Cleft lip/palate and hereditary diffuse gastric cancer: report of a family harboring a CDH1 c.687 + 1G > A germline mutation and review of the literature

  • Florian ObermairEmail author
  • Melanie Rammer
  • Jonathan Burghofer
  • Theodora Malli
  • Anna Schossig
  • Katharina Wimmer
  • Wolfgang Kranewitter
  • Beate Mayrbaeurl
  • Hans-Christoph Duba
  • Gerald Webersinke
Original Article


Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominantly inherited cancer syndrome associated with a high risk for diffuse gastric and lobular breast cancer, caused by heterozygous CDH1 germline mutations. Of note, also cleft lip/palate (CLP) has been described in few HDGC families. Here we report on an extensive pedigree presenting with HDGC, CLP and a CDH1 splice site mutation (c.687 + 1G > A) and review the literature for families with CDH1 mutations, HDGC and CLP. Transcript analysis showed that the c.687 + 1G > A mutation leads to loss of the last 42 bp of exon 5 and is consequently predicted to cause loss of 14 amino acids in the first extracellular cadherin repeat (EC) domain. Five mutation carriers developed diffuse gastric cancer and four individuals presented with CLP. Wild type CDH1 expression levels did not differ between CDH1 mutation carriers with CLP compared to those without CLP. Beside this extensive pedigree, we outline another previously unreported HDGC/CLP family with a CDH1 (c.1711 + 1G > C) germline mutation in this study. Review of the literature revealed a significant enrichment of CDH1 mutations within the EC domains in CLP/HDGC families (Fisher’s exact test, p = 0.007) in comparison to CDH1 mutations associated with HDGC only. Report of further CLP/HDGC associated mutations is necessary to confirm this observation. This study highlights that CLP represents an important phenotypic feature of CDH1 germline mutation carriers and emphasizes the inclusion of CLP in the HDGC testing criteria. The underlying causes for the appearance of variable phenotypes in CDH1 mutation carriers could include genetic variation, epigenetic changes and environmental factors and should be investigated in future studies.


Stomach neoplasms Neoplastic syndromes Hereditary Orofacial cleft CDH1 protein Human 



We want to thank the patients who gave consent for sharing their data in this report.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10689_2018_111_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 KB)


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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Florian Obermair
    • 1
    • 4
    Email author
  • Melanie Rammer
    • 1
  • Jonathan Burghofer
    • 1
  • Theodora Malli
    • 1
  • Anna Schossig
    • 2
  • Katharina Wimmer
    • 2
  • Wolfgang Kranewitter
    • 1
  • Beate Mayrbaeurl
    • 3
  • Hans-Christoph Duba
    • 4
  • Gerald Webersinke
    • 1
  1. 1.Laboratory for Molecular Biology and Tumor Cytogenetics, Department of Internal Medicine IOrdensklinikum Linz Barmherzige SchwesternLinzAustria
  2. 2.Division of Human GeneticsInnsbruck Medical UniversityInnsbruckAustria
  3. 3.Fourth Department of Internal MedicineKlinikum Wels-GrieskirchenWelsAustria
  4. 4.Institute of Medical Genetics, Med Campus IVKepler University HospitalLinzAustria

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