Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Priolo M

PROVIDER: S-EPMC9141324 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Priolo Manuela M Mancini Cecilia C Pizzi Simone S Chiriatti Luigi L Radio Francesca Clementina FC Cordeddu Viviana V Pintomalli Letizia L Mammì Corrado C Dallapiccola Bruno B Tartaglia Marco M

Genes 20220516 5

<h4>Objective</h4>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.<h4>Patients and methods</h4>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 his ...[more]

PMID: 35627274

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Project description:Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.

Dataset Information

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

Objective

Patients and methods

Results

Conclusions

Publications

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

Similar Datasets

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