1 - Serviço de Genética Médica, Centro Hospitalar e Universitário de Lisboa Central, Lisboa, Portugal
2 - Consulta de Genética Médica, Hospital dos Lusíadas, Lisboa, Portugal
3 - Serviço de Genética Médica, Centro Hospitalar e Universitário de Lisboa Norte, Lisboa, Portugal
- Comunicação oral - 27.ª Reunião Anual da Sociedade Portuguesa de Genética Humana (SPGH), 23-25 de novembro 2023, Lisboa
Introduction: Hickam’s dictum is the principle upon is statistically more likely that a patient with multiple symptoms has a combination of diseases rather than only one diagnosis that fully explains the complete phenotype. Dual genetic diagnoses (DGD) consist of distinct or blend clinical diagnoses of more than one locus that segregates independently. Increasing diagnostic yield with techniques such as whole exome sequencing (WES) is associated with rise of unbiased DGD. Data from literature estimates that 7% of cases have DGD.
Aim and methods: Retrospective review of paediatric patients with DGD referred to our Genetics Department (2001-2023), to identify and assess their clinical and genetic characteristics.
Results: 25 patients were identified with a confirmed or potentially DGD. In 20/25 DGD were confirmed, clinical consistent with the phenotype and genetic results were classified as likely pathogenic/pathogenic. In 5/25 cases, one variant was classified as uncertain significance but considered to be of potential clinical relevance. The main indication for referral was multisystemic disease 22/25. 3/25 patients were referred with a previous genetic diagnosis that did not fully explained the phenotype. Of the cases without previous diagnosis (22/25), 12 presented with atypical features, 2 had a blended phenotype and 8 had a second diagnosis after clinical validation of incidental/secondary findings reported. In most cases on 15/25 the first-tier test provided DGD. Primary diagnoses were obtained by WES in 13 cases and by array in 7, and secondary diagnoses by WES in 14 and array in 8.
Conclusion: DGD should be considered when a patient presents with atypical features, especially if associated with multisystemic phenotype. In most cases, clinical suspicion was the main drive to continue investigation. WES data improves our diagnostic capacity by identifying diagnoses that might be difficult to assert, even with deep phenotyping. This review provides important data suggesting that a diagnostic investigation is not necessarily complete after achieving one diagnosis and pursuing a DGD have implications in establishing patient’s prognosis, management and proper genetic counselling.
Palavras Chave: atypical phenotype, dual genetic diagnoses, multisystemic phenotype, whole exome sequencing