Herein, we described two children with congenital anomalies/growth retardation who were diagnosed as PWS because of partial heterodisomy and partial isodisomy UPD15 based on karyotyping, CMA and MS-PCR/MS-MLPA as well as the clinical manifestations. The SNP-based CMA results of both patients showed CN-LOH on the distal long arm of chromosome 15, which did not overlap with the critical region of PWS, but the methylation-specific test supported the diagnosis of PWS, which was consistent with the clinical data.
PWS results from the loss of gene expression within the paternally-inherited genes on the 15q11.2-q13 chromosome, and 25% of the cases result from errors in genomic imprinting due to maternal uniparental disomy[7]. Gametic complementation, trisomy/disomy rescue, non-disjunction meiosis I/II error could be responsible for UPD[8]. partial heterodisomy and partial isodisomy can result from the recombination between chromatids prior to the meiotic segregations. The mechanism of formation of partial heterodisomy and partial isodisomy in the two cases may be the combination of several consecutive events: recombination takes place between chromatids prior to the meiotic segregations, then a disomic gamete arises from nondisjunction in meiosis I/II, and finally, fertilization of the disomic gamete by a normal gamete followed by the loss of chromosome 15 from the normal zygote, which is also called trisomy rescue (Fig. 4).
The International Standard Cytogenomic Array Consortium has proposed that CMA, in place of G-banded karyotype should be considered a first-tier test for patients with unexplained developmental delay/intellectual disability, autism spectrum disorders, or multiple congenital anomalies[1]. SNP-based CMA can detect the long stretches of homozygosity, which might represent UPD, but can only detect heterodisomic UPD in the cases with blocks of isodisomy[1], so SNP-based CMA may miss up to one-third of all UPD cases. Hence, methylation-specific test, which is considered as the first-tier test for the diagnosis of PWS, should be conducted when there are large blocks of homozygosity restricted to single chromosome 15.
Recombinant human growth hormone (rhGH) treatment is suggested before the onset of obesity, which often begins by two years of age[10]. rhGH is believed to improve the child’s body composition, by increasing lean body mass and reducing fat mass. The rhGH treatment along with a healthy lifestyle may prevent obesity, which is a major threat to PWS children. Children who began rhGH treatment before 12 months of age were found to have higher nonverbal and composite IQs than children who began treatment between 1-5 years of age[11]. So early diagnosis and treatment will help to improve the quality of life and care of PWS children.
In summary, CN-LOH detected on the distal long arm of chromosome 15 by SNP-based CMA should warrant methylation-specific test for the diagnosis of PWS. Early management may benefit children with PWS. Hence, the detection of CN-LOH on the distal long arm of chromosome 15 may be an allusion for PWS and should prompt immediate follow-up confirmatory tests.