Novel Variant in PLAG1 in a Familial Case with Silver-Russell Syndrome Suspicion.

Yerai Vado,Isabel Llano-Rivas,Arrate Pereda,Nerea Gorria-Redondo,Ignacio Díez,Guiomar Perez De Nanclares

doi:10.3390/genes11121461

Abstract

Silver–Russell syndrome (SRS) is a rare growth-related genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Molecular causes are not clear in all cases, the most common ones being loss of methylation on chromosome 11p15 (≈50%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (≈10%). However, pathogenic variants in genes such as CDKN1C, HMGA2, IGF2, or PLAG1 have also been described. Previously, two families and one sporadic case have been reported with PLAG1 alterations. Here, we present a case of a female with clinical suspicion of SRS (i.e., intrauterine and postnatal growth retardation, triangular face, psychomotor delay, speech delay, feeding difficulties). No alterations in methylation or copy number were detected at chromosomes 11p15 and 7 using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The custom panel study by next-generation sequencing (NGS) revealed a frameshift variant in the PLAG1 gene (NM_002655.3:c.551delA; p.(Lys184Serfs *45)). Familial studies confirmed that the variant was inherited from the mother and it was also present in other family members. New evidence of pathogenic alterations in the HMGA2-PLAG1-IGF2 pathway suggest the importance of studying and taking into account these genes as alternative molecular causes of Silver–Russell syndrome.

Highlights

IntroductionSilver–Russell syndrome (SRS, OMIM#180860) is a rare imprinting genetic disorder that is mainly associated with intrauterine (IUGR) and postnatal growth retardation (PNGR) without catch-up
Silver–Russell syndrome (SRS, OMIM#180860) is a rare imprinting genetic disorder that is mainly associated with intrauterine (IUGR) and postnatal growth retardation (PNGR) without catch-up.Initially, it was defined by other features such as relative macrocephaly at birth, triangular face, body asymmetry, facial dysmorphic features, and severe feeding difficulties [1,2]
Intrauterine growth restriction, gestational hypertension, gestational diabetes, and a small placenta were detected during pregnancy, so delivery was induced at 38 gestational weeks and she was born small for her gestational age (SGA)

Summary

Introduction

Silver–Russell syndrome (SRS, OMIM#180860) is a rare imprinting genetic disorder that is mainly associated with intrauterine (IUGR) and postnatal growth retardation (PNGR) without catch-up. It was defined by other features such as relative macrocephaly at birth, triangular face, body asymmetry, facial dysmorphic features, and severe feeding difficulties [1,2]. New case reports led to the inclusion of other signs, such as a low body mass index (BMI) or speech delay (for review, see Reference [3]). The incidence of the disease varies from 1/30,000 to 1/100,000 [3]. Most of SRS cases are sporadic, with few familial cases that suggest following an autosomal dominant inheritance pattern [4].

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