Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A

Am J Med Genet C Semin Med Genet. 2014 Sep;166C(3):262-75. doi: 10.1002/ajmg.c.31407. Epub 2014 Aug 28.

Abstract

Coffin-Siris syndrome (CSS) is a rare congenital malformation syndrome, recently found to be caused by mutations in several genes encoding components of the BAF complex. To date, 109 patients have been reported with their mutations: SMARCB1 (12%), SMARCA4 (11%), SMARCE1 (2%), ARID1A (7%), ARID1B (65%), and PHF6 (2%). We review genotype-phenotype correlation of all previously reported patients with mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A through reassessment of their clinical and molecular findings. Cardinal features of CSS included variable degrees of intellectual disability (ID) predominantly affecting speech, sucking/feeding difficulty, and craniofacial (thick eyebrows, long eyelashes), digital (hypoplastic 5th fingers or toes, hypoplastic 5th fingernails or toenails), and other characteristics (hypertrichosis). In addition, patients with SMARCB1 mutations had severe neurodevelopmental deficits including severe ID, seizures, CNS structural abnormalities, and no expressive words as well as scoliosis. Especially, those with a recurrent mutation "p.Lys364del" represented strikingly similar phenotypes including characteristic facial coarseness. Patients with SMARCA4 mutations had less coarse craniofacial appearances and behavioral abnormalities. Patients with SMARCE1 mutations had a wide spectrum of manifestations from severe to moderate ID. Patients with ARID1A also had a wide spectrum of manifestations from severe ID and serous internal complications that could result in early death to mild ID. Mutations in SMARCB1, SMARCA4, and SMARCE1 are expected to exert dominant-negative or gain-of-function effects, whereas those in ARID1A are expected to exert loss-of-function effects.

Keywords: ARID1A; BAF (mSWI/SNF) complex; Coffin-Siris syndrome; SMARCA4; SMARCB1; SMARCE1; intellectual disability (ID).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / etiology*
  • Abnormalities, Multiple / genetics
  • Adolescent
  • Child
  • Child, Preschool
  • Chromosomal Proteins, Non-Histone / genetics*
  • DNA Helicases / genetics*
  • DNA-Binding Proteins / genetics*
  • Face / abnormalities*
  • Female
  • Genetic Association Studies
  • Hand Deformities, Congenital / etiology*
  • Hand Deformities, Congenital / genetics
  • Humans
  • Intellectual Disability / etiology*
  • Intellectual Disability / genetics
  • Male
  • Micrognathism / etiology*
  • Micrognathism / genetics
  • Mutation
  • Neck / abnormalities*
  • Nuclear Proteins / genetics*
  • SMARCB1 Protein
  • Toes / abnormalities
  • Transcription Factors / genetics*
  • Young Adult

Substances

  • ARID1A protein, human
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Nuclear Proteins
  • SMARCB1 Protein
  • SMARCB1 protein, human
  • SMARCE1 protein, human
  • Transcription Factors
  • SMARCA4 protein, human
  • DNA Helicases

Supplementary concepts

  • Coffin-Siris syndrome