Familial 1.3-Mb 11p15.5p15.4 Duplication in Three Generations Causing Silver-Russell and Beckwith-Wiedemann Syndromes

Abstract

along with other distinctive characteristics like asymmetry of body and limbs, craniofacial features, and 5th finger (F5) clinodactyly. Beckwith-Wiedemann syndrome (BWS, OMIM: 130650) is also a growth-affecting disorder which causes overgrowth with many additional clinical features like macroglossia, organomegaly, and increased risk of childhood tumors [Weksberg et al., 2010]. The most common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15 [Gicquel et al., 2005], where 2 imprinting control regions (ICR1 and ICR2) control fetal and postnatal growth. ICR1 contains the maternally expressed H19 gene and the paternally expressed IGF2 gene, whereas ICR2 contains the maternally expressed KCNQ1 and CDKN1C genes and the paternally expressed KCNQ1OT1 gene. Normally, genes that are expressed in 1 allele are imprinted (methylated) and silenced in the other allele. Imprinting disturbances lead to abnormal expression of these genes and the clinical phenotypes of SRS or BWS. Approximately 40% of SRS patients show hypomethylation of ICR1, whereas up to 50% of BWS patients have ICR2 hypomethylation [Eggermann et al., 2008]. In addition, in SRS and BWS patients, numerous submicroscopic chromosomal disturbances have been described, among them duplications, deletions, inversions and/or translocations affecting chromosome 11p15 [Begemann et al., 2012;Fokstuen and Kotzot, 2014]. Large duplicaKey Words 11p15 duplication · 11p15 imprinting disorders · Beckwith-Wiedemann syndrome · Imprinting control region 1 · Imprinting control region 2 · Silver-Russell syndrome Abstract Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 opposite growth-affecting disorders. The common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15, where 2 imprinting control regions (ICR) control fetal and postnatal growth. Also, many submicroscopic chromosomal disturbances like duplications in 11p15 have been described among SRS and BWS patients. Duplications involving both ICRs cause SRS or BWS, depending on which parent the aberration is inherited from. We describe to our knowledge the smallest familial pure 1.3-Mb duplication in chromosomal region 11p15.5p15.4 that involves both ICRs and is present in 3 generations causing an SRS or BWS phenotype.

Silver-Russell Syndrome and Beckwith-Wiedemann Syndrome: Opposite Phenotypes with Heterogeneous Molecular Etiology

“…Other minor features are neonatal hypoglycemia, hemihyperplasia, and characteristic facial features. A rec- [Kotzot et al, 1995;Eggermann et al, 1997;Preece et al, 1997;Netchine et al, 2007;Abu-Amero et al, 2008;Binder et al, 2008] Methylation abnormality at ICR1 in the 11p15 region hypomethylation in 37 -63% [Netchine et al, 2007;Binder et al, 2008;Bartholdi et al, 2009;Bruce et al, 2009;Abu-Amero et al, 2010;Turner et al, 2010;Vals et al, 2015b] hypermethylation 5 -10% [Gaston et al, 2001;Cooper et al, 2005Cooper et al, , 2007Sasaki et al, 2007] Methylation abnormality at ICR2 in the 11p15 region few cases with the hypomethylation of both ICRs [Begemann et al, 2011] hypomethylation in 50 -60% [Gaston et al, 2001;Cooper et al, 2005;Weksberg et al, 2010;Begemann et al, 2012b] Duplication in the 11p15 region (may involve ICR1 and/or ICR2) maternal 1 -2% [Eggermann et al, 2010a[Eggermann et al, , 2014b paternal microdeletions involving ICR1 (~5%) and microduplications of ICR2 (<1%) [Niemitz et al, 2004;Sparago et al, 2004;Bliek et al, 2009b;Demars et al, 2011;Begemann et al, 2012b;Vals et al, 2015a] Other chromosomal aberrations (including cryptic) 2% (the most frequent are 1q21 microdeletion, 12q24 microdeletion, ring chromosome 15, and deletion 15qter) [Bruce et al, 2010;Spengler et al, 2012;Fuke et al, 2013;Fokstuen and Kotzot, 2014;Azzi et al, 2015] rare cases, maternally inherited balanced translocations/inversions …”

“…The craniofacial dysmorphic features are most apparent before the age of 3 years, and after the age of 5 years often only minor dysmorphism is present . In adolescence, it is difficult to recognize BWS by facial phenotype only [Vals et al, 2015a]. Hypoglycemia is reported in 30-50% of babies with BWS and likely caused by islet cell hyperplasia and hyperinsulinism [Weksberg et al, 2010].…”

“…Most reported duplications involve ICR1 and ICR2 and are usually caused by unbalanced translocations, but duplication of the entire ICR2 as well as a partial duplication of ICR1 can also cause SRS [Fisher et al, 2002;Eggermann et al, 2005Eggermann et al, , 2010bSchönherr et al, 2007;South et al, 2008;Bliek et al, 2009b;Cardarelli et al, 2010;Bonaldi et al, 2011;Demars et al, 2011;Begemann et al, 2012b;Chiesa et al, 2012;Hu et al, 2013;Brown et al, 2014;Vals et al, 2015a]. The identification of an SRS patient with a duplication restricted to ICR2 suggests that both ICRs on 11p15 are involved in the etiology of SRS [Schönherr et al, 2007].…”

“…Few cases of duplications or deletions involving the ICR1 and/or ICR2 in the 11p15 region have been reported as a cause of BWS [Bliek et al, 2009b;Demars et al, 2011;Begemann et al, 2012b;Vals et al, 2015a]. Microdeletions involving ICR1 are identified in ∼ 5% and microduplications of ICR2 occur very seldom, in <1% of BWS cases [Niemitz et al, 2004;Sparago et al, 2004].…”

The Frequency of Methylation Abnormalities Among Estonian Patients Selected by Clinical Diagnostic Scoring Systems for Silver–Russell Syndrome and Beckwith–Wiedemann Syndrome

“…All the parents, except one, had normal CNV and methylation analyses. The mother of a patient with 11p15 duplication and SRS syndrome (Table 2, patient 7) had also the same duplication, but with opposite methylation and clinical diagnosis of BWS (Vals et al, 2015). …”