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Familial Cancer

, Volume 18, Issue 2, pp 261–265 | Cite as

Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome

  • Shahid Mahmood Baig
  • Ambrin Fatima
  • Muhammad Tariq
  • Tahir Naeem Khan
  • Zafar Ali
  • Mohammad Faheem
  • Humera Mahmood
  • Patrick Killela
  • Matthew Waitkus
  • Yiping He
  • Fangping Zhao
  • Sizhen Wang
  • Yuchen Jiao
  • Hai YanEmail author
Short Communication

Abstract

Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.

Keywords

Constitutional mismatch repair deficiency (CMMRD) syndrome Hereditary brain tumor Prenatal diagnosis Genetic counseling PMS2 

Notes

Acknowledgements

We would like to thank Uzma Abdullah (HMGL/NIBGE of Pakistan) for her coordination of communication with the patient family and Maggie McIntyre (Genetron Health Technologies Inc of USA) for editing the manuscript. This study was supported by Higher Education Commission (HEC) of Pakistan Projects No. 1461 and 4865 (S.M.B).

Compliance with ethical standards

Conflict of interest

H.Y. receives royalties from Agios Pharmaceuticals and Personal Genome Diagnostics. H.Y. and S.W are co-founders of Genetron Health (Beijing) Co. Ltd.

Supplementary material

10689_2018_112_MOESM1_ESM.pdf (40 kb)
Supplementary material 1 (PDF 40 KB)

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Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Shahid Mahmood Baig
    • 1
  • Ambrin Fatima
    • 1
  • Muhammad Tariq
    • 1
  • Tahir Naeem Khan
    • 1
  • Zafar Ali
    • 1
  • Mohammad Faheem
    • 2
  • Humera Mahmood
    • 2
  • Patrick Killela
    • 3
  • Matthew Waitkus
    • 3
  • Yiping He
    • 3
  • Fangping Zhao
    • 4
  • Sizhen Wang
    • 4
  • Yuchen Jiao
    • 5
  • Hai Yan
    • 3
    Email author
  1. 1.Human Molecular Genetics Laboratory, Health Biotechnology DivisionNational Institute for Biotechnology and Genetic Engineering (NIBGE)-PIEASFaisalabadPakistan
  2. 2.Oncology DepartmentNuclear Medicine Oncology and Radiotherapy Institute (NORI)IslamabadPakistan
  3. 3.Department of PathologyDuke University Medical CenterDurhamUSA
  4. 4.Genetron Health (Beijing) Co. LtdBeijingChina
  5. 5.Cancer Institute & Cancer HospitalChinese Academy of Medical Sciences & Peking Union Medical CollegeBeijingChina

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