We integrate 16 genomic features to construct an evidence-weighted functional-linkage network comprising 21,657 human genes. The functional-linkage network is used to prioritize candidate genes for 110 diseases, and to reliably disclose hidden associations between disease pairs having dissimilar phenotypes, such as hypercholesterolemia and Alzheimer's disease. Many of these disease-disease associations are supported by epidemiology, but with no previous genetic basis. Such associations can drive novel hypotheses on molecular mechanisms of diseases and therapies.

Objective Macrophage activation syndrome (MAS), a life-threatening complication of systemic Juvenile Idiopathic Arthritis (SJIA), resembles Familial Hemophagocytic Lymphohistiocytosis (FHLH), a constellation of autosomal recessive immune disorders resulting from deficiency in cytolytic pathway proteins. We hypothesized that MAS predisposition in SJIA could be attributed to rare gene sequence variants affecting the cytotolytic pathway. Methods Whole exome sequencing (WES) was used in 14 SJIA/MAS patients and their parents to identify protein altering SNPs/indels in the known HLH-associated genes. To discover new candidate genes, the entire WES data were filtered to identify protein altering, rare recessive homozygous, compound heterozygous, and de novo variants with the potential to affect the cytolytic pathway. Results Heterozygous protein-altering rare variants in the known genes (LYST, MUNC13-4, and STXBP2) were found in 5 of 14 SJIA/MAS patients (35.7%). This was in contrast to only 4 variants in 4 of 29 (13,7%) SJIA patients without MAS. Homozygosity and compound heterozygosity analysis applied to the entire WES data in SJIAMAS, revealed 3 recessive pairs in 3 genes, and 76 compound heterozygotes in 75 genes. We also identified 22 heterozygous rare protein altering variants that occurred in at least two patients. Many of the identified genes encode proteins with a role in actin and microtubule reorganization and vesicle-mediated transport. “Cellular assembly and organization” was the top cellular function category based on Ingenuity Pathways Analysis (p<3.10E-05). Conclusion WES performed in SJIA/MAS patients identified rare protein altering variants in the known HLH associated genes as well as new candidate genes.

Key Points Acalabrutinib had good tolerability in patients with relapsed or refractory CLL who were intolerant to ibrutinib. Acalabrutinib demonstrated a high response rate (81%) in patients with relapsed or refractory CLL who were intolerant to ibrutinib.

Ciliopathies are a large group of clinically and genetically heterogeneous disorders caused by defects in primary cilia. Here we identified mutations in TRAF3IP1 (TNF Receptor-Associated Factor Interacting Protein 1) in eight patients from five families with nephronophthisis (NPH) and retinal degeneration, two of the most common manifestations of ciliopathies. TRAF3IP1 encodes IFT54, a subunit of the IFT-B complex required for ciliogenesis. The identified mutations result in mild ciliary defects in patients but also reveal an unexpected role of IFT54 as a negative regulator of microtubule stability via MAP4 (microtubule-associated protein 4). Microtubule defects are associated with altered epithelialization/polarity in renal cells and with pronephric cysts and microphthalmia in zebrafish embryos. Our findings highlight the regulation of cytoplasmic microtubule dynamics as a role of the IFT54 protein beyond the cilium, contributing to the development of NPH-related ciliopathies.

LMX1B encodes a homeodomain-containing transcription factor that is essential during development. Mutations in LMX1B cause nail-patella syndrome, characterized by dysplasia of the patellae, nails, and elbows and FSGS with specific ultrastructural lesions of the glomerular basement membrane (GBM). By linkage analysis and exome sequencing, we unexpectedly identified an LMX1B mutation segregating with disease in a pedigree of five patients with autosomal dominant FSGS but without either extrarenal features or ultrastructural abnormalities of the GBM suggestive of nail-patella-like renal disease. Subsequently, we screened 73 additional unrelated families with FSGS and found mutations involving the same amino acid (R246) in 2 families. An LMX1B in silico homology model suggested that the mutated residue plays an important role in strengthening the interaction between the LMX1B homeodomain and DNA; both identified mutations would be expected to diminish such interactions. In summary, these results suggest that isolated FSGS could result from mutations in genes that are also involved in syndromic forms of FSGS. This highlights the need to include these genes in all diagnostic approaches to FSGS that involve next-generation sequencing.