Familial clustering of psychiatric disorders and low IQ

Background Although the ICD and DSM differentiate between different psychiatric disorders, these often share symptoms, risk factors, and treatments. This was a population-based, case–control, sibling study examining familial clustering of all psychiatric disorders and low IQ, using data from the Israel Draft-Board Registry on all Jewish adolescents assessed between 1998 and 2014. Methods We identified all cases with autism spectrum disorder (ASD, N = 2128), severe intellectual disability (ID, N = 9572), attention-deficit hyperactive disorder (ADHD) (N = 3272), psychotic (N = 7902), mood (N = 9704), anxiety (N = 10 606), personality (N = 24 816), or substance/alcohol abuse (N = 791) disorders, and low IQ (⩾2 SDs below the population mean, N = 31 186). Non-CNS control disorders were adolescents with Type-1 diabetes (N = 2427), hernia (N = 29 558) or hematological malignancies (N = 931). Each case was matched with 10 age-matched controls selected at random from the Draft-Board Registry, with replacement, and for each case and matched controls, we ascertained all full siblings. The main outcome measure was the relative recurrence risk (RRR) of the sibling of a case having the same (within-disorder RRR) or a different (across-disorder RRR) disorder. Results Within-disorder RRRs were increased for all diagnostic categories, ranging from 11.53 [95% confidence interval (CI): 9.23–14.40] for ASD to 2.93 (95% CI: 2.80–3.07) for personality disorders. The median across-disorder RRR between any pair of psychiatric disorders was 2.16 (95% CI: 1.45–2.43); the median RRR between low IQ and any psychiatric disorder was 1.37 (95% CI: 0.93–1.98). There was no consistent increase in across-disorder RRRs between the non-CNS disorders and psychiatric disorders and/or low IQ. Conclusion These large population-based study findings suggest shared etiologies among most psychiatric disorders, and low IQ.

Whole Genome Sequencing Uncovers a Rare Germline Variant in ATM Associated with Familial Myeloproliferative Neoplasms

Introduction: Myeloproliferative neoplasms (MPN) are sporadic diseases characterized by a somatic driver mutation in the JAK2, CALR or MPL gene. Although it is generally considered a sporadic disease, approximately 10% of MPN cases display familial clustering, and there is a 5 to 7-fold increased risk of developing an MPN among first degree relatives of MPN patients. In contrast to other myeloid malignancies, investigation of large pedigrees with familial clustering of MPN has failed to identify high-risk predisposition genes relevant to the general MPN population. Genome wide association studies (GWAS) have identified common, low penetrance risk alleles for MPN predisposition in multiple genes including JAK2, TERT, TET2, ATM and SH2B3. In order to identify novel germline predisposition variants in MPN, an unbiased whole genome sequencing (WGS) approach was utilized to examine genomic structure and germline variations in a cohort of individuals with familial MPN. Methods: The study cohort was comprised of 67 individuals with familial MPN enrolled in a prospective research registry at Johns Hopkins Hospital. Familial MPN was defined as a diagnosis of MPN in an individual with a family history of MPN or related myeloid malignancy (myelodysplastic syndrome and chronic myelomonocytic leukemia) in a first or second degree relative. Neutrophil genomic DNA was subjected to WGS using Illumina HiSeq platform and sequenced to 60x depth. We performed germline variant calling using HaplotypeCaller and following the GATK best practices. The variants detected were further enriched for germline by allele frequency 40-60% or >90% and presence in the gnomAD database. Non-synonymous coding variants that occurred in the study cohort at a statistically higher frequency that in the general population (gnomAD) were selected for further analysis. Prediction of variant deleteriousness was assessed by 4 algorithms (Provean, SIFT, Polyphen-2, CADD). Results: Filtering of 32,788 non-synonymous, likely germline variants produced 148 that occurred at a higher frequency in our cohort than in the general population (p < 0.01, Fisher's exact test). Of these, 29 were predicted to be pathogenic in 3 out of 4 algorithms. Five unrelated individuals were found to harbor a heterozygous p.Leu2307Phe variant in the ATM gene (chr11:108326169 C>T). The clinical characteristics of these individuals are presented in Table 1. The structure prediction of ATM indicates that Ser2306 is a potential phosphorylation site of protein kinase A, suggesting that the methionine-aromatic bond between M2026 and the mutated F2307 may block the phosphorylation of S2306 (Figure 1). Conclusions: We identified a rare ATM germline variant (chr11:108326169 C>T; p.Leu2307Phe) present in 5 individuals with familial MPN. ATM is involved in DNA damage repair and important in the maintenance of genomic integrity. Heterozygous germline variants in ATM are known to predispose to multiple cancer types, including breast, prostate, pancreatic and melanoma. Further, common polymorphisms in ATM have been found to be associated with the MPN phenotype via GWAS. Our data suggests that this variant may impact ATM activation and its function in DNA damage repair, and functional studies are in progress. These data implicate a rare germline ATM variant as a novel risk factor for development of MPN. Figure 1 Figure 1. Disclosures Hourigan: Sellas: Research Funding.

Suicide and genes: Commentary on Hawton and van Heeringen (Lancet 2009; 373: 1372-81)

Hawton’s and van Heeringen’s seminar on suicide is a rich source of current knowledge on the topic and highly useful for generalists. However, genetic risk factors for suicide are underappreciated in the seminar. Although family history of suicide is mentioned as important and genetic loading is listed under distal risk factors, their close connection is not emphasised: familial clustering of suicide is partly due to genetic risk factors. Convergent evidence towards this end has emerged from distinctly different genetically informative research designs. Appropriate consideration of these insights is an important public health agenda and matters for mental health literacy, as international surveys suggest disbelief in the genetics of suicide is widespread among medical and psychology undergraduates and in the general population.

Analysis of 23 Pediatric Patients with SARS-CoV-2 Infection in Anhui Province, China

Background: The global spread of coronavirus disease 2019 (COVID-19) continues to threaten all human health worldwide. Although the symptoms, signs, responses, and outcomes associated with the disease varies for individuals, few studies have reported on pediatric patients with COVID-19.Methods: This study retrospectively reviewed the medical records from three tertiary hospitals in Anhui province, China, of 23 children with COVID-19. Here, epidemiologic characteristics, clinical features, laboratory test results, and treatment strategies for these pediatric patients are reported and analyzed.Results: In total, 23 children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were analyzed. All patients were given a nucleic acid detection test for SARS-CoV-2, and positive results confirmed the diagnosis of COVID-19. Ten patients (43.5%) were female, and 19 patients (82.6%) had defined exposure history and familial clustering. The youngest patient was 16 months of age, the oldest, 17 years. The clinical symptoms of all included pediatric patients with SARS-CoV-2 infection were mild, with cough (12, 52.2%) and fever (10, 43.5%) being the most frequent, making their symptoms indistinguishable from common respiratory infections. There was no difference in clinical manifestation between males and females (P > 0.05). Eight patients (34.8%) showed changes on chest computed tomography imaging. The median level of each laboratory test parameter was within the normal reference range. Treatments primarily included antiviral therapies, traditional Chinese medicine therapies, and symptomatic supportive treatment.Conclusions: The symptoms of all 23 pediatric patients with SARS-CoV-2 infection included in this study were mild. Because the primary presenting symptoms were indistinguishable from common respiratory infections and because most patients had an exposure history and familial clustering, we recommend supporting the diagnosis of mild or atypical COVID-19 in children with detailed epidemiologic information and chest computed tomography imaging as well as with nucleic acid detection tests. Obtaining a correct diagnosis in the early stage of the disease will contribute to controlling the spread of SARS-CoV-2 infection and to providing more immediate relevant treatment for infected children.

Effect of familial clustering in the genetic screening of 235 French ALS families

ObjectivesTo determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved.MethodsWe conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed.ResultsRegarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years.ConclusionOur results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.