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

• Published in: Journal of medical genetics Vol. 56; no. 3; pp. 149 - 153
• Main Authors: Butler, Merlin G, Hartin, Samantha N, Hossain, Waheeda A, Manzardo, Ann M, Kimonis, Virginia, Dykens, Elisabeth, Gold, June Anne, Kim, Soo-Jeong, Weisensel, Nicolette, Tamura, Roy, Miller, Jennifer L, Driscoll, Daniel J
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.03.2019
• Subjects: Adolescent; Adult; Age; Autism; Behavior; Child; Child, Preschool; Chromosome 15; Chromosome Deletion; Chromosomes; Chromosomes, Human, Pair 15; Cohort analysis; Cohort Studies; Deoxyribonucleic acid; DNA; DNA Copy Number Variations; DNA methylation; Female; Genetic Association Studies - methods; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genomic imprinting; Genotyping; Heterozygosity; Humans; Infant; Loss of heterozygosity; Male; Middle Aged; Mutation; Obesity; Pediatrics; Polymorphism, Single Nucleotide; Prader-Willi syndrome; Prader-Willi Syndrome - diagnosis; Prader-Willi Syndrome - genetics; Young Adult; United States > US; pws deletion subtypes; Prader-Willi syndrome; maternal age effects; PWS maternal disomy subclasses; molecular genetic classification
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmedgenet-2018-105301

BackgroundPrader-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.MethodsHigh-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.ResultsWe 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).ConclusionsWe 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.