Report of a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris phenotype, and schwannomatosis

Am J Med Genet A. 2015 Dec;167A(12):3186-91. doi: 10.1002/ajmg.a.37356. Epub 2015 Sep 14.


We report a patient with a constitutional missense mutation in SMARCB1, Coffin-Siris Syndrome (CSS), and schwannomatosis. CSS is a rare congenital syndrome with characteristic clinical findings. This thirty-three-year-old man was diagnosed early in life with the constellation of moderate intellectual disability, hypotonia, mild microcephaly, coarse facies, wide mouth with full lips, hypoplasia of the digits, and general hirsutism. At age 26, he was found to have schwannomatosis after presenting with acute spinal cord compression. Blood and tissue analysis of multiple subsequent schwannoma resections revealed a germline missense mutation of SMARCB1, acquired loss of 22q including SMARCB1 and NF2 and mutation of the remaining NF2 wild-type allele-thus completing the four-hit, three-event mechanism associated with schwannomatosis. Variations in five genes have been associated with the Coffin-Siris phenotype: ARID1A, ARID1B, SMARCA4, SMARCB1, and SMARCE1. Of these genes, SMARCB1 has a well-established association with schwannomatosis and malignancy. This is the first report of a patient with a constitutional missense mutation of SMARCB1 resulting in CSS and subsequent development of schwannomatosis. This finding demonstrates that a SMARCB1 mutation may be the initial "hit" (constitutional) for a genetic disorder with subsequent risk of developing schwannomas and other malignancies, and raises the possibility that other patients with switch/sucrose non-fermenting (SWI/SNF) mutations may be at increased risk for tumors.

Keywords: Coffin-Siris syndrome; schwannomatosis.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Adult
  • Chromosomal Proteins, Non-Histone / genetics*
  • DNA-Binding Proteins / genetics*
  • Exome / genetics
  • Face / abnormalities*
  • Face / pathology
  • Hand Deformities, Congenital / genetics*
  • Hand Deformities, Congenital / pathology
  • Humans
  • Intellectual Disability / genetics*
  • Intellectual Disability / pathology
  • Male
  • Micrognathism / genetics*
  • Micrognathism / pathology
  • Mutation, Missense / genetics*
  • Neck / abnormalities*
  • Neck / pathology
  • Neurilemmoma / genetics*
  • Neurilemmoma / pathology
  • Neurofibromatoses / genetics*
  • Neurofibromatoses / pathology
  • Phenotype
  • Prognosis
  • SMARCB1 Protein
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Transcription Factors / genetics*


  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • Transcription Factors

Supplementary concepts

  • Coffin-Siris syndrome
  • Schwannomatosis