Prader–Willi and PURA Syndromes Concurrently Diagnosed Using High-Throughput Sequencing with Methylation-Specific Multiplex Ligation-Dependent Probe Amplification: A Case Report

Background: A broad and heterogeneous spectrum of disorders present as feeding difficulties and hypotonia during the neonatal period, which are characterized by complex etiologies, diverse clinical manifestations, and considerable symptom overlap, posing diagnostic challenges. The co-occurrence of different genetic disorders in a single patient is rare. We report the a case of Prader–Willi syndrome (PWS) co-occurring with PURA syndrome diagnosed during the neonatal period. Case Presentation: We describe a case of a neonate admitted with feeding difficulties and hypotonia. The infant exhibited persistent feeding problems, hypotonia, a thin upper lip, and immature genitalia. The initial diagnostic workup included high-throughput whole-exome sequencing (WES). The WES results revealed a heterozygous de novo variant, c.764dupA (p.Asn255Lysfs*39), in PURA . This specific variant was absent from all population databases and has not been previously reported in the literature. The variant was classified as pathogenic based on the standards and guidelines of the American College of Medical Genetics and Genomics. This finding was consistent with a diagnosis of PURA syndrome (OMIM #616158). However, PWS could not be ruled out given the clinical phenotype of the patient. Subsequently, methylation-specific multiplex ligation-dependent probe amplification was performed. The paternal methylation imprint at the SNURF-SNRPN locus was completely absent (100%) , confirming the diagnosis of PWS caused by an imprinting center defect. The patient was definitively diagnosed with co-occurring PWS and PURA syndrome. The infant received rehabilitative therapy and growth hormone treatment. The patient showed satisfactory gains in length and weight during follow-up until 9 months of age. However, neurological improvement was poor, and the long-term prognosis remains under observation. Conclusions: We report a case of PWS co-occurring with PURA syndrome diagnosed during the neonatal period. The overlapping clinical presentation challenges the conventional diagnostic paradigm of one disease, one phenotype. We emphasize that the possibility of a dual diagnosis should be considered in infants with complex, rapidly progressive, or atypical features, even after one genetic disorder is identified. A multitiered molecular testing approach should be used to enable precise diagnosis and enabling individualized management, which are fundamental for establishing an accurate prognosis and predicting treatment outcomes.