ABSTRACT
Imprinting disorders (ImpDis) represent a small group of rare congenital diseases primarily affecting growth, development, and the hormonal and metabolic systems. The aim of present study was to identify the prevalence of the ImpDis in Estonia, to describe trends in the live birth prevalence of these disorders between 1998 and 2016, and to compare the results with previously published data. We retrospectively reviewed the records of all Estonian patients since 1998 with both molecularly and clinically diagnosed ImpDis. A prospective study was also conducted, in which all patients with clinical suspicion for an ImpDis were molecularly analyzed. Eighty-seven individuals with ImpDis were identified. Twenty-seven (31%) of them had Prader-Willi syndrome (PWS), 15 (17%) had Angelman syndrome (AS), 15 (17%) had Silver-Russell syndrome (SRS), 12 (14%) had Beckwith-Wiedemann syndrome (BWS), 10 (11%) had pseudo- or pseudopseudohypoparathyroidism, four had central precocious puberty, two had Temple syndrome, one had transient neonatal diabetes mellitus, and one had myoclonus-dystonia syndrome. One third of SRS and BWS cases fulfilled the diagnostic criteria for these disorders, but tested negative for genetic abnormalities. Seventy-six individuals were alive as of January 1, 2018, indicating the total prevalence of ImpDis in Estonia is 5.8/100,000 (95% CI 4.6/100,000-7.2/100,000). The minimum live birth prevalence of all ImpDis in Estonia in 2004-2016 was 1/3,462, PWS 1/13,599, AS 1/27,198, BWS 1/21,154, SRS 1/15,866, and PHP/PPHP 1/27,198. Our results are only partially consistent with previously published data. The worldwide prevalence of SRS and GNAS-gene-related ImpDis is likely underestimated and may be at least three times higher than expected.
Subject(s)
Chromosome Disorders/epidemiology , Chromosome Disorders/genetics , Genomic Imprinting , Adolescent , Adult , Aged , Aged, 80 and over , Angelman Syndrome/epidemiology , Angelman Syndrome/genetics , Beckwith-Wiedemann Syndrome/epidemiology , Beckwith-Wiedemann Syndrome/genetics , Child , Child, Preschool , Chromosome Disorders/diagnosis , Cyclin-Dependent Kinase Inhibitor p57/genetics , DNA Methylation , Estonia/epidemiology , Humans , Infant , Infant, Newborn , Middle Aged , Prader-Willi Syndrome/epidemiology , Prader-Willi Syndrome/genetics , Prevalence , Prospective Studies , Retrospective Studies , Silver-Russell Syndrome/epidemiology , Silver-Russell Syndrome/genetics , Young AdultABSTRACT
AIMS: To study the frequency of methylation abnormalities among Estonian patients selected according to published clinical diagnostic scoring systems for Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS). MATERIALS AND METHODS: Forty-eight patients with clinical suspicion of SRS (n = 20) or BWS (n = 28) were included in the study group, to whom methylation-specific multiplex ligation-dependant probe amplification analysis of 11p15 region was made. In addition, to patients with minimal diagnostic score for either SRS or BWS, multilocus methylation-specific single nucleotide primer extension assay was performed. RESULTS: Five (38%) SRS patients with positive clinical scoring had abnormal methylation pattern at chromosome 11p15, whereas in the BWS group, only one patient was diagnosed with imprinting control region 2 (ICR2) hypomethylation (8%). An unexpected hypomethylation of the PLAGL1 (6q24) and IGF2R (6q25) genes in the patient with the highest BWS scoring was found. CONCLUSIONS: Compared to BWS, diagnostic criteria used for selecting SRS patients gave us a similar detection rate of 11p15 imprinting disorders as seen in other studies. A more careful selection of patients with possible BWS should be considered to improve the detection of molecularly confirmed cases. Genome-wide multilocus methylation tests could be used in routine clinical practice as it increases the detection rates of imprinting disorders.
Subject(s)
Beckwith-Wiedemann Syndrome , Cell Cycle Proteins , DNA Methylation , Receptor, IGF Type 2 , Silver-Russell Syndrome , Transcription Factors , Tumor Suppressor Proteins , Beckwith-Wiedemann Syndrome/diagnosis , Beckwith-Wiedemann Syndrome/genetics , Beckwith-Wiedemann Syndrome/metabolism , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Estonia , Female , Humans , Infant , Infant, Newborn , Male , Receptor, IGF Type 2/genetics , Receptor, IGF Type 2/metabolism , Silver-Russell Syndrome/diagnosis , Silver-Russell Syndrome/genetics , Silver-Russell Syndrome/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
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.
