Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study

Abstract

Background: Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects.

Methods: High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age.

Results: We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200).

Conclusions: We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.

Keywords: PWS maternal disomy subclasses; Prader-Willi syndrome; maternal age effects; molecular genetic classification; pws deletion subtypes.

Figure 1

(A) Chromosome microarray results using CNV and SNP probes to identify 15q11-q13 type I and type II deletion subtypes in Prader-Willi syndrome (PWS) with involvement of chromosome 15 breakpoints (BP1, BP2 and BP3). The circled region is not deleted in type II. (B) Methylation-specific multiplex ligation probe amplification (MS-MLPA) results of copy number comparison for PWS relative to a control subject. The circle indicates the probes (ie, TUBGCP5, CYFIP1) that are not deleted in type II. High-resolution chromosome microarrays using CNV and SNP probes to identify maternal UPD15 subclasses. (C) Segmental isodisomy of chromosome 15. The arrows indicate areas of chromosome regions (DNA segments) with loss of heterozygosity. (D) Heterodisomy 15. Chromosome regions (DNA segments) display no loss of heterozygosity. (E) Isodisomy 15. The arrow indicates the entire length of chromosome 15 from PWS individual with loss of heterozygosity due to uniparental maternal disomy 15 (meiosis II error) or postzygotic monosomy rescue. (F) Distribution of chromosome 15 bands involved in segmental isodisomy 15 by high-resolution microarrays and dense genotyping of chromosome 15. The number of protein-coding genes in parenthesis is noted per chromosome 15 band as referenced in McGuire et al.