Paternal Uniparental Disomy of the Entire Chromosome 20 in a Child with Beckwith-Wiedemann Syndrome.

Sanaa Choufani,Leona Fishman,Cheryl Shuman,Jung Min Ko,Youliang Lou,Rosanna Weksberg

doi:10.3390/genes12020172

Abstract

Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and pseudohypoparathyroidism type 1b (PHP1b). Here, we present a male patient with these two distinct IDs caused by two independent mechanisms-loss of methylation (LOM) at chromosome 11p15.5 associated with multi-locus imprinting disturbances (MLID and paternal uniparental disomy of chromosome 20 (patUPD20). A clinical diagnosis of BWS was made based on the clinical features of macrosomia, macroglossia, and umbilical hernia. The diagnosis of PHP1b was supported by the presence of reduced growth velocity and mild learning disability as well as hypocalcemia and hyperphosphatemia at 14 years of age. Molecular analyses, including genome-wide DNA methylation (Illumina 450k array), bisulfite pyrosequencing, single nucleotide polymorphism (SNP) array and microsatellite analysis, demonstrated loss of methylation (LOM) at IC2 on chromosome 11p15.5, and paternal isodisomy of the entire chromosome 20. In addition, imprinting disturbances were noted at the differentially methylated regions (DMRs) associated with DIRAS3 on chromosome 1 and PLAGL1 on chromosome 6. This is the first case report of PHP1b due to patUPD20 diagnosed in a BWS patient with LOM at IC2 demonstrating etiologic heterogeneity for multiple imprinting disorders in a single individual.

Highlights

Introduction published maps and institutional affilBeckwith–Wiedemann syndrome (BWS, OMIM#130650) and pseudohypoparathyroidism (PHP, OMIM#103580, #603233, #612463) are genetic imprinting disorders (IDs), caused by genetic and epigenetic alterations involving imprinting control regions (ICs) and differentially methylated regions (DMRs) on chromosomes 11p15.5 and 20q13.32, respectively
Homozygosity screening showed copy neutral loss of heterozygosity (LOH) affecting the entirety of chromosome 20 (Figure 2). These findings indicated that the two chromosomes 20 are identical and the patient has uniparental disomy (UPD) for chromosome 20
We demonstrated that the PHP1b was associated with methylation alterations at the GNAS cluster and was caused by pat UPD 20 rather than multilocus imprinting disturbance (MLID); whereas the other methylation alterations at IC2, DIRAS3 and PLAGL1 were not associated with UPD and were attributable to MLID

Summary

Introduction

Beckwith–Wiedemann syndrome (BWS, OMIM#130650) and pseudohypoparathyroidism (PHP, OMIM#103580, #603233, #612463) are genetic imprinting disorders (IDs), caused by genetic and epigenetic alterations involving imprinting control regions (ICs) and differentially methylated regions (DMRs) on chromosomes 11p15.5 and 20q13.32, respectively. BWS is the most common genetic overgrowth syndrome involving a predisposition to embryonal tumor development in childhood. The clinical presentation in BWS is variable and findings may include neonatal hypoglycemia, macrosomia, macroglossia, abdominal wall defects, visceromegaly, renal abnormalities, cytomegaly of the fetal adrenal cortex, ear creases and/or pits, embryonal tumor, etc [1,2]. PHP includes a number of conditions associated primarily with target organ tissue resistance to parathyroid hormone (PTH). Its pathogenesis has been linked to dysfunctional Gs α subunit of G proteins and PHP can be divided into several clinical iations

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