The tale of two genes: from next-generation sequencing to phenotype

Cold Spring Harb Mol Case Stud. 2020 Apr 1;6(2):a004846. doi: 10.1101/mcs.a004846. Print 2020 Apr.


An 18-yr-old man with a history of intellectual disability, craniofacial dysmorphism, seizure disorder, and obesity was identified to carry a de novo, pathogenic variant in ASXL1 (c.4198G>T; p.E1400X) associated with the diagnosis of Bohring-Opitz syndrome based on exome sequencing. In addition, he was identified to carry a maternally inherited and likely pathogenic variant in MC4R (c.817C>T; p.Q273X) associated with monogenic obesity. Dual genetic diagnosis occurs in 4%-6% of patients and results in unique clinical phenotypes that are a function of tissue-specific gene expression, involved pathways, clinical expressivity, and penetrance. This case highlights the utility of next-generation sequencing in patients with an unusual combination of clinical presentations for several pillars of precision medicine including (1) diagnosis, (2) prognosis and outcome, (3) management and therapy, and (4) utilization of resources.

Keywords: childhood-onset truncal obesity; intellectual disability, profound; microretrognathia; prominent glabella.

Publication types

  • Case Reports

MeSH terms

  • Adolescent
  • Alleles
  • Craniosynostoses / diagnosis
  • Craniosynostoses / genetics
  • Developmental Disabilities / diagnosis
  • Developmental Disabilities / genetics
  • Exome Sequencing
  • Facies
  • Genetic Association Studies*
  • Genotype
  • Growth Charts
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics
  • Male
  • Medical History Taking
  • Mutation*
  • Obesity, Morbid / diagnosis
  • Obesity, Morbid / genetics
  • Pedigree
  • Phenotype*
  • Receptor, Melanocortin, Type 4 / genetics*
  • Repressor Proteins / genetics*


  • ASXL1 protein, human
  • MC4R protein, human
  • Receptor, Melanocortin, Type 4
  • Repressor Proteins

Supplementary concepts

  • Bohring syndrome