Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants

Genes (Basel). 2022 May 16;13(5):889. doi: 10.3390/genes13050889.


Objective: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation.

Patients and methods: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition.

Results: Four co-occurring genomic events fully explaining the proband's clinical features were identified. A de novo truncating USP7 variant was disclosed as the cause of Hao-Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in CFTR explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating PKD2 variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis.

Conclusions: The co-occurring variants in USP7 and CFTR variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the CFTR-related disorder symptoms and monitor renal function and other complications associated with PKD2 haploinsufficiency, addressing proper care and surveillance.

Keywords: CFTR; HAFOUS; PKD2; USP7; WES; cystic fibrosis; dual molecular diagnosis.

Publication types

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

MeSH terms

  • Abnormalities, Multiple
  • Bone Diseases, Developmental
  • Bronchiectasis* / genetics
  • Constipation / genetics
  • Craniofacial Abnormalities
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Deafness
  • Exome / genetics
  • Exome Sequencing
  • Genomics
  • Humans
  • Intellectual Disability
  • Polycystic Kidney, Autosomal Dominant* / genetics
  • Ubiquitin-Specific Peptidase 7 / genetics


  • Cystic Fibrosis Transmembrane Conductance Regulator
  • USP7 protein, human
  • Ubiquitin-Specific Peptidase 7

Supplementary concepts

  • Fountain syndrome

Grants and funding

This work was supported, in part, by the Italian Ministry of Health (CCR-2017-23669081 and RCR-2020-23670068_001 to M.T; RF-2018-12366931 to B.D. and F.C.R.).