetic complexity and relative rarity. Additionally, deletions of 18q are particularly heterogeneous, with no two people having the same breakpoints. We identified 16 individuals with deletions that, despite unique breakpoints, encompass the same set of genes within a 17.6-Mb region. This group represents the most genotypically similar group yet identified with distal 18q deletions. As the deletion is of average size when compared with other 18q deletions, this group can serve as a reference point for the clinical and molecular description of this condition. We performed a thorough medical record review as well as a series of clinical evaluations on 14 of the 16 individuals. Common functional findings included developmental delays, hypotonia, growth hormone deficiency, and hearing loss. Structural anomalies included foot anomalies, ear canal atresia/stenosis, and hypospadias. The majority of individuals performed within the low normal range of cognitive ability but had more serious deficits in adaptive abilities. Of interest, the hemizygous region contains 38 known genes, 26 of which are sufficiently understood to tentatively determine dosage sensitivity. Published data suggest that 20 are unlikely to cause an abnormal phenotype in the hemizygous state and five are likely to be dosage sensitive: TNX3, NETO1, ZNF407, TSHZ1, and NFATC. A sixth gene, ATP9B, may be conditionally dosage sensitive. Not all distal 18q- phenotypes can be attributed to these six genes; however, this is an important advance in the molecular characterization of 18q deletions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Bayley N (1993) Bayley scales of infant development, 2nd edn. The Psychological Corporation, San Antonio

    Google Scholar 

  • Bayley N (2006) Bayley scales of Infant and toddler development, 3rd edn. Harcourt Assessment Inc., San Antonio

    Google Scholar 

  • Chao R, Nevin L, Agarwal P, Riemer J, Bai X, Delaney A, Akana M, JimenezLopez N, Bardakjian T, Schneider A, Chassaing N, Schorderet DF, FitzPatrick D, Kwok PY, Ellgaard L, Gould DB, Zhang Y, Malicki J, Baier H, Slavotinek A (2010) A male with unilateral microphthalmia reveals a role for TMX3 in eye development. PLoS ONE 5(5):e10565. doi:10.1371/journal.pone.0010565

    Article  PubMed Central  PubMed  Google Scholar 

  • Cody JD, Hale DE (2011) Linking chromosome abnormality and copy number variation. Am J Med Genet A 155A(3):469–475. doi:10.1002/ajmg.a.33849

    Article  PubMed  Google Scholar 

  • Cody JD, Ghidoni PD, DuPont BR, Hale DE, Hilsenbeck SG, Stratton RF, Hoffman DS, Muller S, Schaub RL, Leach RJ, Kaye CI (1999) Congenital anomalies and anthropometry of 42 individuals with deletions of chromosome 18q. Am J Med Genet 85(5):455–462

    Article  CAS  PubMed  Google Scholar 

  • Cody JD, Sebold C, Malik A, Heard P, Carter E, Crandall A, Soileau B, Semrud-Clikeman M, Cody CM, Hardies LJ, Li J, Lancaster J, Fox PT, Stratton RF, Perry B, Hale DE (2007) Recurrent interstitial deletions of proximal 18q: a new syndrome involving expressive speech delay. Am J Med Genet Part A 143:1181–1190

    Article  Google Scholar 

  • Cody JD, Heard P, Crandall AC, Carter EM, Li J, Hardies LJ, Lancaster J, Perry B, Stratton RF, Sebold C, Schaub RL, Soileau B, Hill A, Hasi M, Fox PT, Hale DE (2009a) Narrowing critical regions and determining penetrance for selected 18q- phenotypes. Am J Med Genet 149A:1421–1430. doi:10.1002/ajmg.a.32899

    Article  CAS  PubMed  Google Scholar 

  • Cody JD, Carter EM, Sebold C, Heard PL, Hale DE (2009b) A gene dosage map of Chromosome 18: a map with clinical utility. Genet Med 11(11):778–782. doi:10.1097/GIM.0b013e3181b6573d

    Article  PubMed  Google Scholar 

  • Daviss WB, O’Donnell L, Soileau BT, Heard P, Carter E, Pliszka SR, Gelfond JA, Hale DE, Cody JD (2013) Mood disorders in individuals with distal 18q deletions. Am J Med Genet B Neuropsychiatr Genet. doi:10.1002/ajmg.b.32197

  • Elliott CD (1990) Differential ability scales. The Psychological Corporation, San Antonio

    Google Scholar 

  • Elliott CD (2007) Differential ability scales, 2nd edn. Harcourt Assessment, Inc, San Antonio

    Google Scholar 

  • Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, Koller DL, Li G, Liu CT, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges-Armstrong LM, Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, González-Macías J, Kähönen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren Ö, Lorenc RS, Marc J, Mellström D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van Hul W, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gómez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw KT, Lehtimäki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HA, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AW, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature Genet 44:491–501. doi:10.1038/ng.2249

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Eudy JD, Pickering DL, Lutz R, Platt K, Dave BJ, Olney AH, Sanger WG (2010) 18q22.3 > 18q23 deletion syndrome and cleft palate. Am J Med Genet Part A 152A:1046–1048. doi:10.1002/ajmg.a.33336

    Article  PubMed  Google Scholar 

  • Feenstra I, Vissers LELM, Pennings RJE, Nillessen W, Pfundt R, Kunst HP, Admiraal RJ, Veltman JA, van Ravenswaaij-Arts CM, Brunner HG, Cremers CWRJ (2011) Disruption of teashirt zinc finger homeobox 1 is associated with congenital aural atresia in humans. An J Hum Genet 89:813–819. doi:10.1016/j.ajhg.2011.11.008

    Article  CAS  Google Scholar 

  • Gilliam JE (1995) Gilliam autism rating scale. Pro-Ed Inc., Austin

    Google Scholar 

  • Gilliam JE (2001) Gilliam asperger’s disorder scale. Pro-Ed Inc., Austin

    Google Scholar 

  • Gilliam JE (2006) Gilliam autism rating scale, 2nd edn. Pro-Ed, Inc., Austin

    Google Scholar 

  • Gioia GA, Isquith PK, Guy SC, Kenworthy L (2000) Behavior rating inventory of executive function. Psychological Assessment Resources Inc., Lutz

    Google Scholar 

  • Hale DE, Cody JD, Baillargeon J, Schaub R, Danney MM, Leach RJ (2000) The spectrum of growth abnormalities in children with 18q deletions. J Clin Endocrinol Metab 85(12):4450–4454

    CAS  PubMed  Google Scholar 

  • Hasi M, Soileau BT, Sebold C, Hill A, Hale DE, O’Donnell L, Cody JD (2011) The role of the TCF4 gene in the phenotype of individuals with 18q segmental deletions. Hum Genet 130:777–787. doi:10.1007/s00439-011-1020-y

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Heard PL, Carter EM, Crandall AC, Sebold C, Hale DE, Cody JD (2009) High resolution genomic analysis of 18q– using oligo-microarray comparative genomic hybridization (aCGH). Am J Med Genet 149A:1431–1437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Linnankivi T, Tienari P, Somer M, Kähkönen M, Lönnqvist T, Valanne L, Pihko H (2006) 18q deletions: clinical, molecular, and brain MRI findings of 14 individuals. Am J Med Genet 140A:331–339

    Article  Google Scholar 

  • Margarit E, Morales C, Rodriguez L, Monne R, Badenas C, Soler A, Clusellas N, Mademont I, Sanchez A (2012) Familial 4.8 Mb deletion on 18q23 associated with growth hormone insufficiency and phenotypic variability. Am J Med Genet 158A:611–616. doi:10.1002/ajmg.a.34221

    Article  PubMed  Google Scholar 

  • Mark PR, Radlinski BC, Core N, Fryer A, Kirk EP, Haldeman-Englert CR (2013) Narrowing the critical region for congenital vertical talus in patients with interstitial 18q deletions. Am J Med Genet A 161(5):1117–1121. doi:10.1002/ajmg.a.35791

    Article  CAS  Google Scholar 

  • Martin M, Hiltner TD, Wood JC, Fraser SE, Jacobs RE, Readhead C (2006) Myelin deficiencies visualized in vivo: visually evoked potentials and T2-weighted magnetic resonance images of shiverer mutant and wild-type mice. J Neurosci Res 84(8):1716–1726

    Article  CAS  PubMed  Google Scholar 

  • Ng D, Pitcher GM, Szilard RK, Sertié A, Kanisek M, Clapcote SJ, Lipina T, Kalia LV, Joo D, McKerlie C, Cortez M, Roder JC, Salter MW, McInnes RR (2009) Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol 7(2):e41. doi:10.1371/journal.pbio.1000041

    Article  PubMed  Google Scholar 

  • Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu XQ, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, Van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466(7304):368–372. doi:10.1038/nature09146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ren CM, Liang Y, Wei F, Zhang YN, Zhong SQ, Gu H, Dong XS, Huang YY, Ke H, Son XM, Tang D, Chen Z (2013) Balanced translocation t (3;18) (p13;q22.3) and points mutation in the ZNF407 gene detected in patients with both moderate non-syndromic intellectual disability and autism. Biochim Biophys Acta 1832(3):431–438. doi:10.1016/j.bbadis.2012.11.009

    Article  CAS  PubMed  Google Scholar 

  • Reynolds CR, Kamphaus RW (1992) Behavior assessment system for children. American Guidance Service Inc., Circle Pines

    Google Scholar 

  • Reynolds CR, Kamphaus RW (2004) Behavior assessment system for children, 2nd edn. AGS Publishing, Circle Pines

    Google Scholar 

  • Roth RM, Isquith PK, Gioia GA (2005) Behavior rating inventory of executive function—adult version. Psychological Assessment Resources Inc., Lutz

    Google Scholar 

  • Sparrow SS, Balla DA, Cicchetti DV (1984) Vineland adaptive behavior scales. American Guidance Service Inc., Circle Pines

    Google Scholar 

  • Sparrow SS, Cicchetti DV, Balla DA (2005) Vineland adaptive behavior scales, 2nd edn. AGS Publishing, Circle Pines

    Google Scholar 

  • van Trier DC, Feenstra I, Bot P, de Leeuw N, Draaisma JMTh (2013) Cardiac anomalies in individuals with the 18q deletion syndrome. Eur J Med Genet 56(8):426–431. doi:10.1016/j.ejmg.2013.05.002

    Google Scholar 

  • Wechsler D (1997) Wechsler adult intelligence scale, 3rd edn. The Psychological Corporation, San Antonio

    Google Scholar 

  • Wechsler D (2008) Wechsler adult intelligence scale, 4th edn. Pearson, San Antonio

    Google Scholar 

Download references

Acknowledgments

Foremost, the authors wish to thank the families who are participants in the Chromosome 18 Clinical Research Center, for their ongoing commitment to this work and to our shared vision of a smoother road for future families. This work was primarily funded by the Chromosome 18 Registry and Research Society and the MacDonald family. Additional support was provided through the UTHSCSA, Institute for the Integration of Medicine and Science (UL1TR000149 NCATS/NIH).

Author information

Author notes

  1. Robert F. Stratton

    Present address: Driscoll Children’s Hospital, Corpus Christi, TX, USA

Authors and Affiliations

  1. Department of Pediatrics, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Jannine D. Cody, Minire Hasi, Bridgette Soileau, Patricia Heard, Erika Carter, Courtney Sebold, Louise O’Donnell, Robert F. Stratton & Daniel E. Hale

  2. Department of Psychiatry, University of Texas Health Science Center, San Antonio, USA

    Louise O’Donnell

  3. The Chromosome 18 Registry and Research Society, San Antonio, TX, USA

    Jannine D. Cody

  4. Ear Medical Group, San Antonio, TX, USA

    Brian Perry

Authors
  1. Jannine D. Cody
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Minire Hasi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bridgette Soileau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patricia Heard
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Erika Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Courtney Sebold
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Louise O’Donnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Brian Perry
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Robert F. Stratton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Daniel E. Hale
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jannine D. Cody.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 96 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cody, J.D., Hasi, M., Soileau, B. et al. Establishing a reference group for distal 18q-: clinical description and molecular basis. Hum Genet 133, 199–209 (2014). https://doi.org/10.1007/s00439-013-1364-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-013-1364-6

Keywords

Search

Navigation