Case Report: Concurrent maternal uniparental disomy-type Prader-Willi syndrome and X-linked G6PD deficiency—an area of focus on multi-gene screening for imprinting disorders

Abstract

Prader-Willi syndrome (PWS) is a rare imprinting disorder caused by functional impairment of imprinted genes within the paternal 15q11.2-q13 region. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked hereditary disorder. Cases describing the coexistence of maternal uniparental disomy (UPD)-type PWS and G6PD deficiency are extremely scarce in global clinical reports. This article summarizes three male infant cases from our center and further sorts out previously published literature on PWS combined with other genetic disorders to analyze shared genetic characteristics and clinical phenotypes of such combined genetic conditions. We performed retrospective sorting and analysis on three male infants simultaneously diagnosed with maternal UPD-type PWS and G6PD deficiency between August 2022 and December 2024 at the Children's Hospital, Zhejiang University School of Medicine. Meanwhile, systematic retrieval of published literature from 1956 to 2025 was carried out across PubMed, Scopus Preview, Cochrane Reviews, Ovid and Semantic Scholar, and 28 documented PWS patients complicated by other single-gene or chromosomal genetic disorders were collated for comparative analysis. Genetic variant pathogenicity was judged against the American College of Medical Genetics and Genomics (ACMG) genetic variant classification criteria. All three enrolled infants presented typical core manifestations of PWS, including neonatal hypotonia, feeding difficulties, and cryptorchidism, without jaundice, anemia, dark urine or other G6PD-related symptoms. Genetic testing confirmed maternally inherited hemizygous G6PD variants: one case carried c.152C >T classified as likely pathogenic, and two carried c.1388G >A classified as pathogenic. Literature collation identified 14 PWS patients complicated with sex chromosome abnormalities and 15 patients with autosomal chromosomal/genomic or monogenic disorders. To our knowledge, this is the first case series reporting maternal UPD-type PWS combined with X-linked G6PD deficiency; it supplements novel clinical observations of this rare dual diagnosis and expands the recognized spectrum of PWS comorbid genetic disorders. For maternal UPD-PWS patients, expanded trio-whole exome sequencing (trio-WES) or trio-whole-genome sequencing (trio-WGS) is worth clinical consideration even without atypical phenotypes, to screen for hidden maternal multi-locus pathogenic variants. Given the small sample size of only three patients, additional multi-center data are needed to validate the clinical and genetic patterns of this combined phenotype. Keywords: Prader-Willi syndrome; Glucose-6-phosphate dehydrogenase deficiency; Uniparental disomy; Comorbid genetic disorders; X-linked hereditary disease