Protein\u2013protein interaction network analysis applied to DNA copy number profiling suggests new perspectives on the aetiology of Mayer\u2013Rokitansky\u2013K\xfcster\u2013Hauser syndrome

Paola Pontecorvi,Simona Ceccarelli,Nicoletta Preziosi,Antonio Pizzuti,Francesca Megiorni,Paola Grammatico,Giorgia Perniola,Maria Fabbretti,Pierluigi Benedetti Panici,Irene Bottillo,Cinzia Marchese,Enrica Vescarelli,Laura Bernardini,Anna Capalbo

doi:10.1038/s41598-020-79827-5

Paola Pontecorvi, Simona Ceccarelli + Show 12 more

Open Access

https://doi.org/10.1038/s41598-020-79827-5

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Abstract

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a rare disease, characterised by the aplasia of vagina and uterus in women with a 46,XX karyotype. Most cases are sporadic, but familial recurrence has also been described. Herein, we investigated an Italian cohort of 36 unrelated MRKH patients to explore the presence of pathogenic copy number variations (CNVs) by array-CGH and MLPA assays. On the whole, aberrations were found in 9/36 (25%) patients. Interestingly, one patient showed a novel heterozygous microduplication at Xp22.33, not yet described in MRKH patients, containing the PRKX gene. Moreover, a novel duplication of a specific SHOX enhancer was highlighted by MLPA. To predict the potential significance of CNVs in MRKH pathogenesis, we provided a network analysis for protein-coding genes found in the altered genomic regions. Although not all of these genes taken individually showed a clear clinical significance, their combination in a computational network highlighted that the most relevant biological connections are related to the anatomical structure development. In conclusion, the results described in the present study identified novel genetic alterations and interactions that may be likely involved in MRKH phenotype determination, so adding new insights into the complex puzzle of MRKH disease.

Highlights

Mayer-Rokitansky-Küster-Hauser syndrome is a rare disease (Online Mendelian Inheritance in Man—OMIM #277000) with an incidence of about 1 in 4500 new-born females
We identified two imbalances in chromosomal regions already associated with MRKH syndrome: a deletion of 1410.6 Kb at chromosome 17q12 (Patient 36) and a deletion of 546 Kb at chromosome 16p11.2 (Patient 39)
When we focused on the highest statistical significance, Gene Ontology (GO) processes linked to our network analysis were embryonic morphogenesis (p = 4.8e−9), tissue morphogenesis (p = 4.8e−9) and urogenital system development (p = 3.7e−8)

Summary

Introduction

Mayer-Rokitansky-Küster-Hauser syndrome is a rare disease (Online Mendelian Inheritance in Man—OMIM #277000) with an incidence of about 1 in 4500 new-born females It is characterised by congenital aplasia of the vagina and uterus in women showing a 46,XX karyotype and normal ovarian function leading to a normal development of secondary sexual features. Aside from CNVs frequently encountered in patients with MRKH syndrome, many chromosomal rearrangements are novel or rare, making uncertain their clinical interpretation Since these imbalances usually involve large genomic regions, including several genes with different functions, a bioinformatic analysis may be helpful in explaining the potential role of the observed CNVs. In recent years, system biology approaches have emerged as powerful tools to study complex diseases. - to identify the presence of known and new genomic imbalances in an Italian cohort of 36 unrelated MRKH women by array-CGH and MLPA assays;

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