{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T11:30:54Z","timestamp":1786447854628,"version":"build-2736575974"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014NextGenerationEU and the Italian Ministry of University and Research","award":["2022L4F87B"],"award-info":[{"award-number":["2022L4F87B"]}]},{"award":["2022L4F87B"],"award-info":[{"award-number":["2022L4F87B"]}],"id":[{"id":"https:\/\/ror.org\/0341vw408","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader\u2013Willi syndrome (PWS). Mosaic UPD(15)mat is rare and may escape routine testing. We describe a 45-year-old male patient in whom persistent clinical suspicion of PWS was not genetically confirmed by repeated methylation-based analyses. Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, short stature, growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD\/MASH with compensated cirrhosis. He presented with very mild neurodevelopmental impairment. Following the detection of proteinuria and microalbuminuria from age 22 years, focal segmental glomerulosclerosis was diagnosed upon renal biopsy. A family history of cerebrovascular events was recorded. Combined SNP-array and MS-MLPA analyses across tissues established a diagnosis of PWS due to mosaic UPD(15)mat. The mosaic fraction, estimated by SNP-array, was approximately 10% in peripheral blood and 40% in buccal cells; MS-MLPA detected abnormal methylation only in buccal cells, explaining the previous negative blood-based results. Exome sequencing identified the paternally inherited pathogenic NOTCH3 variant NM_000435.2:c.3016C&gt;T, p.(Arg1006Cys). Subsequent brain MRI showed chronic vascular-type leukoencephalopathy consistent with CADASIL, despite the absence of overt ischemic events in the proband. Collectively, these investigations established a dual molecular diagnosis of PWS due to mosaic UPD(15)mat and NOTCH3-related CADASIL. This report highlights the pivotal role of clinical genetics in assessing the precise diagnosis in rare diseases. With respect to PWS, it demonstrates that mosaicism can lead to a missed diagnosis when the genetic investigation is limited to peripheral blood. In addition, following the diagnosis of CADASIL, and based on the available evidence linking NOTCH3 to renal physiology and disease, we discuss whether NOTCH3-related renal microangiopathy may have contributed to the renal phenotype. However, given the patient\u2019s multiple renal risk factors, FSGS was considered most likely multifactorial, and a causal association with CADASIL cannot be established from this single case.<\/jats:p>","DOI":"10.3390\/genes17080937","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T10:32:16Z","timestamp":1786444336000},"page":"937","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Clinical Genetics-Driven Dual Diagnosis of Prader\u2013Willi Syndrome Due to Mosaic Maternal UPD(15) and NOTCH3-Related CADASIL"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-2721-1898","authenticated-orcid":false,"given":"Francesco Maria","family":"Bogliardi","sequence":"first","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0640-4923","authenticated-orcid":false,"given":"Pino","family":"D\u2019Ambrosio","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5415-1020","authenticated-orcid":false,"given":"Giorgia","family":"Quattromini","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5273-3552","authenticated-orcid":false,"given":"Giordana","family":"Di Mario","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0417-9939","authenticated-orcid":false,"given":"Maria Grazia","family":"Pomponi","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3464-0068","authenticated-orcid":false,"given":"Luca","family":"Miele","sequence":"additional","affiliation":[{"name":"CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Vergani","sequence":"additional","affiliation":[{"name":"Complex Operative Unit of Internal Medicine, Endocrinology and Diabetology, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Zampino","sequence":"additional","affiliation":[{"name":"Centre for Rare Diseases and Congenital Defects, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0801-7152","authenticated-orcid":false,"given":"Antonio","family":"Liguori","sequence":"additional","affiliation":[{"name":"CEMAD Digestive Diseases Center, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4871-9519","authenticated-orcid":false,"given":"Marcella","family":"Zollino","sequence":"additional","affiliation":[{"name":"Section of Genomic Medicine, Department of Life Sciences and Public Health, Universit\u00e0 Cattolica del Sacro Cuore, 00168 Rome, Italy"},{"name":"Medical Genetics Unit, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Crin\u00f2","sequence":"additional","affiliation":[{"name":"Centre for Rare Diseases and Congenital Defects, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"ref_1","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Pagon, R.A., Wallace, S.E., and Amemiya, A. (1998). Prader-Willi Syndrome. GeneReviews\u00ae, University of Washington. updated 2026."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/gim.0b013e31822bead0","article-title":"Prader-Willi syndrome","volume":"14","author":"Cassidy","year":"2012","journal-title":"Genet. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ramsden, S.C., Clayton-Smith, J., Birch, R., and Buiting, K. 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