Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology

Abstract

BackgroundRecently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features.ObjectiveTo clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS.MethodsWe studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR.ResultsWe identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes.ConclusionWe suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.

Syndromic Disorders Caused by Disturbed Human Imprinting

“…Taken together, these data seem to indicate, as for UPD(6)mat, that a specific chromosome 16 associated imprinting disorder does not exist (105). On the other hand, some imprinted genes with unknown function have been identified on chromosome 16 and further studies are required to clarify the issue (106).…”

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum

“…Next, to detect IDs, we performed methylation analysis with pyrosequencing for 9 DMRs related to known IDs, namely, the H19 / IGF2 :IG-DMR on chromosome 11, PEG10 :transcription start site (TSS)-DMR and MEST :alt-TSS-DMR on chromosome 7, PLAGL1 :alt-TSS-DMR on chromosome 6, KCNQ1OT1 :TSS-DMR chromosome 11, MEG3 / DLK1 :IG-DMR and MEG3 :TSS-DMR on chromosome 14, SNURF: TSS-DMR on chromosome 15, and GNAS - A / B :TSS-DMR on chromosome 20, as previously reported ( 7 , 8 ). Furthermore, to detect UPD(16)mat, we performed methylation analysis for the ZNF597 :TSS-DMR on chromosome 16 ( 10 ). Patients with hypomethylation of the H19 / IGF2 :IG-DMR were diagnosed as H19 LOM.…”

“…For structural analysis, we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA, MRC Holland, Amsterdam, Netherlands) analysis for each imprinted region (ME030 for 11p15.5, ME028 for 15q11.3–5, ME031 for 20q13) and/or aCGH analysis using custom built array (Design ID 080262, Agilent Technologies, Palo Alto, CA) and/or genome-wide comparative genomic hybridization and single-nucleotide polymorphism array (catalog number G4890A, Agilent Technologies, Palo Alto, CA), according to the manufacturer’s instructions. For patients with abnormal methylation levels of the DMRs related to known IDs other than H19 LOM and UPD(7)mat, but not structural abnormalities, we carried out microsatellite analysis for chromosomes 6 ( 16 ), 14 ( 8 ), 15 ( 17 ), 16 ( 10 ), and 20 ( 11 ) using patients’ and their parental genomic DNA samples. If patients had aberrant methylated DMR(s) other than their disease-related DMR(s), we considered these patients as having multilocus imprinting disturbance (MLID).…”

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

“…None of the patients had 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or upd(16)mat ( Fig. 1) [5][6][7][8][9][10]. We performed multigene screening for four genes responsible for SRS and 406 genes related to growth failure and/or skeletal dysplasia (Additional file 1: Table S1).…”