Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

Abstract

In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many appears a distant target. This article presents three paradigmatic cases to exemplify how this translational effort can, at least in some instances, be undertaken today with very positive results: (a) a young girl carrying a chr. 16p11.2 duplication can be screened using targeted exams and undertake therapeutic/preventive interventions related to her genetic diagnosis; (b) a 13-year-old boy with intellectual disability and autism spectrum disorder carries a chr. 11q14.1 deletion, partly spanning the DLG2 gene important for synaptic function, and gained over 20 I.Q. points ostensibly due to carbolithium, prescribed in the absence of affective symptoms, exclusively following the pathophysiology pointed out by the genetic results; (c) a 58-year-old woman carries a COL3A1 gene variant responsible for the vascular form of Ehler–Danlos syndrome with colon rupture. Detection of this variant in six members of her extended family allows for better clinical management of the proband and targeted genetic counselling for family members at risk of this connective tissue disorder. The unprecedented flow of genetic information available today through new technologies, if interpreted in the light of current knowledge in clinical diagnosis and care of those with connective tissue disorders and neurodevelopmental disturbances, in biology and in neuropsychopharmacology, can promote better clinical and pharmacological treatment, disease surveillance, and management provided and incorporated into the clinical setting.

Yield of array‐CGH analysis in Tunisian children with autism spectrum disorder

“…Despite the limitations discussed above, our results support the use of aCGH as a first‐tier genetic test for ASD, both (a) to identify recurrent CNVs and genetic syndromes associated with ASD, and (b) to detect rare or “unique” pathogenic and likely pathogenic CNVs. This level of genetic characterization can, at least in some cases, foster a better understanding of phenotype–genotype correlations and improved management at the clinical level (Butler et al, 2022 ). At the same time, these results confirm that despite using the most advanced technologies, only a minority of cases with ASD finds a satisfactory monogenic explanation to their disorder.…”

“…How to cite this article: Chehbani, F., Tomaiuolo, P., Picinelli, C., Baccarin, M., Castronovo, P., Scattoni, M. L., Gaddour, N., Persico, A. M. (2022). Yield of array-CGH analysis in Tunisian children with autism spectrum disorder.…”

From Genes to Therapy in Autism Spectrum Disorder

“…Within groups of patients at risk for neurodevelopmental disorders based on shared carriership of a high impact genetic variant, refinement of individual risk is required to overcome the challenge of variable expressivity and pleiotropy invariably associated with genetic risk. Individualized treatments can in some instances be already pursued today, provided genetic results are analyzed also with this aim in mind [ 7 , 8 ], and clinicians have received sufficient training in their interpretation [ 58 ]. Further momentum will hopefully be provided by the translation of iPSC-based approaches into individualized pharmacological treatments [ 11 , 20 ].…”

“…For example, Dyar et al, discuss how dosage of various psychotropic medications may require adjustment in those patients with Phelan–McDermid Syndrome with 22q13.3 deletions including the gene CYP2D6 [ 7 ]. Clinically actionable information derived from genetic testing is also center stage in the discussion of three individual patients with different genetic conditions, reported by Butler et al, These examples, drawn from clinical practice, illustrate how such knowledge can already inform clinicians about preventive monitoring, the need for additional medical examinations or for surveillance for specific conditions associated with the genetic variant as well as guide the choice of psychotropic medications [ 8 , 9 ].…”

Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders

“…The availability of known compounds with certain functions is crucial here. Several papers in the present Special Issue discuss these ideas, for example, through presenting possible new pharmacological options for carriers of specific genetic syndromes [ 13 , 22 ], or the authors translate neurobiological findings in relation to specific genetic syndromes into clinical care [ 23 ]. Finally, in addition to drug repurposing, gene therapies also may be developed in the future as new treatment option for ASD [ 24 ].…”