Molecular diagnosis of tuberous sclerosis complex in fetuses and infants: an institutional case series.

OBJECTIVE: We describe the clinical and genetic characteristics of fetuses and infants diagnosed with tuberous sclerosis complex (TSC) in our centre, prenatally or neonatally, for a better understanding of the benefits of early screening. METHODS: In this retrospective study, we analysed the data on one fetus and nine infants with a definitive TSC diagnosis by genetic criteria (five patients carrying TSC1 variants and 5 patients carrying TSC2 variants). We explored the differences between phenotypes of patients carrying TSC1 and TSC2 pathogenic variants. RESULTS: The most common initial presenting features of TSC were cardiac rhabdomyomas (CRs) that were observed in nine out of ten patients. The most common postnatal features, besides CR, were presented with subependymal nodules-in five patients, and hypomelanotic macules-in four patients. In total, 10 variants causing TSC were detected in this study, including 5 novel variants. We demonstrated that patients with TSC2 variants had earlier onset and more severe clinical manifestations compared with patients carrying TSC1 variants. CONCLUSION: Early diagnosis of TSC improves genetic counselling and perinatal management.

CAMK2D De Novo Missense Variant in Patient with Syndromic Neurodevelopmental Disorder: A Case Report.

BACKGROUND: Intellectual disability with developmental delay is the most common developmental disorder. However, this diagnosis is rarely associated with congenital cardiomyopathy. In the current report, we present the case of a patient suffering from dilated cardiomyopathy and developmental delay. METHODS: Neurological pathology in a newborn was diagnosed immediately after birth, and the acquisition of psychomotor skills lagged behind by 3-4 months during the first year of life. WES analysis of the proband did not reveal a causal variant, so the search was extended to trio. RESULTS: Trio sequencing revealed a de novo missense variant in the CAMK2D gene (p.Arg275His), that is, according to the OMIM database and available literature, not currently associated with any specific inborn disease. The expression of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) protein is known to be increased in the heart tissues from patients with dilated cardiomyopathy. The functional effect of the CaMKIIδ Arg275His mutant was recently reported; however, no specific mechanism of its pathogenicity was proposed. A structural analysis and comparison of available three-dimensional structures of CaMKIIδ confirmed the probable pathogenicity of the observed missense variant. CONCLUSIONS: We suggest that the CaMKIIδ Arg275His variant is highly likely the cause of dilated cardiomyopathy and neurodevelopmental disorders.