Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice

IMPORTANCE: It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. OBJECTIVE: To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. EXPOSURES: Genetic test results. MAIN OUTCOMES AND MEASURES: Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. RESULTS: Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). CONCLUSIONS AND RELEVANCE: Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes

Narrowing the Critical Region for Congenital Vertical Talus in Patients With Interstitial 18q Deletions

International audienc

Narrowing the Critical Region for Congenital Vertical Talus in Patients With Interstitial 18q Deletions

International audienc

Identification of familial and de novo microduplications of 22q11.21-q11.23 distal to the 22q11.21 microdeletion syndrome region

Deletions of the 22q11.2 region distal to the 22q11.21 microdeletion syndrome region have recently been described in individuals with mental retardation and congenital anomalies. Because these deletions are mediated by low-copy repeats (LCRs), located distal to the 22q11.21 DiGeorge/velocardiofacial microdeletion region, duplications are predicted to occur with a frequency equal to the deletion. However, few microduplications of this region have been reported. We report the identification of 18 individuals with microduplications of 22q11.21-q11.23. The duplication boundaries for all individuals are within LCRs distal to the DiGeorge/velocardiofacial microdeletion region. Clinical records for nine subjects reveal shared characteristics, but also several examples of contradicting clinical features (e.g. macrocephaly versus microcephaly and upslanting versus downslanting palpebral fissures). Of 12 cases for whom parental DNA samples were available for testing, one is de novo and 11 inherited the microduplication from a parent, three of whom reportedly have learning problems or developmental delay. The variable phenotypes and preponderance of familial cases obfuscate the clinical relevance of the molecular data and emphasize the need for careful parental assessments and clinical correlations

Genes and biological processes commonly disrupted in rare and heterogeneous developmental delay syndromes

Rare copy number variations (CNVs) are a recognized cause of common human disease. Predicting the genetic element(s) within a small CNV whose copy number loss or gain underlies a specific phenotype might be achieved reasonably rapidly for single patients. Identifying the biological processes that are commonly disrupted within a large patient cohort which possess larger CNVs, however, requires a more objective approach that exploits genomic resources. In this study, we first identified 98 large, rare CNVs within patients exhibiting multiple congenital anomalies. All patients presented with global developmental delay (DD), while other secondary symptoms such as cardiac defects, craniofacial features and seizures were varyingly presented. By applying a robust statistical procedure that matches patients’ clinical phenotypes to laboratory mouse gene knockouts, we were able to strongly implicate anomalies in brain morphology and, separately, in long-term potentiation as manifestations of these DD patients’ disorders. These and other significantly enriched model phenotypes provide insights into the pathoetiology of human DD and behavioral and anatomical secondary symptoms that are specific to DD patients. These enrichments set apart 103 genes, from among thousands overlapped by these CNVs, as strong candidates whose copy number change causally underlies approximately 46% of the cohort's DD syndromes and between 59 and 80% of the cohort's secondary symptoms. We also identified significantly enriched model phenotypes among genes overlapped by CNVs in both DD and learning disability cohorts, indicating a congruent etiology. These results demonstrate the high predictive potential of model organism phenotypes when implicating candidate genes for rare genomic disorders

The numbers of differentially expressed genes with a p-value less than 0.05 are shown for each comparison.

See S1–S4 Tables for full lists of significant differentially expressed genes.</p

Burden analysis results showing statistically significant difference when comparing the number of rare functional variants in the proband group to the control group for <i>HIF1A</i>, <i>VHL</i>, and <i>IDH1</i>.

Burden analysis results showing statistically significant difference when comparing the number of rare functional variants in the proband group to the control group for HIF1A, VHL, and IDH1.</p