Skip to main content
SpringerLink
Log in

Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity

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

Abstract

We previously reported a Vietnamese-American family with isolated autosomal dominant occipital cephalocele. Upon further neuroimaging studies, we have recharacterized this condition as autosomal dominant Dandy-Walker with occipital cephalocele (ADDWOC). A similar ADDWOC family from Brazil was also recently described. To determine the genetic etiology of ADDWOC, we performed genome-wide linkage analysis on members of the Vietnamese-American and Brazilian pedigrees. Linkage analysis of the Vietnamese-American family identified the ADDWOC causative locus on chromosome 2q36.1 with a multipoint parametric LOD score of 3.3, while haplotype analysis refined the locus to 1.1 Mb. Sequencing of the five known genes in this locus did not identify any protein-altering mutations. However, a terminal deletion of chromosome 2 in a patient with an isolated case of Dandy-Walker malformation also encompassed the 2q36.1 chromosomal region. The Brazilian pedigree did not show linkage to this 2q36.1 region. Taken together, these results demonstrate a locus for ADDWOC on 2q36.1 and also suggest locus heterogeneity for ADDWOC.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Bassuk AG, McLone D, Bowman R, Kessler JA (2004) Autosomal dominant occipital cephalocele. Neurology 62:1888–1890

    PubMed  Google Scholar 

  • Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, Celli J, van Beusekom E, van der Zwaag B, Kayserili H, Merlini L, Chitayat D, Dobyns WB, Cormand B, Lehesjoki AE, Cruces J, Voit T, Walsh CA, van Bokhoven H, Brunner HG (2002) Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 71:1033–1043

    Article  Google Scholar 

  • Bien-Willner GA, Stankiewicz P, Lupski JR (2007) SOX9cre1, a cis-acting regulatory element located 1.1 Mb upstream of SOX9, mediates its enhancement through the SHH pathway. Hum Mol Genet 16:1143–1156

    Article  PubMed  CAS  Google Scholar 

  • Carvalho DR, Giuliani LR, Simao GN, Santos AC, Pina-Neto JM (2006) Autosomal dominant atretic cephalocele with phenotype variability: report of a Brazilian family with six affected in four generations. Am J Med Genet A 140:1458–1462

    PubMed  CAS  Google Scholar 

  • Descipio C, Schneider L, Young TL, Wasserman N, Yaeger D, Lu F, Wheeler PG, Williams MS, Bason L, Jukofsky L, Menon A, Geschwindt R, Chudley AE, Saraiva J, Schinzel AA, Guichet A, Dobyns WE, Toutain A, Spinner NB, Krantz ID (2005) Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Am J Med Genet A 134:3–11

    PubMed  Google Scholar 

  • Dixon-Salazar T, Silhavy JL, Marsh SE, Louie CM, Scott LC, Gururaj A, Al-Gazali L, Al-Tawari AA, Kayserili H, Sztriha L, Gleeson JG (2004) Mutations in the AHI1 gene, encoding jouberin, cause Joubert syndrome with cortical polymicrogyria. Am J Hum Genet 75:979–987

    Article  PubMed  CAS  Google Scholar 

  • Ferland RJ, Eyaid W, Collura RV, Tully LD, Hill RS, Al-Nouri D, Al-Rumayyan A, Topcu M, Gascon G, Bodell A, Shugart YY, Ruvolo M, Walsh CA (2004) Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome. Nat Genet 36:1008–1013

    Article  PubMed  CAS  Google Scholar 

  • Franz T, Kothary R (1993) Characterization of the neural crest defect in Splotch (Sp1H) mutant mice using a lacZ transgene. Brain Res Dev Brain Res 72:99–105

    Article  PubMed  CAS  Google Scholar 

  • Grinberg I, Northrup H, Ardinger H, Prasad C, Dobyns WB, Millen KJ (2004) Heterozygous deletion of the linked genes ZIC1 and ZIC4 is involved in Dandy-Walker malformation. Nat Genet 36:1053–1055

    Article  PubMed  CAS  Google Scholar 

  • Gudbjartsson DF, Thorvaldsson T, Kong A, Gunnarsson G, Ingolfsdottir A (2005) Allegro version 2. Nat Genet 37:1015–1016

    Article  PubMed  CAS  Google Scholar 

  • Gurnett CA, Bowcock AM, Dietz FR, Morcuende JA, Murray JC, Dobbs MB (2007) Two novel point mutations in the long-range SHH enhancer in three families with triphalangeal thumb and preaxial polydactyly. Am J Med Genet A 143:27–32

    PubMed  Google Scholar 

  • Hart MN, Malamud N, Ellis WG (1972) The Dandy-Walker syndrome. A clinicopathological study based on 28 cases. Neurology 22:771–780

    PubMed  CAS  Google Scholar 

  • Hoffmann K, Lindner TH (2005) easyLINKAGE-Plus-automated linkage analyses using large-scale SNP data. Bioinformatics 21:3565–3567

    Article  PubMed  CAS  Google Scholar 

  • Hol FA, Hamel BC, Geurds MP, Mullaart RA, Barr FG, Macina RA, Mariman EC (1995) A frameshift mutation in the gene for PAX3 in a girl with spina bifida and mild signs of Waardenburg syndrome. J Med Genet 32:52–56

    Article  PubMed  CAS  Google Scholar 

  • Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951

    Article  PubMed  CAS  Google Scholar 

  • Jeong Y, El-Jaick K, Roessler E, Muenke M, Epstein DJ (2006) A functional screen for sonic hedgehog regulatory elements across a 1 Mb interval identifies long-range ventral forebrain enhancers. Development 133:761–772

    Article  PubMed  CAS  Google Scholar 

  • Keller C, Hansen MS, Coffin CM, Capecchi MR (2004) Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin. Genes Dev 18:2608–2613

    Article  PubMed  CAS  Google Scholar 

  • Kujat A, Veith VP, Faber R, Froster UG (2007) Prenatal diagnosis and genetic counseling in a case of spina bifida in a family with Waardenburg syndrome type I. Fetal Diagn Ther 22:155–158

    Article  PubMed  Google Scholar 

  • Kyttala M, Tallila J, Salonen R, Kopra O, Kohlschmidt N, Paavola-Sakki P, Peltonen L, Kestila M (2006) MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 38:155–157

    Article  PubMed  CAS  Google Scholar 

  • Lu W, Zhu H, Wen S, Laurent C, Shaw GM, Lammer EJ, Finnell RH (2007) Screening for novel PAX3 polymorphisms and risks of spina bifida. Birth Defects Res A Clin Mol Teratol 79:45–49

    Article  PubMed  CAS  Google Scholar 

  • Mansouri A, Stoykova A, Gruss P (1994) Pax genes in development. J Cell Sci Suppl 18:35–42

    PubMed  CAS  Google Scholar 

  • Mansouri A, Hallonet M, Gruss P (1996) Pax genes and their roles in cell differentiation and development. Curr Opin Cell Biol 8:851–857

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Lage JF, Martinez Robledo A, Poza M, Sola J (1996) Familial occurrence of atretic cephaloceles. Pediatr Neurosurg 25:260–264

    Article  PubMed  CAS  Google Scholar 

  • Mavrogiannis LA, Antonopoulou I, Baxova A, Kutilek S, Kim CA, Sugayama SM, Salamanca A, Wall SA, Morriss-Kay GM, Wilkie AO (2001) Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Nat Genet 27:17–18

    Article  PubMed  CAS  Google Scholar 

  • Moase CE, Trasler DG (1989) Spinal ganglia reduction in the splotch-delayed mouse neural tube defect mutant. Teratology 40:67–75

    Article  PubMed  CAS  Google Scholar 

  • Murray JC, Johnson JA, Bird TD (1985) Dandy-Walker malformation: etiologic heterogeneity and empiric recurrence risks. Clin Genet 28:272–283

    Article  PubMed  CAS  Google Scholar 

  • Nye JS, Balkin N, Lucas H, Knepper PA, McLone DG, Charrow J (1998) Myelomeningocele and Waardenburg syndrome (type 3) in patients with interstitial deletions of 2q35 and the PAX3 gene: possible digenic inheritance of a neural tube defect. Am J Med Genet 75:401–408

    Article  PubMed  CAS  Google Scholar 

  • O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266

    Article  PubMed  CAS  Google Scholar 

  • Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, McDonald R, Eddy A, Chance PF, Glass IA (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 75:82–91

    Article  PubMed  CAS  Google Scholar 

  • Reddy AT, Hedlund GL, Percy AK (2000) Enlarged parietal foramina: association with cerebral venous and cortical anomalies. Neurology 54:1175–1178

    PubMed  CAS  Google Scholar 

  • Robert A (1954) Analysis of the developmental effects of a lethal mutation in the house mouse. J Exp Zool 127:305–329

    Article  Google Scholar 

  • Sertie AL, Sossi V, Camargo AA, Zatz M, Brahe C, Passos-Bueno MR (2000) Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum Mol Genet 9:2051–2058

    Article  PubMed  CAS  Google Scholar 

  • Shim SH, Wyandt HE, McDonald-McGinn DM, Zackai EZ, Milunsky A (2004) Molecular cytogenetic characterization of multiple intrachromosomal rearrangements of chromosome 2q in a patient with Waardenburg’s syndrome and other congenital defects. Clin Genet 66:46–52

    Article  PubMed  CAS  Google Scholar 

  • Smith UM, Consugar M, Tee LJ, McKee BM, Maina EN, Whelan S, Morgan NV, Goranson E, Gissen P, Lilliquist S, Aligianis IA, Ward CJ, Pasha S, Punyashthiti R, Malik Sharif S, Batman PA, Bennett CP, Woods CG, McKeown C, Bucourt M, Miller CA, Cox P, Algazali L, Trembath RC, Torres VE, Attie-Bitach T, Kelly DA, Maher ER, Gattone VH II, Harris PC, Johnson CA (2006) The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat. Nat Genet 38:191–196

    Article  PubMed  CAS  Google Scholar 

  • Tal Y, Freigang B, Dunn HG, Durity FA, Moyes PD (1980) Dandy-Walker syndrome: analysis of 21 cases. Dev Med Child Neurol 22:189–201

    Article  PubMed  CAS  Google Scholar 

  • Tassabehji M, Read AP, Newton VE, Patton M, Gruss P, Harris R, Strachan T (1993) Mutations in the PAX3 gene causing Waardenburg syndrome type 1 and type 2. Nat Genet 3:26–30

    Article  PubMed  CAS  Google Scholar 

  • Terwilliger JD, Ott J (1994) Handbook of human genetic linkage. Johns Hopkins University Press, Baltimore

    Google Scholar 

  • Terzic J, Saraga-Babic M (1999) Expression pattern of PAX3 and PAX6 genes during human embryogenesis. Int J Dev Biol 43:501–508

    PubMed  CAS  Google Scholar 

  • Thiele H, Nurnberg P (2005) HaploPainter: a tool for drawing pedigrees with complex haplotypes. Bioinformatics 21:1730–1732

    Article  PubMed  CAS  Google Scholar 

  • Valente EM, Silhavy JL, Brancati F, Barrano G, Krishnaswami SR, Castori M, Lancaster MA, Boltshauser E, Boccone L, Al-Gazali L, Fazzi E, Signorini S, Louie CM, Bellacchio E, Bertini E, Dallapiccola B, Gleeson JG (2006) Mutations in CEP290, which encodes a centrosomal protein, cause pleiotropic forms of Joubert syndrome. Nat Genet 38:623–625

    Article  PubMed  CAS  Google Scholar 

  • Valente KD, Valente M (2004) Epilepsy in one family with parietal foramina: an incidental finding? J Neurol Neurosurg Psychiatry 75:1648–1649

    Article  PubMed  CAS  Google Scholar 

  • van Reeuwijk J, Janssen M, van den Elzen C, Beltran-Valero de Bernabe D, Sabatelli P, Merlini L, Boon M, Scheffer H, Brockington M, Muntoni F, Huynen MA, Verrips A, Walsh CA, Barth PG, Brunner HG, van Bokhoven H (2005) POMT2 mutations cause alpha-dystroglycan hypoglycosylation and Walker-Warburg syndrome. J Med Genet 42:907–912

    Article  PubMed  CAS  Google Scholar 

  • Vega H, Waisfisz Q, Gordillo M, Sakai N, Yanagihara I, Yamada M, van Gosliga D, Kayserili H, Xu C, Ozono K, Jabs EW, Inui K, Joenje H (2005) Roberts syndrome is caused by mutations in ESCO2, a human homolog of yeast ECO1 that is essential for the establishment of sister chromatid cohesion. Nat Genet 37:468–470

    Article  PubMed  CAS  Google Scholar 

  • Waters BL, Allen EF, Gibson PC, Johnston T (1993) Autopsy findings in a severely affected infant with a 2q terminal deletion. Am J Med Genet 47:1099–1103

    Article  PubMed  CAS  Google Scholar 

  • Zhao X, Chi L, Zhao Y, Chi Z (2007) A five-generation family with occipital encephalocele. Clin Neurol Neurosurg 109:81–84

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Hoang Le and Dung Tri Pham, HoChiMinh City Hospital, HoChiMinh City, Vietnam, for their assistance in patient recruitment. A.J. is supported by NIH pre-doctoral NRSA grant F30-NS51962. K.A.A. is supported by NIH Pre-doctoral grant GM007839–26. A.G.B. is supported by NIH grant K08-NS48174.

Author information

Authors and Affiliations

  1. Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Ali Jalali, John A. Kessler & Alexander G. Bassuk

  2. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Ajit Chary & Alexander G. Bassuk

  3. Department of Neurosurgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    David G. Mclone & Robin M. Bowman

  4. Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Nadereh Jafari

  5. Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Eric J. Russell, John Curran & Pam Nguyen

  6. Committee on Neurobiology, The University of Chicago, Chicago, IL, USA

    Kimberly A. Aldinger

  7. Departments of Human Genetics and Neurology, The University of Chicago, Chicago, IL, USA

    William B. Dobyns & Kathleen J. Millen

  8. HoChiMinh City Hospital, HoChiMinh City, Vietnam

    Luan Cong Le

  9. Department of Paediatrics, Bristol Royal Hospital for Children, Bristol, UK

    Phillip Jardine

  10. Department of Clinical Genetics, St Michael’s Hospital, Bristol, UK

    Ruth Newbury-Ecob

  11. Department of Paediatrics, Yeovil Hospital, Somerset, UK

    Andrew Mallick

  12. Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, UK

    Karim Ouahchi & Charles Lee

  13. Department of Genetics, School of Medicine, Universidade de São Paolo, Ribeirão Preto, Brazil

    Joao M. Pina-Neto

  14. 303 E. Chicago Ave., Ward 10-233, Chicago, IL, 60611, USA

    Ali Jalali

Authors
  1. Ali Jalali
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly A. Aldinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ajit Chary
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David G. Mclone
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robin M. Bowman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luan Cong Le
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Phillip Jardine
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ruth Newbury-Ecob
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Andrew Mallick
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nadereh Jafari
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eric J. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. John Curran
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Pam Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Karim Ouahchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Charles Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. William B. Dobyns
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Kathleen J. Millen
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Joao M. Pina-Neto
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. John A. Kessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Alexander G. Bassuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Jalali.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jalali, A., Aldinger, K.A., Chary, A. et al. Linkage to chromosome 2q36.1 in autosomal dominant Dandy-Walker malformation with occipital cephalocele and evidence for genetic heterogeneity. Hum Genet 123, 237–245 (2008). https://doi.org/10.1007/s00439-008-0467-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-008-0467-y

Keywords

Search

Navigation