Case Report: Diagnostic odyssey in rare diseases: when genetic variants are misinterpreted

Introduction The diagnostic odyssey in rare diseases often involves the misinterpretation of genetic data, particularly when multidisciplinary approaches are lacking. This study illustrates the critical process of interpreting variants from next-generation sequencing (NGS) through a real-life case of a child misdiagnosed with Marfan Syndrome (MFS). The misdiagnosis was maintained for over seven years despite repeated clinical evaluations by different specialists. An initial clinical suspicion of MFS due to joint hypermobility at 3 years of age became a definitive diagnosis after an external laboratory reported a heterozygous variant in the MYH11 gene at age 5, despite the patient never fulfilling the established clinical diagnostic criteria for the disease. Methods To provide an accurate diagnosis and end the family's diagnostic odyssey, a complete clinical and genetic reinterpretation was performed when the patient was 7 years old. The proband and 9 asymptomatic relatives were recruited for a functional study of the MYH11 c. 5544₅548del, p. (D1848Efs*60) variant. Results The functional analysis demonstrated that the variant operates through a loss-of-function mechanism, leading to nonsense-mediated mRNA decay. While gain-of-function variants in MYH11 are associated with thoracic aortic aneurysms and dissections, loss-of-function variants are linked to autosomal recessive Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome (MMIHS). As a heterozygous carrier of a loss-of-function variant, the patient is asymptomatic for MMIHS and definitively does not have MFS. Currently, the 11-year-old child is progressing favorably without any notable pathology. Conclusions This case exposes the entire diagnostic odyssey suffered by the patient's family and highlights three fundamental systemic errors: the critical delay in genetic counseling, the over-interpretation of NGS data by external laboratories lacking phenotypic context, and the health system's inefficiency in integrating clinical geneticists. Overcoming these barriers is essential for the true implementation of personalized precision medicine.