Marked overlap of four genetic syndromes with dyskeratosis congenita confounds clinical diagnosis

Haematologica. 2016 Oct;101(10):1180-1189. doi: 10.3324/haematol.2016.147769. Epub 2016 Sep 9.


Dyskeratosis congenita is a highly pleotropic genetic disorder. This heterogeneity can lead to difficulties in making an accurate diagnosis and delays in appropriate management. The aim of this study was to determine the underlying genetic basis in patients presenting with features of dyskeratosis congenita and who were negative for mutations in the classical dyskeratosis congenita genes. By whole exome and targeted sequencing, we identified biallelic variants in genes that are not associated with dyskeratosis congenita in 17 individuals from 12 families. Specifically, these were homozygous variants in USB1 (8 families), homozygous missense variants in GRHL2 (2 families) and identical compound heterozygous variants in LIG4 (2 families). All patients had multiple somatic features of dyskeratosis congenita but not the characteristic short telomeres. Our case series shows that biallelic variants in USB1, LIG4 and GRHL2, the genes mutated in poikiloderma with neutropenia, LIG4/Dubowitz syndrome and the recently recognized ectodermal dysplasia/short stature syndrome, respectively, cause features that overlap with dyskeratosis congenita. Strikingly, these genes also overlap in their biological function with the known dyskeratosis congenita genes that are implicated in telomere maintenance and DNA repair pathways. Collectively, these observations demonstrate the marked overlap of dyskeratosis congenita with four other genetic syndromes, confounding accurate diagnosis and subsequent management. This has important implications for establishing a genetic diagnosis when a new patient presents in the clinic. Patients with clinical features of dyskeratosis congenita need to have genetic analysis of USB1, LIG4 and GRHL2 in addition to the classical dyskeratosis congenita genes and telomere length measurements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Ligase ATP / genetics
  • DNA-Binding Proteins / genetics
  • Dyskeratosis Congenita / diagnosis*
  • Dyskeratosis Congenita / genetics*
  • Exome / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Pedigree
  • Phosphoric Diester Hydrolases / genetics
  • Sequence Analysis, DNA
  • Syndrome
  • Transcription Factors / genetics


  • DNA-Binding Proteins
  • GRHL2 protein, human
  • LIG4 protein, human
  • Transcription Factors
  • Phosphoric Diester Hydrolases
  • USB1 protein, human
  • DNA Ligase ATP