Publications

Authors:

Vimercati, Alessandro; Tannorella, Pierpaola; Guzzetti, Sara; Calzari, Luciano; Gentilini, Davide; Manfredini, Emanuela; Gori, Giulia; Gaudino, Rossella; Antona, Vincenzo; Piccione, Maria; Daolio, Cecilia; Auricchio, Renata; Sirchia, Fabio; Minelli, Antonella; Rossi, Elena; Bellini, Melissa; Biasucci, Giacomo; Raucci, Annalisa Russo; Pozzobon, Gabriella; Patti, Giuseppa; Napoli, Flavia; Larizza, Lidia; Maghnie, Mohamad; Russo, Silvia

Title:

Distinguishing genetic alterations versus (epi)mutations in Silver-Russell syndrome and focus on the IGF1R gene

Year:

2024

Type of item:

Articolo in Rivista

Tipologia ANVUR:

Articolo su rivista

Language:

Inglese

Referee:

No

Name of journal:

The Journal of Clinical Endocrinology and Metabolism

ISSN of journal:

0021-972X

Page numbers:

1-32

Keyword:

IGF1R; IGF2-PLAG1-HMGA2 axis; (epi)genetic phenotype; Silver-Russell syndrome; body asymmetry; familial cases

Short description of contents:

Context: Silver-Russell Syndrome (SRS) is a growth retardation disorder characterized by pre- and post-natal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry, and feeding difficulties. The main molecular mechanisms are imprinting alterations at multiple loci, though a small number of pathogenic variants have been reported in the SRS genes IGF2-PLAG1-HMGA2 and CDKN1C. However, around 40% of clinically suspected SRS cases do not achieve a molecular diagnosis, highlighting the necessity to uncover the underlying mechanism in unsolved cases. Objective: evaluate the frequency of genetic variants in undiagnosed SRS patients (NH-CSS≥4), and investigate whether (epi)genetic patients may be distinguished from genetic patients. Methods: 132 clinically SRS patients without (epi)genetic deregulations were investigated by Whole Exome (n=15) and Targeted (n=117) Sequencing. Clinical data from our cohort and from an extensive revision of literature were compared. Results: pathogenic variants were identified in 9.1% of this cohort: 3% in IGF2, PLAG1, and HMGA2 genes, while 3% in the IGF1R gene, associated with IGF-1 resistance (IGF1RES), an SRS differential diagnosis. Overall, IGF2-PLAG1-HMGA2 and IGF1R account for 3.6% of SRS with NH-CSS score ≥ 4. A clinical cross-comparison of (epi)genetic versus genetic SRS underlined (epi)genotype-phenotype correlation, highlighted the prevalence of body asymmetry and relative macrocephaly in mosaic (epi)genetic SRS and recurrence of genetic familial cases. Furthermore, overlapping features were evidenced in (epi)genetic SRS and IGF1RES patients. Conclusion: Our study explores the frequency of genetic SRS, underscores body asymmetry as distinctive phenotype in (epi)genetic SRS and suggests IGF1R sequencing in SRS diagnostic flow-chart.

Product ID:

142456

Handle IRIS:

11562/1144772

Last Modified:

January 31, 2025

Bibliographic citation:

Vimercati, Alessandro; Tannorella, Pierpaola; Guzzetti, Sara; Calzari, Luciano; Gentilini, Davide; Manfredini, Emanuela; Gori, Giulia; Gaudino, Rossella; Antona, Vincenzo; Piccione, Maria; Daolio, Cecilia; Auricchio, Renata; Sirchia, Fabio; Minelli, Antonella; Rossi, Elena; Bellini, Melissa; Biasucci, Giacomo; Raucci, Annalisa Russo; Pozzobon, Gabriella; Patti, Giuseppa; Napoli, Flavia; Larizza, Lidia; Maghnie, Mohamad; Russo, Silvia, Distinguishing genetic alterations versus (epi)mutations in Silver-Russell syndrome and focus on the IGF1R gene «The Journal of Clinical Endocrinology and Metabolism» , 2024 , pp. 1-32

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