Introduction. Nonmodifiable cardiovascular risk factors, like age and sex, are easily quantifiable. Due to immense technical progress in diagnostics and medical data storage, the aim of this study ...was to quantify, verify, and to compare parental cardiovascular events (CVE) as an additional nonmodifiable risk factor for young and middle-aged ischaemic stroke patients and controls. Methods. Information about parental CVE was first obtained by standardized questionnaires answered by 385 acute ischaemic stroke patients (15-60 years of age) and 260 controls. After consent to contact living and include deceased parents, patients and controls provided necessary personal identification of their parents. Thereafter, CVE were verified by standardized questionnaires answered by parents or medical records in case of deceased parents. Results. One hundred-and-nine (14.2%) of 770 patient parents vs. 128 (24.6%) of 520 control parents were not available for verification. Active participation was obtained for 229 (73.9%) of 310 patient parents vs.113 (58.2%) of 194 control parents. Medical record verification was obtained for 192 (54.7%) of 351 deceased patient parents, vs.103 (52.0%) of 198 deceased control parents. This study showed highest death rates of fathers (65.3% patient fathers and 57.6% control fathers) and highest numbers of CVE, especially myocardial infarction among patient fathers of patients aged 50-60 years. Discussion and Conclusion. Obtaining verified parental CVE as a nonmodifiable risk factor is still challenging, despite widely available digital medical information. To attain more accurate information on parental CVE, we recommend active involvement of family members in addition to medical record verification, especially for patients aged <50 years. Trial Registration. This trial is registered with NCT01597453
Purpose:
Patients with rare or ultra-rare genetic diseases, which affect 350 million people worldwide, may experience a diagnostic odyssey. High-throughput sequencing leads to an etiological ...diagnosis in up to 50% of individuals with heterogeneous neurodevelopmental or malformation disorders. There is a growing interest in additional omics technologies in translational research settings to examine the remaining unsolved cases.
Methods:
We gathered 30 individuals with malformation syndromes and/or severe neurodevelopmental disorders with negative trio exome sequencing and array comparative genomic hybridization results through a multicenter project. We applied short-read genome sequencing, total RNA sequencing, and DNA methylation analysis, in that order, as complementary translational research tools for a molecular diagnosis.
Results:
The cohort was mainly composed of pediatric individuals with a median age of 13.7 years (4 years and 6 months to 35 years and 1 month). Genome sequencing alone identified at least one variant with a high level of evidence of pathogenicity in 8/30 individuals (26.7%) and at least a candidate disease-causing variant in 7/30 other individuals (23.3%). RNA-seq data in 23 individuals allowed two additional individuals (8.7%) to be diagnosed, confirming the implication of two pathogenic variants (8.7%), and excluding one candidate variant (4.3%). Finally, DNA methylation analysis confirmed one diagnosis identified by genome sequencing (Kabuki syndrome) and identified an episignature compatible with a BAFopathy in a patient with a clinical diagnosis of Coffin-Siris with negative genome and RNA-seq results in blood.
Conclusion:
Overall, our integrated genome, transcriptome, and DNA methylation analysis solved 10/30 (33.3%) cases and identified a strong candidate gene in 4/30 (13.3%) of the patients with rare neurodevelopmental disorders and negative exome sequencing results.
