Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern.

Genetic determinants of response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) remain insufficiently characterized. We developed a targeted sequencing panel of candidate immunogenetic variants identified through a literature review and evaluated associations with response to TNF-α inhibitors, response to IL-6 inhibitors, and difficult-to-treat RA (D2TRA). Whole-blood DNA was sequenced using custom hybridization capture on a DNBSEQ-G400 platform (2 × 150 bp). Reads were aligned to hg38 using BWA-MEM, and variants were called with GATK HaplotypeCaller. After quality control, the D2TRA analysis included 154 patients (59 D2TRA and 95 non-D2TRA); drug-response analyses included 66 anti-TNF patients (26 responders, 40 non-responders) and 69 anti-IL-6 patients (29 responders, 40 non-responders). Treatment-response associations were assessed using unadjusted allelic chi-square tests with multiple-testing correction; D2TRA was analyzed using logistic regression adjusted for age, sex, and body mass index. For IL-6 inhibitor response, rs11656130/MAP2K6 (p = 0.0163; FDR = 0.3704) and rs4910008/GALNT18 (p = 0.0212; FDR = 0.3704) were identified, while rs7767069/LINC02549 was associated with TNF-α inhibitor response (p = 0.0171; FDR = 0.5968). For D2TRA, rs1813443 in CNTN5 (OR = 1.85, p = 0.017) and rs12081765, an intergenic variant near LMX1A/RXRG (OR = 0.59, p = 0.028), were nominally associated; neither association remained significant after multiple-testing correction. With the current sample sizes, the study could detect only large genetic effects, and was underpowered for these after Bonferroni correction (α = 0.00143). The findings highlight the limited reproducibility of candidate pharmacogenetic markers in RA and provide a targeted panel and analytical framework for larger replication studies.

Effective molecular diagnosis of congenital diseases hinges on comprehensive genomic analysis, traditionally reliant on various methodologies specific to each variant type—whole exome or genome sequencing for single nucleotide variants (SNVs), array CGH for copy-number variants (CNVs), and microscopy for structural variants (SVs). We introduce a novel, integrative approach combining exome sequencing with chromosome conformation capture, termed Exo-C. This method enables the concurrent identification of SNVs in clinically relevant genes and SVs across the genome and allows analysis of heterozygous and mosaic carriers. Enhanced with targeted long-read sequencing, Exo-C evolves into a cost-efficient solution capable of resolving complex SVs at base-pair accuracy. Through several case studies, we demonstrate how Exo-C’s multifaceted application can effectively uncover diverse causative variants and elucidate disease mechanisms in patients with rare disorders.

The primary lymphedema of the extremities is a rare disease. Understanding the spectrum of genes and mutations that most commonly underlie primary lymphedema will lead to improved patient care through the development of new targeted therapies. We performed Whole Exome Next-generation sequencing (NGS) for probands from two families with multiple members affected by primary lymphedema. We have discovered a new mutation in gene HGF that is the etiological factor in primary lymphedema. Nevertheless, further cohort studies are required to better understand the genetic diversity of primary lymphedema.