Genomic autopsy in neonatal‐onset mucopolysaccharidosis type <scp>VII</scp> : Key for diagnosis and future planning

Mucopolysaccharidosis (MPS) type VII (OMIM 253220), also known as Sly syndrome, is a rare lysosomal storage disorder caused by β-glucuronidase deficiency, resulting in glycosaminoglycan accumulation.1 Patients with MPS VII show skeletal deformities, cardiac valve abnormalities, and developmental delays. Due to the rarity of neonatal-onset cases, early diagnosis is challenging but essential for proper management. We present the case of a neonate born to a Japanese couple (a 32-year-old male and a 37-year-old female [G2P0110]). Fetal ascites was detected at 17 weeks of gestation and worsened by 20 weeks of gestation. Ultrasound confirmed fetal hydrops (Figure 1a). At 31 weeks of gestation, a cesarean section was performed due to nonreassuring fetal status. The neonate had a birthweight of 2300 g and bilateral pleural effusions, massive ascites, and severe respiratory failure caused by pulmonary hypoplasia. Despite intensive care, including mechanical ventilation and nitric oxide therapy, the neonate died on day 1. Due to early lethality and generalized edema, typical MPS VII features such as hepatosplenomegaly and skeletal dysplasia were not observed. The first pregnancy was terminated at 21 weeks of gestation due to fetal hydrops. Both pregnancies exhibited similar complications, suggesting a possible connection. Autopsy showed severe subcutaneous edema, pleural and peritoneal effusions, and pulmonary hypoplasia (Figure 1b). Histopathological evaluation revealed foamy histiocytes in the liver and spleen (Figure 1c). Toluidine blue staining for acidic mucopolysaccharides and CD68, an indicator of activated macrophages, was negative (Figure 1d,e). With foamy histiocytes suggesting a lysosomal storage disorder, further genetic testing was performed, despite the absence of acidic mucopolysaccharides or activated macrophages. Chromosome analysis revealed a normal karyotype (46,XX). Trio whole-exome sequencing using parental blood samples and preserved DNA identified two pathogenic variants in the GUSB gene (a novel NM_000181.4:c.1838_1839del p.(Arg613Thrfs*19) of maternal origin and a known variant, NM_000181.4:c.1618G>A p.(Glu540Lys),2 of paternal origin). The diagnosis was MPS type VII with a compound heterozygous mutation in the GUSB gene. The c.1618G>A mildly reduced enzymatic activity.2 The novel c.1838_1839del frameshift variant is located within a region predicted to escape nonsense-mediated mRNA decay. Previous expression studies in COS-7 cells have shown that a different frameshift variant (c.1874_1875del) reduces β-glucuronidase protein activity and causes a loss of GUSB activity.2, 3 By analogy, the c.1838_1839del variant may also cause loss of GUSB activity. Fetal edema occurs in 30%–40% of neonates with MPS VII; the 1-year survival rate is 40%–60%.1 Although survival beyond infancy is rare, perinatal survivors follow a severe course. Early genetic diagnosis is crucial for introducing enzyme replacement therapy when survival is expected. The diagnosis of life-threatening fetal-onset MPS VII is challenging due to nonspecific symptoms such as fetal edema. Foamy histiocytes observed at autopsy were key to genetic testing, which confirmed MPS VII in this case. This is the first reported autopsy of neonatal-onset MPS VII, highlighting the need for a “genomic autopsy,” which combines conventional autopsy with genetic techniques, especially in unexplained neonatal deaths.4 Despite the value, NICU autopsy rates vary widely, with some studies reporting a 20% rate due to concerns about invasiveness and cultural beliefs.5 However, a genomic autopsy provides a definitive diagnosis or key information for genetic counseling in approximately 50% of cases,4 providing insights inaccessible through conventional methods. Genetic diagnosis can support reproductive decisions, including amniocentesis, chorionic villus sampling, and preimplantation genetic testing for monogenic disorders, and is essential for understanding prognosis and assessing recurrence risk in future pregnancies. Ethical challenges in genomic autopsy, including timing, cultural acceptability, and balancing family benefits with readiness, require sensitive communication from multidisciplinary teams. A detailed family history, tissue preservation, and informed consent for autopsy and genetic testing are key to diagnosing severe congenital diseases. Genomic autopsies improve diagnostic accuracy and provide families with essential information for genetic counseling and future pregnancy planning. T.O., M.I., M.Y., A.M., L.F., N.M., and A.W. contributed to the data collection, analysis, and manuscript preparation. All have approved the final manuscript. Written consent was obtained from the patients' families to publish clinical notes. This case report was supported by the Initiative on Rare and Undiagnosed Diseases (IRUD) from the Japan Agency for Medical Research and Development. This work was supported in part by the Japan Agency for Medical Research and Development (AMED) P25ek0109674, JP25ek0109760, JP25ek0109617, JP25ek0109648, and JP25ek0109677 (Matsumoto N), the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid for Scientific Research JP24K02230 (Matsumoto N), and the Takeda Science Foundation (Matsumoto N). The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.