With a population prevalence of 1%, schizophrenia is widespread, yet the aetiology of this psychiatric disorder remains elusive. There is an evident genetic component of schizophrenia, with heritability estimates lying at 60%-80%. While genome-wide association studies have identified 120 gene loci associated with schizophrenia risk, these involved common variants that confer only small effects on individual risk (median odds ratio < 1.2). The recent emergence of whole exome sequencing (WES) technologies has facilitated the identification of rare sequence variants, including some protein-truncating variants that have significant effects on risk. Three key large-scale WES studies have demonstrated that rare sequence variants in the genes SETD1A, CACNA1G, CUL1, GRIA3, GRIN2A, HERC1, RB1CC1, SP4, TRIO, XPO7, and AKAP11 confer substantial risk for schizophrenia. These genes are highly expressed in central nervous system neurons and their products participate in diverse molecular functions including synaptic transmission, transcriptional regulation, and ubiquitin ligation. The understanding of these functional roles illuminates putative molecular mechanisms which may lead to schizophrenia-like phenotypes. It will also be possible to develop model systems in which the effects of impaired function of these genes can be further explored. Genetic studies of rare variants to date suggest that glutamatergic system dysregulation, chromatin modification, and the ubiquitin-proteasome system play key roles in schizophrenia aetiology.

Young-onset type 2 diabetes (YOD), defined as diabetes diagnosis before age 40, has an aggressive clinical course with premature mortality, in part due to long disease duration and lack of evidence to guide diagnosis and management. Autoimmune type 1 diabetes, maturity-onset diabetes of the young (MODY), and latent autoimmune diabetes in adults (LADA) are subtypes of diabetes in young people, which, however, cannot fully explain their complex clinical course. Similarly, family members carrying the same rare genetic variant of monogenic diabetes can have different presentations and outcomes. Ancestral heterogeneity, ecological transition, inter-ethnic differences in genomic architecture, and variations in living environment, lifestyles, access to care, and timeliness of diagnosis and treatment can influence the age of diagnosis and exposure to these cardiometabolic-renal risk factors. Despite the wealth of literature on genetic associations with diabetes, the familial cosegregation of rare variants and their relevance to YOD remains uncertain. This perspective was motivated by decades of clinical observations and learnings from an ongoing randomized controlled trial that uses biogenetic markers to classify patients with YOD for improving outcomes. Apart from highlighting the need to use family-based studies to improve the precision of diagnosis, we discussed atypical causes for diabetic ketoacidosis and the importance of lifecourse and psychosocial-behavioral factors in patients with YOD. Apart from detailed clinical evaluation, we propose using plasma C peptide, homeostasis model of assessment (HOMA) indexes, autoantibodies, and polygenic risk scores to stratify risk, classify diabetes subtypes, and personalize treatment in YOD. To achieve these goals, we advocate changing the practice environment and team structure to enable physicians to use the insights they learn from patients and their family members to implement precision medicine and improve the outlook of these high-risk individuals.

Aims: The revised 2022 World Health Organization classification recognizes myeloid neoplasms with associated germline predisposition as a defined subcategory, underscoring the clinical significance of likely pathogenic (LPV) and pathogenic (PV) germline variation in these diseases. To better understand the role of LPV/PV in blood or marrow transplants (BMT), a curative therapy for myeloid neoplasms, we measure their frequency and association with mortality in two cohorts of donor-recipient pairs.

Methods: LPV/PV frequencies in 665 cancer-related genes were measured using exomechip genotyping data in 1990 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients and their unrelated donors, registered with the Center for International Blood and Marrow Transplant Research. Cox proportional hazard models were used to test variant association with recipient mortality one-year post-transplant.

Results: Thirteen autosomal dominant (AD) LPV/PV in eight genes were found in 2.8% of patients and 2.2% of donors; those linked to autosomal recessive conditions appeared in 11.1% of patients and 11% of donors. The most common AD LPV/PV mutations in recipients were found in DDX41 (n = 18). For donors, the most frequent AD PVs occurred in CHEK2 (n = 21) and Fanconi Anemia (FA) genes (n = 7). DDX41 and CHEK2 variation did not correlate with patient survival, but patients with donors with an LPV/PVs in an FA gene had lower survival (HR = 2.38, 95%CI: 1.06-5.31, P = 0.035) than patients whose donors did not have an FA LPV/PV.

Conclusion: We identified LPVs/PVs in cancer genes in donors and recipients and are the first to show an association of donor FA PVs with mortality after BMT.

Prostate cancer remains the most common malignancy among men in the United States. Advancements in androgen receptor signaling blockade have led to landmark approvals for its use in patients with locally advanced and metastatic disease. However, additional novel therapeutic strategies for both hormone-sensitive and castration-resistant diseases remain ongoing areas of study. Thus, we turn to the growth of immuno-oncology, which has led to improved treatment outcomes for a variety of hematologic and solid tumor malignancies. Prostate cancers have shown only modest results with immune checkpoint inhibition in published trials, and innovative strategies are now looking into enhancing cytotoxic T-cell activity against cancer cells. This review provides a thorough evaluation of tumor-associated antigens that are integrated into novel chimeric antigen receptor T-cell and bispecific T-cell engager therapies. Our review will evaluate the most recent advancements in immunotherapies, while also illustrating major obstacles and underlying limiting factors.

Aim: 47,XXY (KS) is the most frequently occurring sex chromosome aneuploidy (SCA) with an incidence rate of 1:500 to 1:650 live male births. 47,XXY is characterized by androgen insufficiency and hypogonadism, diminished phallus size, hypotonia, and increased stature. This investigation examines the relationship between Early Hormonal Treatment (EHT) and growth in boys with 47,XXY from birth to 5 years.

Methods: A cohort of 134 males with 47,XXY was seen as part of a natural history study and anthropometric measurements were completed at each evaluation for height (HT), weight (WT), and head circumference (HC). Data was analyzed for these factors in the group receiving testosterone as EHT (T group) and a no treatment (No-T) control group.

Results: Significant differences in HC were observed between the T group and No-T group for birth to 12 months. There was no other significant difference in HC for boys between the ages of 13 to 60 months. Only significant differences were observed in the birth to 12 months group for HT between the T group and No-T group. There were only significant differences in WT in the birth to 12-month age range between the T group and the No-T group, as well as in the 12-24-month age range.

Conclusion: EHT is not associated with reducing or advancing growth in children with 47,XXY over 2 years old. After 24 months of age there is no discernible difference between boys with 47,XXY with EHT and without EHT.