Matthew Arthur Brown

Despite the introduction of genome sequencing (GS) for rare disease diagnostics, a genetic cause is not identified in most patients. Here, we explored the potential of proteomics to improve the diagnostic yield in 424 patients with rare diseases from the 100,000 Genomes Project (100kGP) without a genetic diagnosis. Serum proteomic profiling was performed using the Olink Explore 1536 assay ( N = 1463 proteins). For 13 patients without genetic diagnoses, detection of lower serum protein “outliers” ( z -score < −2) led to confirmed genetic diagnoses by resolving variants of uncertain significance or prioritizing genes for targeted GS reanalysis. For 23 additional patients without genetic diagnoses (64% of findings), we identified candidate gene-disease links and variants through convergent evidence from lower protein outliers and variants ranked through the variant prioritization tool Exomiser. For example, we identified a candidate heterozygous missense variant [Genome Aggregation Database (gnomAD) minor allele frequency = 0.006%] in tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains 1 ( TIE1 ) that was only present in a patient with lower TIE1 serum abundance ( z -score = −5.12) and their father, both of whom were affected by the same monogenic cardiac disorder, but in no other individuals from the 100kGP. Missense (52.5%) and splice region (27.5%) variants accounted for most diagnostic or candidate variants prioritized. This proof-of-principle study demonstrated that serum proteomics can support rare disease diagnosis and identify disease-causing genes in patients undiagnosed after GS, although successful implementation will likely depend on tissue specificity of protein expression, detectability in blood, proteomic platform coverage, and sensitivity.

Objective: To examine whether baseline comorbidity burden and extra-musculoskeletal manifestations (EMMs)—psoriasis, uveitis, IBD—are associated with spinal radiographic progression in AS. Methods: We analysed participants fulfilling modified New York criteria with one or more lateral cervical or lumbar radiograph. Radiographic progression was quantified using the modified Stoke AS Severity Score (mSASSS), excluding score 1 at each vertebral corner (range 0–48). Comorbidity count (22 self-reported conditions: none, one, two, three or more) and ever-presence of each EMM at baseline were exposures. mSASSS change over time with exposure-time interactions was modelled using generalized estimating equations; coefficients were rescaled to represent mean difference in progression (units/10 years). Models adjusted for baseline mSASSS, sex, symptom duration, CRP, HLA-B27, smoking, TNF inhibitor use, and number of EMMs or comorbidity count. Secondary analyses examined potential sex- and segment-specific effects. Results: Among 1150 individuals (mean age 44 years; 75% male; 84% HLA-B27 positive), 3441 patient-years were analysed (median follow-up 2 years; median two radiographs). Compared with those with no comorbidities, progression was greater amongst patients with two (2.7 units/10 years; 95% CI 1.9–3.5) and three or more (2.3; 1.5–3.1) comorbidities. Uveitis (2.2 units/10 years; 1.3–3.0) and psoriasis (2.4 units/10 years; 1.4–3.5), but not IBD, were associated with greater progression. Sex-specific analyses suggested greater spinal progression in females than males with psoriasis. Cervical-predominant changes were seen with uveitis and psoriasis. Conclusion: Comorbidity burden, uveitis and psoriasis are independently associated with greater spinal radiographic progression in AS. These readily identifiable features may inform risk stratification and targeted management strategies.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in “The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations” which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

The worldwide epidemiology of axial spondyloarthritis (axSpA), psoriatic arthritis (PsA) and peripheral spondyloarthritis, as well as of HLA-B27 and other MHC and non-MHC genes in these diseases, is reviewed herein. The frequency of axSpA is highest in circumpolar groups (such as Sami people and certain Indigenous American groups) and lowest in those of Japanese and African ancestry. The same pattern holds for PsA, although the overall prevalence of PsA seems much lower in East Asia, where it is less frequent than axSpA. The prevalence of PsA in people with psoriasis is increased where rheumatological assessment was carried out and seems to be increasing over time. HLA-B27 remains the most important genetic factor in axSpA susceptibility, although its frequency is lower in African American, South American and Middle Eastern populations than in others. The presence of HLA-B27 and other HLA alleles seems to be important in discerning clinical subsets of SpA and PsA, particularly those characterized by acute anterior uveitis or by axSpA with psoriasis, although these HLA-B27 and other MHC and non-MHC associations are derived from genome-wide association studies and other chip-based studies in large populations. These studies have been carried out mainly in populations of European and East Asian ancestry, and similar data from Latin America, sub-Saharan Africa and South Asia are lacking. This under-representation is an unmet need in applying genetic factors to understand the pathogenesis, diagnosis and classification of SpA and PsA.

Chondrocalcinosis (CCAL), also known as calcium pyrophosphate dihydrate deposition disease (CPPDD), is a frequent multifactorial condition in the elderly, but there are two rare autosomal dominant Mendelian forms, CCAL1 (OMIM %600668) and CCAL2. Only three families with molecularly proven CCAL1 have been reported. Here, we describe an additional family from Germany (12 individuals, nine living) with CPPDD manifesting in the third decade of life, presenting with severe spinal problems and variable levels of disability, only two of them with hip problems. The mildly impaired growth in this family (median height at age 20: 10th percentile) may represent an as yet undescribed sign of CCAL1, or alternatively familial short stature. In all documented families and in this family, the disorder resulted from the recurrent heterozygous stop‐loss variant NM_002546.4:c.1205A>T; p.(Ter402Leuext*19) in TNFRSB11B on chromosome 8q24, which predicts an extended osteoprotegerin protein with 19 additional amino acid residues. The pathomechanism of CCAL1 is not known. Biallelic TNFRSF11B loss‐of‐function variants cause autosomal recessive juvenile Paget's disease of bone (PDB5); shared features between CCAL1 and PDB5 include demineralization, osteoporosis, increased fractures, and a progressive height loss with age, but PDB5 and CCAL1 have very different phenotypes and heterozygous carriers of PDB5‐associated variants are asymptomatic. Summing up, NM_002546.4:c.1205A>T represents a rare type of stop‐lost variant, likely a gain‐of‐function variant, and to date no other variant is known to cause CCAL1. Our findings expand the phenotypic spectrum of CCAL1 and underscore that CCAL1 is a distinct rare Mendelian disorder for which the underlying molecular basis is now known.

We report the largest genome-wide association study meta-analysis in ankylosing spondylitis (AS) to date (25,645 cases, 71,224 controls), identifying 27 novel loci and 86 independent genetic associations. Variations in FUT2 (non-secretor status) and ABO (blood group A) increase AS risk, with Mendelian randomisation (MR) linking non-secretor status to increased AS risk from reduced gut carriage of Ruminococcus torques. Associations with three telomerase maintenance genes (TERT, TERC, RTEL1), and MR analysis, suggest increased telomere length causally increases AS susceptibility. Fine-mapping prioritised likely causal variants at multiple loci. Transcriptome- and proteome-wide association studies implicated 644 genes, highlighting immune-related pathways. Lower genetically-determined IL-6 and IL-12, and similar IL-23, levels were found in AS cases, offering a genetic explanation for the failure of IL-6, IL-12, and IL-23 inhibition in AS treatment. Finally, multi-omic analyses showed chromosome 2p15 association acts via reduced B3GNT2 expression. These findings deepen understanding of AS pathogenesis, highlighting new pathways and therapeutic opportunities.

Despite their deleterious effects, small insertions and deletions (InDels) have received far less attention than substitutions. Here we generated isogenic CRISPR-edited human cellular models of postreplicative repair dysfunction (PRRd), including individual and combined gene edits of DNA mismatch repair (MMR) and replicative polymerases (Pol ε and Pol δ). Unique, diverse InDel mutational footprints were revealed. However, the prevailing InDel classification framework was unable to discriminate these InDel signatures from background mutagenesis and from each other. To address this, we developed an alternative InDel classification system that considers flanking sequences and informative motifs (for example, longer homopolymers), enabling unambiguous InDel classification into 89 subtypes. Through focused characterization of seven tumor types from the 100,000 Genomes Project, we uncovered 37 InDel signatures; 27 were new. In addition to unveiling previously hidden biological insights, we also developed PRRDetect—a highly specific classifier of PRRd status in tumors, with potential implications for immunotherapies.

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To refine the genetic map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 46 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.