Tooth agenesis is among the most prevalent congenital anomalies affecting human dentition, characterized by the developmental absence of one or more teeth. This condition may be present in either syndromic or non-syndromic forms, with significant implications for oral function, aesthetics, and craniofacial development. This narrative review aims to provide a comprehensive overview of tooth agenesis, defining its classification, genetic underpinnings, epidemiological aspects, phenotypic features, and therapeutic approaches. Recent advances in genetic research have identified numerous causative genes, notably EDA, MSX1, WNT10A, and PAX9, each associated with specific patterns of missing teeth and involved in isolated and/or syndromic forms. Additionally, genes such as TSPEAR, LRP6, PITX2, and GREM2 contribute to varying degrees of severity and tooth distribution, often blurring the lines between syndromic and isolated cases. The genotype-phenotype correlations underscore the complexity of the underlying molecular pathways involved in odontogenesis. From a therapeutic perspective, the management of tooth agenesis requires a multidisciplinary approach, often involving orthodontic, prosthetic, and surgical interventions tailored to the severity of tooth loss and patient age. Early diagnosis represents a crucial role in treatment planning, facilitating timely intervention during growth and enhancing long-term outcomes. In conclusion, tooth agenesis remains a complex clinical condition with a strong genetic basis. A patient-centered and interdisciplinary strategy is essential to address both functional and psychosocial needs.

Maternal uniparental disomy of chromosome 15 [UPD(15)mat] and imprinting defects account for about 30% of cases of Prader–Willi 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>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’s multiple renal risk factors, FSGS was considered most likely multifactorial, and a causal association with CADASIL cannot be established from this single case.