Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases.

Pierpaola Tannorella,Piergiorgio Modena,Giulietta Scuvera,Milena Mariani,Anna Elsa Maria Allegri,Silvia Russo,Giuseppa Patti,Alessandro Vimercati,Daniele Minervino,Lidia Larizza,Donatella Milani,Angelo Selicorni,Sara Guzzetti,Mohamad Maghnie,Luciano Calzari

doi:10.3390/genes12040588

Abstract

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS.

Highlights

Silver Russell Syndrome (SRS, MIM #180860) is a rare (1:30,000–1:100,000) growth retardation condition characterized by a wide spectrum of signs and symptoms
This study aims to further define the common features shared by patients affected by this rare condition and the uniparental disomy (UPD)(20)mat prevalence in the clinically diagnosed SRS/SRSlike disorder
Negative patients were investigated for chromosome 20 uniparental disomy (UPD) using the approaches indicated in the rectangle framed by the broken lines

Summary

Introduction

Silver Russell Syndrome (SRS, MIM #180860) is a rare (1:30,000–1:100,000) growth retardation condition characterized by a wide spectrum of signs and symptoms. The etiology of SRS involves genetic and epigenetic mechanisms acting in various chromosomal regions subject to imprinting [1,3], with a high recurrence among the genetic alterations of uniparental disomy (UPD). Both maternal and paternal UPDs have been described for all human chromosomes except 19 and Y; they occur when both homolog chromosomes are inherited by a single parent [4]. When UPD encompasses an imprinted locus, the overall balance of methylation between parental alleles and consequent gene expression is deregulated

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