Integration of EpiSign, facial phenotyping, and likelihood ratio interpretation of clinical abnormalities in the re-classification of an ARID1B missense variant

Am J Med Genet C Semin Med Genet. 2023 Sep;193(3):e32056. doi: 10.1002/ajmg.c.32056. Epub 2023 Aug 31.


Heterozygous ARID1B variants result in Coffin-Siris syndrome. Features may include hypoplastic nails, slow growth, characteristic facial features, hypotonia, hypertrichosis, and sparse scalp hair. Most reported cases are due to ARID1B loss of function variants. We report a boy with developmental delay, feeding difficulties, aspiration, recurrent respiratory infections, slow growth, and hypotonia without a clinical diagnosis, where a previously unreported ARID1B missense variant was classified as a variant of uncertain significance. The pathogenicity of this variant was refined through combined methodologies including genome-wide methylation signature analysis (EpiSign), Machine Learning (ML) facial phenotyping, and LIRICAL. Trio exome sequencing and EpiSign were performed. ML facial phenotyping compared facial images using FaceMatch and GestaltMatcher to syndrome-specific libraries to prioritize the trio exome bioinformatic pipeline gene list output. Phenotype-driven variant prioritization was performed with LIRICAL. A de novo heterozygous missense variant, ARID1B p.(Tyr1268His), was reported as a variant of uncertain significance. The ACMG classification was refined to likely pathogenic by a supportive methylation signature, ML facial phenotyping, and prioritization through LIRICAL. The ARID1B genotype-phenotype has been expanded through an extended analysis of missense variation through genome-wide methylation signatures, ML facial phenotyping, and likelihood-ratio gene prioritization.

Keywords: ARID1B; Coffin-Siris syndrome; FaceMatch; GestaltMatcher; LIRICAL; episignature.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple* / diagnosis
  • DNA-Binding Proteins / genetics
  • Face / pathology
  • Hand Deformities, Congenital* / genetics
  • Humans
  • Intellectual Disability* / pathology
  • Male
  • Micrognathism* / genetics
  • Muscle Hypotonia / pathology
  • Neck / pathology
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • Transcription Factors
  • ARID1B protein, human