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Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants

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Abstract

Purpose

Poikiloderma with neutropenia (PN) is a genodermatosis currently described in 77 patients, all presenting with early-onset poikiloderma, neutropenia, and several additional signs. Biallelic loss-of-function mutations in USB1 gene are detected in all molecularly tested patients but genotype-phenotype correlation remains elusive. Cancer predisposition is recognized among PN features and pathogenic variants found in patients who developed early in life myelodysplasia (n = 12), acute myeloid leukemia (n = 2), and squamous cell carcinoma (n = 2) should be kept into account in management and follow-up of novel patients. This will hopefully allow achieving data clustered on specific mutations relevant to oncological surveillance of the carrier patients.

Methods

We describe the clinical features of three unreported PN patients and characterize their USB1 pathogenic variants by transcript analysis to get insights into the effect on the overall phenotype and disease evolution.

Results

A Turkish boy is homozygous for the c.531delA deletion, a recurrent mutation in Turkey; an adult Italian male is compound heterozygous for two nonsense mutations, c.243G>A and c.541C>T, while an Italian boy is homozygous for the splicing c.683_693+1del variant. The identified mutations have already been reported in PN patients who developed hematologic or skin cancer. Aberrant mRNAs of all four mutated alleles could be identified confirming that transcripts of USB1 main isoform either carrying stop codons or mis-spliced may at least partially escape nonsense-mediated decay.

Conclusions

Our study addresses the need of gathering insights on genotype-phenotype correlations in newly described PN patients, by transcript analysis and information on disease evolution of reported patients with the same pathogenic variants.

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Acknowledgements

We thank the patients and their families for their kind participation in this study.

Authorship Contributions

EAC interpreted the molecular results, drafted, revised, and approved the final version; NHE contributed with clinical data and biological samples of family no. #32, drafted the clinical paragraph, and approved the final version; CG contributed with clinical data and biological samples of family no. #49, drafted the clinical paragraph, and approved the final version; PF contributed with clinical data and biological samples of family no. #48, drafted the clinical paragraph, and approved the final version; EDF performed molecular analyses; IN contributed with clinical data and biological samples of family no. #49, drafted the clinical paragraph, and approved the final version; EF contributed with clinical data and biological samples of family no. #49, drafted the clinical paragraph, and approved the final version; MG contributed with clinical data and biological samples of family no. #48, drafted the clinical paragraph, and approved the final version; CG supported the molecular work and software access; LL conceived and coordinated the study, and drafted, revised, and approved the final version of the manuscript.

Funding

This work was supported by Italian Ministry of Health to Istituto Auxologico Italiano (LL- Ricerca Corrente 08C624).

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Authors and Affiliations

  1. Dipartimento di Scienze della Salute, Università degli Studi di Milano, via Antonio di Rudinì 8, 20142, Milan, Italy

    Elisa A. Colombo, Elisabetta Di Fede & Cristina Gervasini

  2. Department of Pediatric Genetics, Marmara University Medical School, 34890, Istanbul, Turkey

    Nursel H. Elcioglu

  3. Department of Pediatric Genetics, Turkey and Eastern Mediterranean University, Cyprus, 10, Mersin, Turkey

    Nursel H. Elcioglu

  4. U.O. Genetica Medica, Policlinico S. Orsola-Malpighi, Via Massarenti 9, 40138, Bologna, Italy

    Claudio Graziano

  5. Clinica Dermatologica, Azienda ospedaliero universitaria “Maggiore della Carità”, Corso Giuseppe Mazzini 18, 28100, Novara, Italy

    Pamela Farinelli

  6. U.O. Dermatologia, Policlinico S. Orsola-Malpighi, Via Massarenti 9, 40138, Bologna, Italy

    Iria Neri

  7. U.O. Pediatria - Programma di Oncologia, Ematologia e Trapianto, Policlinico S. Orsola-Malpighi, Via Massarenti 9, 40138, Bologna, Italy

    Elena Facchini

  8. Divisione di Ematologia, Azienda Ospedaliero Universitaria “Maggiore della Carità”, Corso Giuseppe Mazzini 18, 28100, Novara, Italy

    Mariangela Greco

  9. Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche IRCCS-Istituto Auxologico Italiano, Via Ariosto 13, 20145, Milan, Italy

    Lidia Larizza

Authors
  1. Elisa A. Colombo
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  2. Nursel H. Elcioglu
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  3. Claudio Graziano
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  4. Pamela Farinelli
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  5. Elisabetta Di Fede
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  7. Elena Facchini
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  9. Cristina Gervasini
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  10. Lidia Larizza
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Corresponding author

Correspondence to Elisa A. Colombo.

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The authors declare that they have no competing interests.

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Colombo, E.A., Elcioglu, N.H., Graziano, C. et al. Insights into Mutation Effect in Three Poikiloderma with Neutropenia Patients by Transcript Analysis and Disease Evolution of Reported Patients with the Same Pathogenic Variants. J Clin Immunol 38, 494–502 (2018). https://doi.org/10.1007/s10875-018-0508-9

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  • DOI: https://doi.org/10.1007/s10875-018-0508-9

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