Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients

Abstract

Background: Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype.

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

“…As previously reported in the literature, PLAG1 pathogenic variants have only been described in three cases: two of them familial and the other one sporadic. In the three cases, the variants produced a truncated protein (two frameshift and a nonsense) and the disease followed a dominant transmission pattern [12,21], as was the case of our patient. All variants are located at the last coding exon of the gene, so a transcribed mutant mRNA will presumably not be degraded by a nonsense-mediated decay (NMD) pathway [30].…”

“…In fact, it has been demonstrated in vitro that when F6 and F7 are removed, the protein F1-F5 does not show any clear DNA binding, revealing the absolute requirement of the last two zinc fingers for the DNA binding [32]. Analysis of previously reported variants reveals that the p.(Ser147Valfs *82) [12] and p.(Arg197 *) [21] would probably have a similar effect because in both cases, F6 and F7 are removed. In p.(Gln455Serfs *16) [12], even if all the zinc fingers seem to be conserved, transcription activation could be affected as residues 385-500 are presumably important for this task.…”

“…Moreover, sequence variants of two non-imprinted genes (HMGA2 and PLAG1) have been associated with SRS. HMGA2 variants have been described in three families and three sporadic cases [12,19,20] and PLAG1 alterations in two families and in a sporadic case [12,21] (Supplementary Table S1).…”

Novel mutation points to a hot spot in CDKN1C causing Silver–Russell syndrome

“…With respect to CDKN1C variants and intrauterine growth retardation, the current literature reports now a total of 12 cases with IMAGe syndrome and adrenal insufficiency, comprehensively summarized by Suntharalingham et al [26], 4 cases with SRS ( [4,5,14], and this study) and a single case with an undefined short stature syndrome with early manifestation of diabetes mellitus [6]. Variants causing IMAGe syndrome affected codons 272, 274, 276, 278 and 279 of the PCNA domain, while variants found in SRS changed codons 279 and 316 and were therefore located toward the carboxy-terminal region of the PCNA domain [26].…”

“…In contrast to IMAGe syndrome, adrenal insufficiency and metaphyseal dysplasia were absent, but the variant was located within the cluster of IMAGe mutations [4,5]. Very recently, a sporadic case with SRS having the novel CDKN1C variant p.(Arg316Gln) was described by Inoue et al, who performed multigene sequencing in 92 Japanese patients with unexplained SRS [14].…”