Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families.

Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation.

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.

Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.

Clinical and technical assessment of MedExome vs. NGS panels in patients with suspected genetic disorders in Southwestern Ontario.

The adaptation of a broad genomic sequencing approach in the clinical setting has been accompanied by considerations regarding the clinical utility, technical performance, and diagnostic yield compared to targeted genetic approaches. We have developed MedExome, an integrated framework for sequencing, variant calling (SNVs, Indels, and CNVs), and clinical assessment of ~4600 medically relevant genes. We compared the technical performance of MedExome with the whole-exome and targeted gene-panel sequencing, assessed the reasons for discordance, and evaluated the added clinical yield of MedExome in a cohort of unresolved subjects suspected of genetic disease. Our analysis showed that despite a higher average read depth in panels (3058 vs. 855), MedExome yielded full coverage of the enriched regions (>20X) and 99% variant concordance rate with panels. The discordance rate was associated with low-complexity regions, high-GC content, and low allele fractions, observed in both platforms. MedExome yielded full sensitivity in detecting clinically actionable variants, and the assessment of 138 patients with suspected genetic conditions resulted in 76 clinical reports (31 full [22.1%], 3 partial, and 42 uncertain/possible molecular diagnoses). MedExome sequencing has comparable performance in variant detection to gene panels. Added diagnostic yield justifies expanded implementation of broad genomic approaches in unresolved patients; however, cost-benefit and health systems impact warrants assessment.

Student-Athletes' Views on APOE Genotyping for Increased Risk of Poor Recovery after a Traumatic Brain Injury.

Use of apolipoprotein E genotyping to personalize the risk of a poor recovery after traumatic brain injury is complicated by the potential for genetic discrimination and the potential to reveal an increased risk for late onset Alzheimer's disease. We developed a survey to gauge interest in testing among athletes participating in National Collegiate Athletic Association programs. Eight hundred and forty seven student-athletes were surveyed to determine their interest in genetic testing, their willingness to share the results of testing with parents, coaches and physicians, their concerns about privacy and/or discrimination, and their interest in genetic counseling. Nearly three quarters of respondents expressed some level of interest in testing, with the largest number describing themselves as 'possibly interested' (54.9 %, n = 463) and a smaller number describing themselves as 'very interested' (18.9 %, n = 159). Most student-athletes said that receiving secondary information about their risk for late-onset Alzheimer's disease made them more likely to test (50.6 %, n = 426) rather than less likely to test (12.4 %, n = 104). Student-athletes were open to apolipoprotein E genotyping and willing to share test results with their parents, coaches and physicians. They did not anticipate that test results would impact their behavior or ability to play. Testing programs may be welcome but should provide clear information as to risks and benefits.

Dual BRCA1 and BRCA2 pathogenic variants in an adolescent with syndromic intellectual disability.

Pathogenic variants in the BRCA1 and BRCA2 genes are associated with increased risk for breast and ovarian cancers. Concurrent mutations in both genes in the same individual are rare but pose specific challenges when identified, usually through multigene panel testing or infrequently from a genome-wide analysis, such as whole-exome sequencing (WES). We present a 15-year-old female patient with syndromic intellectual disability whose exome reanalysis identified secondary findings of pathogenic BRCA1 and BRCA2 variants, both inherited paternally. We discuss the significant challenges posed by this finding in genetic counseling and cancer risk management of an adolescent with nonverbal intellectual disability, as well as the impact on their family. This rare case highlights the potential increased diagnostic yield of whole exome sequencing reanalysis and the consequences of secondary medically actionable results in a pediatric patient.