A Clinical Genetics-Driven Dual Diagnosis of Prader-Willi Syndrome Due to Mosaic Maternal UPD(15) and NOTCH3-Related CADASIL.

Mosaic UPD(15)mat was confirmed as the cause of PWS after repeated methylation-based analyses on peripheral blood had previously failed to establish the diagnosis.

• The patient was a 45-year-old male with longstanding clinical suspicion of PWS that was not genetically confirmed by repeated methylation-based analyses prior to this investigation.
• Combined SNP-array and MS-MLPA analyses across multiple tissue types established the diagnosis of PWS due to mosaic UPD(15)mat.
• The mosaic fraction estimated by SNP-array was approximately 10% in peripheral blood and approximately 40% in buccal cells.
• MS-MLPA detected abnormal methylation only in buccal cells, directly explaining why previous blood-based testing had returned negative results.
• UPD(15)mat and imprinting defects account for about 30% of cases of Prader-Willi syndrome, and mosaic UPD(15)mat is described as rare.

The patient's clinical phenotype included classical PWS features but with notably very mild neurodevelopmental impairment, potentially consistent with the mosaic nature of the condition.

• Clinical manifestations included neonatal hypotonia with low birth weight, early hyperphagia, severe obesity, and short stature.
• Endocrine and metabolic features included growth hormone deficiency, type 2 diabetes mellitus, dyslipidemia, and MASLD/MASH with compensated cirrhosis.
• The patient presented with very mild neurodevelopmental impairment, which may reflect the lower mosaic fraction in blood and other tissues.

Exome sequencing identified a paternally inherited pathogenic NOTCH3 variant consistent with a diagnosis of CADASIL.

• The pathogenic variant identified was NM_000435.2:c.3016C>T, p.(Arg1006Cys) in the NOTCH3 gene.
• The variant was paternally inherited, and a family history of cerebrovascular events was recorded.
• Subsequent brain MRI showed chronic vascular-type leukoencephalopathy consistent with CADASIL.
• Despite the leukoencephalopathy on MRI, the proband had no overt ischemic events at the time of investigation.

The patient had renal disease in the form of focal segmental glomerulosclerosis (FSGS), and the potential contribution of NOTCH3-related renal microangiopathy was considered but not established.

• Proteinuria and microalbuminuria were first detected from age 22 years, and focal segmental glomerulosclerosis was diagnosed upon renal biopsy.
• The authors discuss available evidence linking NOTCH3 to renal physiology and disease, raising the possibility that NOTCH3-related renal microangiopathy may have contributed to the renal phenotype.
• However, given the patient's multiple renal risk factors (including obesity, type 2 diabetes, and dyslipidemia), FSGS was considered most likely multifactorial.
• The authors explicitly state that 'a causal association with CADASIL cannot be established from this single case.'

This case establishes a dual molecular diagnosis — PWS due to mosaic UPD(15)mat and NOTCH3-related CADASIL — in a single patient.

• The two diagnoses were established through complementary genomic technologies: SNP-array and MS-MLPA for PWS, and exome sequencing for CADASIL.
• The co-occurrence of two rare genetic conditions in one patient was uncovered through persistent clinical genetics evaluation despite prior negative testing.
• The report highlights 'the pivotal role of clinical genetics in assessing the precise diagnosis in rare diseases.'

Multi-tissue genetic analysis is essential for detecting mosaic UPD(15)mat, as restriction to peripheral blood can yield false-negative results.

• The mosaic fraction was approximately 10% in peripheral blood versus approximately 40% in buccal cells, illustrating significant tissue variability.
• MS-MLPA failed to detect abnormal methylation in blood but succeeded in buccal cells, confirming that tissue choice is critical for diagnosis.
• The paper concludes that 'mosaicism can lead to a missed diagnosis when the genetic investigation is limited to peripheral blood.'