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Eur J Med Genet. 2019 Aug;62(8):103701. doi: 10.1016/j.ejmg.2019.103701. Epub 2019 Jun 10.

Expanding the clinical history associated with syndromic Klippel-Feil: A unique case of comorbidity with medulloblastoma.

Author information

1
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA. Electronic address: Kathleen.Schieffer@nationwidechildrens.org.
2
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.
3
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
4
Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA.
5
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
6
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Biomedical Education and Anatomy, The Ohio State University, Columbus, OH, USA.
7
Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
8
Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Pathology, The Ohio State University College of Medicine, Columbus, OH, USA.

Abstract

Klippel-Feil syndrome (KFS) is an exceedingly rare constitutional disorder in which a paucity of knowledge exists about the disease and its associated morbidity and mortality. We present a 4-year-old male with KFS, who notably was also diagnosed with large-cell anaplastic medulloblastoma. We evaluated the genetic basis of co-occurring KFS and medulloblastoma and the role of MYO18B as related to medulloblastoma. Constitutional and somatic variant and copy number analyses were performed from DNA-based exome studies, along with RNA-sequencing of tumor tissue, to elucidate the genetic etiology of the co-existing disease states. We identified novel constitutional compound heterozygous frameshift variants (NM_032608.5: p.Leu2257SerfsTer16 and p.Arg2220SerfsTer74) each encoding a premature stop of translation in MYO18B, consistent with a diagnosis of KFS. We did not identify any somatic variants of known relevance or disease-relevant therapeutic targets in the tumor. The somatic copy number profile was suggestive of Group 3γ medulloblastoma. Relative to pediatric brain tumors, medulloblastoma, particularly, Group 3, had increased gene expression of MYO18B. In summary, coexisting constitutional and somatic diagnoses in this patient enabled the elucidation of the genetic etiology of KFS and provided support for the role of MYO18B in tumor suppression.

KEYWORDS:

Brain cancer; Constitutional disease; Exome sequencing; MYO18B; Pediatric

PMID:
31195167
DOI:
10.1016/j.ejmg.2019.103701

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