Exclusion of maternal uniparental disomy of chromosome 14 in patients referred for Prader-Willi syndrome using a multiplex methylation polymerase chain reaction assay.

Uniparental disomy (UPD) is the inheritance of both homologues of a chromosome from one parent. For most of the autosomes, there is no definitive clinical consequence of this abnormal inheritance. However, UPDs of chromosomes 6, 7, 11, 14, and 15 are associated with abnormal phenotypes owing to overexpression or underexpression of imprinted genes on those chromosomes. 2 Maternal UPD(14) (matUPD(14)) has been described in over 20 cases and is primarily characterised by intrauterine growth retardation and precocious puberty. Additional features can include hypotonia at birth, feeding difficulties in early infancy, short stature, musculoskeletal findings including small hands and feet and scoliosis, mild developmental delay, and early childhood obesity. Most patients with matUPD(14) are described with minor facial dysmorphism including frontal bossing, short philtrum, and high arched palate. Paternal UPD(14) (patUPD(14)) is less common, more severe, and is characterised by polyhydramnios, facial and skeletal anomalies, and severe developmental delay. 4 Recently, Wylie et al described reciprocally imprinted genes DLK1 and MEG3, positioned ∼90 kb apart at 14q32, which are candidate genes for the UPD(14) phenotypes. DLK1, a cell surface transmembrane protein, is paternally expressed, and MEG3, which lacks an open reading frame, is maternally expressed. Dlk1 knockout mice show features of matUPD(14), providing evidence that many of the phenotypic consequences of matUPD(14) may be attributed to a lack of DLK1 expression in these patients. UPD(14) is usually ascertained through a combination of clinical features and a karyotype suggestive of UPD, such as confined placental mosaicism for trisomy 14, a nonhomologous Robertsonian or reciprocal translocation involving chromosome 14, or an isochromosome 14. These karyotypes are consistent with, or predispose to, monosomy or trisomy rescue events, which are the most common mechanisms leading to UPD. Recently, three patients with matUPD(14) were described who were originally referred for molecular analysis for Prader-Willi syndrome (PWS) based on clinical phenotypes suggestive of PWS. The authors suggested that there are enough phenotypic similarities between PWS and matUPD(14) such that some patients without PWS might have matUPD(14) syndrome. 8 We recently described a rapid multiplex methylation polymerase chain reaction (mPCR) assay to identify UPD for chromosome 14 based on parent of origin differential methylation associated with the promoter region of the MEG3 gene, an imprinted gene on chromosome 14q32. In this communication, we report the analysis of 200 patients previously referred for PWS to determine if any were unrecognised as having matUPD(14) syndrome.