11p13 microduplication: a differential diagnosis of Silver-Russell syndrome?

BACKGROUND: Silver-Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging. CASE PRESENTATION: A girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver-Russel syndrome. CONCLUSIONS: The identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.

A de novo 11p13 Microduplication in a Patient with Some Features Invoking Silver-Russell Syndrome.

Patients with Silver-Russell syndrome (SRS) show an intrauterine and postnatal growth restriction associated with a variable spectrum of additional features. Genetic or epigenetic alterations on chromosomes 7 and 11 can be detected in several SRS patients; however, a large fraction of cases remains with unknown genetic etiology. Here, we describe the clinical and molecular findings of a patient with a phenotype invoking SRS showing intrauterine and postnatal growth retardation, psychomotor retardation, relative macrocephaly, slightly triangular face with pointed chin, clinodactyly, and a slight body asymmetry, in whom single-nucleotide polymorphism oligonucleotide array analysis led to the identification of a de novo 11p13 duplication containing many genes that could be functionally related with the observed clinical features. Many deletions of chromosome 11p13, resulting in WAGR (Wilms tumor, aniridia, genital anomalies, mental retardation) syndrome, have been described, while only few duplications spanning the same region have been reported so far. To our knowledge, this is the first reported case presenting a SRS carrier of an 11p13 duplication. We propose candidate genes for the observed traits, and in particular, we discuss the possible role of the involvement of 2 noncoding RNAs in the etiology of the phenotype.