アッシャー症候群

BACKGROUND: MSH3 and MLH3 are non-canonical DNA mismatch repair genes, involved in repairing insertion-deletion mutations. Colorectal cancer (CRC) and adenomas have been reported in patients with bi-allelic germline MSH3 mutations, and in a very few bi-allelic MLH3 mutation carriers. OBJECTIVES: We hypothesised that germline loss-of-function MSH3 and MLH3 mutations were akin to constitutional mismatch repair deficiency (cMMRd) and Lynch syndrome, such that CRC could result from either bi-allelic germline mutations or heterozygous germline mutations after second hits. DESIGN: About 12 000 CRC and multiple polyp cases and 460 000 controls were studied. 2023 patients underwent cancer genome sequencing. RESULTS: One CRC/multiple polyp case had bi-allelic MSH3 mutations and another, bi-allelic MLH3 mutations. MSH3 and MLH3 germline heterozygotes had an increased risk of CRC (2.2-fold, p=6.6×10-5 and 1.6-fold, p=0.028, respectively), owing to somatic 'second hits' that inactivated the wildtype allele. Single second hits sometimes inactivated both MSH3 and the nearby APC gene. All CRCs with MSH3 or MLH3 deficiency were microsatellite-stable but hypermutant. Deletions of ≥2 bp were particularly increased (~12-fold) and signature ID4 was usually present (p<0.0001). CRCs from heterozygotes without 'second hits' showed no hypermutation. CONCLUSION: The phenotypes of bi-allelic MSH3 and MLH3 mutation carriers resemble some patients with cMMRd. Heterozygous germline MSH3 and MLH3 alleles have incomplete penetrance, but increase CRC risk via hypermutation, phenotypically resembling PMS2-mutant Lynch syndrome. A causal association with specific mutations has not previously been reported for ID4 in human tumours. ID4 probably does not have a single aetiology, but can result from MSH3 or MLH3 deficiency.

PURPOSE: To describe the molecular genetic spectrum and age-related clinical features of USH2A-associated retinitis pigmentosa in Korean patients. DESIGN: Retrospective cohort study. METHODS: A total of 182 Korean patients with biallelic pathogenic or likely pathogenic USH2A variants were included. Patients were classified as Usher syndrome (USH) or non-syndromic retinitis pigmentosa (NSRP), and stratified by the number of truncating USH2A variants (0, 1, or 2). Best-corrected visual acuity (BCVA), Goldmann visual field, ellipsoid zone (EZ) band length on optical coherence tomography, and ultra-widefield fundus and autofluorescence imaging were assessed. Age-related changes were modeled using restricted cubic splines with generalized estimating equations. RESULTS: The cohort comprised 56 patients with USH (30.8%) and 126 with NSRP (69.2%); mean age was 44.3 ± 12.7 years. Among 364 pathogenic or likely pathogenic alleles, c.2802T>G (p.Cys934Trp) was the most common (23.6%), followed by c.8559-2A>G (12.1%). The European hotspots c.2299delG and c.2276G>T were not identified. Missense variants accounted for 53.8% of alleles. At least one c.2802T>G allele was present in 82 patients (45.1%), including 4 homozygotes. Both Usher syndrome and an increasing truncating variant burden were associated with worse age-adjusted patterns of visual acuity, visual field, and EZ band length. CONCLUSION: USH2A-associated retinitis pigmentosa in Korean patients follows an East Asian variant spectrum that is distinct from European populations. Approximately half of patients carried at least one c.2802T>G allele, supporting inclusion of East Asian patients in emerging exon 13-targeted therapies.

BACKGROUND: Many patients with suspected acute coronary syndrome in whom myocardial infarction has been ruled out in the emergency department remain at risk for cardiovascular events. Whether further investigation reduces this risk is unknown. METHODS: In a multicenter, randomized, controlled trial, patients who presented to an emergency department in 14 hospitals across the United Kingdom were enrolled if myocardial infarction had been ruled out and high-sensitivity cardiac troponin testing indicated an intermediate risk of a cardiovascular event (maximum high-sensitivity cardiac troponin I or T concentration, >5 ng per liter). Participants were randomly assigned in a 1:1 ratio to receive either outpatient computed tomographic (CT) coronary angiography-guided care or standard care. The primary outcome was a composite of myocardial infarction or death from a cardiac cause. RESULTS: From September 18, 2019, to May 11, 2023, a total of 3170 participants (median age, 61 years; female sex, 30.2%) were assigned to undergo CT coronary angiography (1587 participants) or receive standard care (1583 participants). At 90 days after randomization, CT coronary angiography had been performed in 1462 participants (92.1%) in the CT coronary angiography group and in 35 participants (2.2%) in the standard-care group. Overall, 7 participants (0.4%) had a CT coronary angiography-related adverse event. After a median of 3.0 years, at which point the number of primary-outcome events in the standard-care group exceeded the prespecified minimum of 97, a primary-outcome event had occurred in 112 participants (7.1%) in the CT coronary angiography group and in 116 (7.3%) in the standard-care group (adjusted hazard ratio, 0.95; 95% confidence interval, 0.73 to 1.23; P = 0.71). CONCLUSIONS: In patients with suspected acute coronary syndrome in whom myocardial infarction had been ruled out, routine CT coronary angiography-guided management did not result in a lower incidence of subsequent myocardial infarction or death from a cardiac cause than standard care. (Funded by the British Heart Foundation; TARGET-CTCA ClinicalTrials.gov number, NCT03952351.).

Ciliopathies comprise a spectrum of disorders involving mutations in over 150 genes affecting the primary cilium, with retinal degeneration as a prominent feature driven by concomitant developmental and maturation defects in photoreceptors and the retinal pigment epithelium (RPE). Current single-gene-targeted therapeutic approaches are expensive with limited scalability. We hypothesize that downstream of primary cilium dysfunction, mutation-agnostic shared pathways initiate tissue defects. To test this hypothesis, we here develop induced pluripotent stem cell-derived RPE models (iRPE) from nine (BBS1, BBS10, BBS16, CEP290, LCA5, MYO7A, PRPF31) patients with ciliopathy with severe retinal degeneration. Despite heterogeneity in disease severity, consistent with underlying ciliary structural defects, all ciliopathy iRPE exhibit abnormal epithelial polarization and impaired mitochondrial health initiated by dysregulated TGF-β signaling-driven mesenchymal drift. Addressing these gene-agnostic disease phenotypes, our study identifies two drugs, pioglitazone, a mitochondrial metabolic modulator, and galunisertib, a TGFBR1 inhibitor, as potential therapeutic candidates for multiple ciliopathy subtypes.

As our results show that very few published variants could currently be considered causative of DFNB due to lack of precise clinical studies, strict and uniform criteria should be applied by authors publishing on USH/DFNB genes.