Blended Phenotype of Prader-Willi Syndrome and HSP-SPG11 Caused by Maternal Uniparental Isodisomy

OBJECTIVE: Uniparental isodisomy can lead to blended phenotypes of imprinting disorders and autosomal recessive diseases. To determine whether a presentation of Prader-Willi syndrome (PWS) and progressive neurologic symptoms was caused by uniparental isodisomy, a detailed clinical and molecular characterization was performed. METHODS: A combination of clinical, molecular, and imaging data was included in this study. RESULTS: We present the case of a 12-year-old boy with a blended phenotype of PWS and hereditary spastic paraplegia type 11 (HSP-SPG11) caused by maternal uniparental isodisomy of chromosome 15 (UPiD(15)mat) covering a loss-of-function variant in SPG11 (NM_025137.4: c.733_734del; p.Met245ValfsTer2). Although symptoms in early childhood including hypotonia, global developmental delay, hyperphagia, obesity, and seizures were consistent with PWS, additional features of progressive spastic paraparesis, parkinsonism, and cognitive decline in later childhood were atypical. Brain MR imaging showed thinning of the corpus callosum and signal abnormalities of the forceps minor, consistent with a “ears of the lynx” sign. Exome sequencing confirmed a frameshift variant in SPG11 located in the PWS imprinting region on chromosome 15. DISCUSSION: This case highlights that atypical clinical features in patients with well-described imprinting disorders should lead to investigations for recessive conditions caused by variants in genes that localize to the region of homozygosity, including autosomal recessive forms of HSP.