Background Metaphyseal anadysplasia 1, which includes Spondyloepimetaphyseal dysplasia Missouri type, is a rare autosomal dominant skeletal dysplasia characterized by short stature, mild limb deformities, and transient metaphyseal irregularities that typically resolve with age. The condition is caused by heterozygous missense variants in the MMP13 gene, encoding matrix metalloproteinase 13, a key enzyme in endochondral ossification and extracellular matrix remodeling. Pathogenic variants in MMP13 are exceedingly rare, with only a few families reported. Case Presentation We report two siblings, aged 3 and 1 years, in Sweden, presenting with clinical and radiological features consistent with Metaphyseal anadysplasia 1. Their father, of Syrian origin, exhibited short stature and mild femoral bowing. Genetic analysis revealed a novel heterozygous missense variant c.217T>C, p.(Ser73Pro) in MMP13, inherited from the affected father, and located within the same MMP13 domain as previously reported patients. The family pedigree demonstrates multiple affected individuals with short stature and bowed femurs, consistent with autosomal dominant inheritance. Radiographic imaging of father confirmed persistent but mild skeletal abnormalities. Conclusion This report expands the genotypic spectrum of Metaphyseal anadysplasia 1 and suggests a putative mutational hotspot in exon 2. It further emphasizes the importance of thorough clinical, radiological, and genetic evaluation in families with short stature and metaphyseal irregularities and a clinical long-term follow-up is proposed with regular radiographic monitoring.

In rare disease research, sharing of individual health data is essential for advancing diagnostics and therapies, requiring robust and ethically sound informed consent processes. Within the Genomic Medicine Sweden Rare Diseases (GMS-RD) multicenter study, an electronic informed consent (eConsent) platform was developed to support data sharing, facilitate participation and enable research engagement. Tailored to the complex consent needs of rare disease contexts, the platform was piloted at three Genomic Medicine Centers in Sweden. A total of 2244 individuals were invited in the clinical routine cohort, with an overall eConsent rate of 18.6%. Uptake was highest among adult singletons (27.8%) and lowest in trios (14.3%). In contrast, the Undiagnosed Diseases Network (UDN) Sweden cohort achieved a 94% consent rate, attributed to targeted communication and active patient organization involvement. Key challenges included technical accessibility limitations, digital literacy deficits, comprehension and language barriers, and the burden of multi-step processes, especially for families. Findings underscore the need to improve usability, strengthen communication, and implement flexible consent management over time. eConsent can broaden participation in genomic research and promote responsible data sharing. However, in rare diseases contexts, it must be designed with inclusivity, clarity, and adaptability to meet the diverse participant needs.

Background Turner syndrome (TS) is a complex genetic disorder with raised mortality. Our objective was to investigate mortality and causes of death in TS. Methods A matched retrospective observational study of women with TS recruited from the Turner centers in Sweden were conducted. A total of 472 women with TS, ≥ 16 years old with a cytogenetically verified diagnosis and 2357 controls, matched for birthyear and sex, were examined and followed since 1995 for up to 26 years. Survival analyses were performed with Cox proportional hazard models. Kaplan-Meier curves were generated. Cumulative incidence rates were evaluated by competing risks analysis, using cumulative incidence function. Results During a mean follow-up of 17 years, 35 (7.4%) women with TS and 70 (3.0%) controls died. All-cause mortality was elevated in TS, hazard ratio (HR) 2.90 (95% CI 1.92-4.37), mainly due to circulatory diseases and notably aortic dissection, with HR of 9.11 (95% CI 4.54-18.25) and 21.79 (95% CI 4.62-102.82), respectively. Aortic dissection was the single largest cause of death in TS, accounting for 23% (8/35) of total deaths. Death by cancer or external causes were not raised in TS. In individuals below 45 years of age death, aortic dissections were greatly increased compared to controls, HR 55.59 (95% CI 2.33-1325.69). From the ages 46 to 80 years a notably higher risk of dying by heart diseases, aortic dissection excluded, was shown in TS compared to controls HR, 7.7 (2.65-22.36). The median survival time was 8 years shorter in TS compared to controls. Conclusions The increased mortality in TS was mainly driven by aortic dissections in the young and by heart diseases in the older. Healthcare professionals should prioritize detection and monitoring, with emphasis on cardiovascular diseases.

Clinical genetic laboratories often require a comprehensive analysis of chromosomal rearrangements/structural variants (SVs), from large events like translocations and inversions to supernumerary ring/marker chromosomes and small deletions or duplications. Understanding the complexity of these events and their clinical consequences requires pinpointing breakpoint junctions and resolving the derivative chromosome structure. This task often surpasses the capabilities of short-read sequencing technologies. In contrast, long-read sequencing techniques present a compelling alternative for clinical diagnostics. Here, Genomic Medicine Sweden-Rare Diseases has explored the utility of HiFi Revio long-read genome sequencing (lrGS) for digital karyotyping of SVs nationwide. The 16 samples from 13 families were collected from all Swedish healthcare regions. Prior investigations had identified 16 SVs, ranging from simple to complex rearrangements, including inversions, translocations, and copy number variants. We have established a national pipeline and a shared variant database for variant calling and filtering. Using lrGS, 14 of the 16 known SVs are detected. Of these, 13 are mapped at nucleotide resolution, and one complex rearrangement is only visible by read depth. Two Chromosome 21 rearrangements, one mosaic, remain undetected. Average read lengths are 8.3-18.8 kb with coverage exceeding 20× for all samples. De novo assembly results in a limited number of phased contigs per individual (N50 6-86 Mb), enabling direct characterization of the chromosomal rearrangements. In a national pilot study, we demonstrate the utility of HiFi Revio lrGS for analyzing chromosomal rearrangements. Based on our results, we propose a 5-year plan to expand lrGS use for rare disease diagnostics in Sweden.

CONTEXT:Turner syndrome (TS) is the most common chromosomal aberration in women; it is the result of structural or numeric abnormalities in the X chromosome. Autoimmune hypothyroidism has been recognized as one of the more prominent disorders associated with TS. OBJECTIVE:This work aimed to study the prevalence of autoimmune diseases in TS. METHODS:A cross-sectional, longitudinal, 25-year follow-up study was conducted of patients from adult Turner centers at the University Hospitals, Sweden. During 1994 to 2020, a total of 503 women aged 16 to 71 years with TS were evaluated consecutively every fifth year according to national guidelines. A random population sample of women, n = 401, aged 25 to 44 years, from the World Health Organization Monitoring of Trends and Determinants for Cardiovascular Disease (MONICA) project served as controls. Serum thyrotropin, free thyroxine, vitamin B12, antithyroid peroxidase (anti-TPO), and antitransglutaminase antibodies were measured. RESULTS:Mean follow-up time (years) was 16 ± 7 for patients and 13 ± 1 for controls. From study start, the prevalence increased in TS for hypothyroidism 40% to 58%, vitamin B12 deficiency 5% to 12%, celiac disease 4% to 7%, positive anti-TPO 26% to 41%, and antitransglutaminase antibodies 6% to 8% (P < .0001 vs controls). Type 1 diabetes and Addison disease were rare. The only interrelationship was between hypothyroidism and vitamin B12 deficiency, both in TS and controls. No association between autoimmune disease and karyotype, antecedent growth hormone treatment, or ongoing estrogen hormone replacement, was seen in TS. CONCLUSION:In women with TS up to older than 80 years, more than half developed hypothyroidism, mainly autoimmune, during follow-up. Awareness of vitamin B12 deficiency and celiac disease throughout life is also recommended in women with TS.

Turner syndrome (TS) is a genetic condition characterized by partial or complete monosomy X. A reduced life expectancy has been shown in TS, depending on an increased risk of aortic dissection, and ischemic heart disease. Studies covering the occurrence of psychiatric conditions are sparse within TS. Several case reports describe concomitant TS and neuropsychiatric abnormalities that may represent a pathogenetic link to genetics, as well as feature correlates of TS. The aim of this study was to determine the presence, and the frequency of psychiatric diagnosis in women with TS in a Swedish cohort followed during 25 years’ time. Statistics from the entire female population in Sweden of corresponding age was used as reference. Data were retrieved from clinical examinations and validated from the National Board of Health and Welfare registries for women with TS (n = 487), aged 16 to 84 years, with respect to mental health disorders. The most common diagnoses in TS were mood and anxiety disorders. There was no increase in psychiatric diagnosis within the group with time, nor correlation to specific karyotype or somatic comorbidity as congenital heart disease and hypothyroidism, hormonal treatment, or childbirth. In addition, the frequency of psychiatric diagnosis in TS was lower than in the population-based data. Further investigations are needed in the view of the fact that women with Turner syndrome should not be burdened with more severe diagnoses.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: Cytoskeletal non-muscle actin isoforms are the most abundant intracellular proteins and extensively interact with other molecules. Biological consequences and genotype-phenotype correlations of the variants in genes encoding these isoforms, ACTB and ACTG1, are not delineated. Methods: Clinical data analysis from 290 individuals with pathogenic ACTB/ACTG1 variants; characterization of patient cells, mutant proteins, patient-derived iPSC-based models and mutant mice. Results: We show that ACTB and ACTG1 variants have distinct clinical profiles. ACTB nonsense, frameshift and missense variants that lead to rapid protein degradation result in milder phenotypes. Heterozygous Actb knockout causes altered neuronal cell morphology and abnormal expression of actin-related genes in newborn mouse brains. Truncating ACTG1 variants are likely to be non-pathogenic, but chromosomal deletions encompassing ACTG1 and flanking genes may result in susceptibility to neurodevelopmental phenotypes. Subsets of disease-causing ACTB missense variants (MVs) result in more severe Type 1 Baraitser-Winter Cerebrofrontofacial (BWCFF1) or Deafness Dystonia syndromes. Pathogenic ACTG1 MVs cause BWCFF2 or isolated hearing loss. These amino acid substitutions are associated with dramatically dysregulated actin polymerization and depolymerization dynamics and, in induced pluripotent stem cells (iPSC) derived models, lead to neuronal migration defects. A significant subset of MVs result in disorders that cannot yet be classified into recognizable groups. Conclusions: ACTB or ACTG1 variants and result in minimum eight mechanistically diverse non-muscle actinopathies. These results will improve their diagnosis and management, and pave the way for new treatment strategies. This study reflects the scale of collaborative clinical studies and multi-modal mechanistic studies required to dissect rare allelic disorders. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NDD received grant support from Deutsche Forschungsgemeischaft (DFG) (DI 2170/3.1 and DI 2170/5.1) and Else-Kroener-Fresenius Stiftung (2020_EKES.04). NDD and DJM are supported through the European Union Horizon 2020 research and innovation program under the EJP RD COFUND EJP N 825575 with support from the German Federal Ministry of Education and Research under Grant Agreements 01GM1922A and 01GM1922B, respectively. DJM acknowledges grant support from: Deutsche Forschungsgemeinschaft (DFG) (MA1081/23.1, MA1081/28.1), the Cluster of Excellence RESIST (EXC 2155; DFG Project ID: 39087428.B11). ASW acknowledges grant support from: Medical Research Council project grant MR/T016809/1; Medical Research Council-National Institute for Health and Care Research rare disease research platform MR/Y008340/1; and Kidneys for Life pump priming grant 2017. SB acknowledges grant support from the NIHR Manchester Biomedical Research Centre (NIHR203308). SB, ASW, and AT acknowledge support from the Davies family for grant support in the form of Marsh Studentship to the University of Manchester. SB and SC acknowledge support from the Great Ormond Street Hospital Charity research grant V4621. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB the TU Dresden and Ethics committee/IRB of the Central Manchester gave ethical approval for this work (EK-127032017, BO-EK-341062021 and (02/CM/238). All patients ID were created specifically for this manuscript and are not known to anyone outside of teh research group. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data sets supporting the results of this article are available in the supplementary material or could be requested from the corresponding authors.

Osteogenesis Imperfecta (OI) is a heterogeneous skeletal dysplasia characterized by bone fragility, skeletal deformities, and short stature. Most commonly, it is caused by autosomal dominant variants in the type I collagen genes, COL1A1 or COL1A2. Type I collagen is the main protein of the extracellular matrix in the skeleton and changes in its structure or quantity may lead to OI. 85%-90% of OI cases occur due to sequence variants in type I collagen genes, while OI caused by structural abnormalities in type I collagen genes is less common. In most cases, haploinsufficiency of type I collagen is associated with a milder OI phenotype. Large genomic deletions often involve several genes within the same chromosomal region, leading to microdeletion syndromes with OI features. Here, we report eight Swedish patients from five unrelated families with OI due to structural variants in the COL1A1 and COL1A2 genes. One patient with OI type III had a complex rearrangement with a deletion and duplication event in COL1A2, leading to reduced COL1A2 expression. Three other patients from two different families with OI type I had whole gene deletions involving COL1A1. In one family, three affected individuals with OI type I had a small intragenic deletion of exons 11-12 in COL1A2. One patient had a 2.1 Mb de novo deletion encompassing COL1A1 and DLX3 genes and features of OI and tricho-dento-osseous syndrome. Overall, this study highlights the importance of investigating gene dosage abnormalities in patients with OI and further delineates clinical and genetic variability of OI caused by structural variants in type I collagen genes.

Background: Aortic dilation, cardiac malformations and hypertension are known risk factors for aortic dissection in Turner syndrome (TS). In the current guidelines, rapid growth of the aorta has been added as a risk marker. This study aimed to estimate the growth of the ascending aorta over time, to identify risk factors of aortic growth, and to describe aortic complications in TS. Methods: A transthoracic echocardiogram was performed at least twice in 101 women with TS, mean age 28 years, with a mean follow-up of 8.3 +/- 3.4 (range 1-17) years. The investigator was blinded to the clinical status. Logistic regression analysis was used to identify risk factors of aortic growth. Results: The prevalence of ascending aortic dilation (ASI >20 mm/m(2)) was 26 % and the mean ascending aortic diameter was 27.0 +/- 4.8 mm at baseline. Significant aortic growth was found at sinus of Valsalva 1.08 (+/- 2.11) mm, sinotubular junction 1.07 (+/- 2.23) mm, and the ascending aorta 2.32 (+/- 2.93) mm, p < 0.001. The mean ascending aortic growth rate was 0.25 (+/- 0.35) mm/year, and higher compared to the general female population, 0.12 (+/- 0.05) mm/year, p < 0.0001. No risk factors for aortic growth (bicuspid aortic valve, coarctatio, hypertension or karyotype) other than body weight could be identified, Odds ratio 1.05 (95 % CI 1.00-1.09), p = 0.029. Eight women had an aortic event of whom all had bicuspid aortic valves. Conclusions: The growth rate of the ascending aorta in TS was increased compared to the general female population. Congenital cardiovascular malformations were not predictive of aortic growth.

Background: Women with Turner syndrome (TS) have an increased risk of aortic dissection. The current recommended cutoff to prevent aortic dissection in TS is an aortic size index (ASI) of >= 2.5 cm/m2. This study estimated which aortic size had the best predictive value for the risk of aortic dissection, and whether adjusting for body size improved risk prediction.Methods: A prospective, observational study in Sweden, of women with TS, n = 400, all evaluated with echocardiography of the aorta and data on medical history for up to 25 years. Receiver operating characteristic (ROC) curves, sensitivity and specificity were calculated for the absolute ascending aortic diameter (AAD), ascending ASI and TS specific z-score.Results: There were 12 patients (3%) with aortic dissection. ROC curves demonstrated that absolute AAD and TS specific z-score were superior to ascending ASI in predicting aortic dissection. The best cutoff for absolute AAD was 3.3 cm and 2.12 for the TS specific z-score, respectively, with a sensitivity of 92% for both. The ascending ASI cutoff of 2.5 cm/m2 had a sensitivity of 17% only. Subgroup analyses in women with an aortic diameter >= 3.3 cm could not demonstrate any association between karyotype, aortic coarctation, bicuspid aortic valve, BMI, antihypertensive medication, previous growth hormone therapy or ongoing estrogen replacement treatment and aortic dissection. All models failed to predict a dissection in a pregnant woman.Conclusions: In Turner syndrome, absolute AAD and TS-specific z-score were more reliable predictors for aortic dissection than ASI. Care should be taken before and during pregnancy.

Thank you for your interest in our study [ [1] Thunström S. Thunström E. Naessen S. et al. Aortic size predicts aortic dissection in turner syndrome - a 25-year prospective cohort study. Int. J. Cardiol. 2023; 373: 47-54 Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar ]. We appreciate your suggestion to improve the estimations with the penalized method to reduce sparse data bias and we agree with its application [ [2] Greenland S. Mansournia M.A. Altman D.G. Sparse data bias: a problem hiding in plain sight. BMJ. 2016; 352i1981 PubMed Google Scholar ].

Background: Clinical genetic laboratories often require comprehensive analysis of chromosomal rearrangements/structural variants (SVs) which can range from gross chromosomal events, such as translocations and inversions, to supernumerary ring/marker chromosomes, and small deletions or duplications. To fully understand the complexity of a specific event and its associated clinical consequences, it is imperative to locate the breakpoint junctions and to resolve the derivative chromosome structure. This task, however, often surpasses the capabilities of conventional short-read sequencing technologies. In contrast, emerging long-read sequencing techniques present a compelling alternative for clinical diagnostics. Methods: Here, the Genomic Medicine Sweden Rare Diseases (GMS-RD) consortium explored the utility of HiFi Revio long-read whole genome sequencing (lrGS) for clinical digital karyotyping of SVs nationwide. The first 16 samples included in this study were collected from all health care regions in Sweden. We established a national pipeline and a shared variant database for variant calling and filtering. The included validation samples cover a spectrum of simple and complex SVs including inversions, translocations and copy number variants. Results: The results from the lrGS analysis match the reported karyotype for 14/16 individuals and 12 known SVs were mapped at nucleotide resolution. A complex rearrangement on chromosome 15 was identified only through read depth analysis and two chromosome 21 rearrangements remained undetected, one of which was mosaic. The average read length ranged from 8.3-18.8 kb and the coverage was >20x for all samples. De novo assembly resulted in a limited number of contigs per individual (N50 range 6-86 Mb) clearly separating the two alleles in most cases, enabling direct characterization of the chromosomal rearrangements. Conclusions: In a national pilot study, we successfully demonstrated the utility of HiFi Revio lrGS as a clinical analysis of chromosomal rearrangements. Based on our results we propose a five-year plan for the wider implementation of lrGS for rare disease diagnostics in Sweden.

OBJECTIVE:The aim was to describe age at diagnosis, cumulative incidence, SCN1A variants, mortality, seizure types and treatments in children with Dravet Syndrome (DS) in Sweden.METHODS:Children diagnosed with DS, born between January 1st 2000 and December 31st 2018 were included in a population-based study. Clinical data, frequency of seizure types and treatments were collected from caregivers and medical records in 42 children. Age at diagnosis, cumulative incidence and treatment were compared between children born in Sweden 2000-2009 and 2010-2018.RESULTS:We identified 55 children with DS, 53 were born in Sweden. Three children had died of definite, probable, or possible sudden unexpected death in epilepsy, one of acute anoxic brain injury and three of pneumonia or pneumonitis. Median age at death was 4.7 (range 3.3-11) years. In 49/53 children with known SCN1A status, a pathogenic/likely pathogenic variant of SCN1A was detected. In two a SCN1A variant of unknown significance was found. For children born in Sweden 2010-2018, median age at DS diagnosis was lower (1.6 vs 4.5 years, p = 0.001) and cumulative incidence higher (1/33,000 vs 1/46,000 live-born children, p = 0.03), compared to children born in 2000-2009. The most common seizure types were focal to bilateral tonic clonic (n = 41/42) and myoclonic (n = 35/42). Tonic seizures were reported in 25/42 children. Sodium-channel inhibitors had been used in 9/24 children born in 2010-2018 and 17/18 children born in 2000-2009 (p = 0.001).SIGNIFICANCE:A SCN1A variant that could explain the syndrome was found in over 90% of children. Tonic seizures seem to be more frequent than earlier described. Median age at diagnosis was lower, cumulative incidence higher and use of contra-indicated sodium-channel inhibitors less common for children born in 2010-2018 compared with children born in 2000-2009. This could indicate an increased awareness of DS.

The recently reported cell division assay (CDA) was optimized to measure the relative sensitivity of cells to cytotoxic drugs in vitro. Here, we investigated the in vitro hypersensitivity of lymphocytes from Fanconi anemia (FA) patients, to cytotoxic drugs using CDA. Peripheral blood mononuclear cells (PBMC) as well as cell lines derived from FA patients were treated with two DNA interstrand crosslinking (ICL) agents, mitomycin C and cyclophosphamide. Our data indicate that the CDA detects hypersensitivity of cells from FA patients to mitomycin C. Further, cell lines derived from FA-patients were also hypersensitive to mitomycin C as well as cyclophosphamide, when assayed by the CDA. This study suggests that the CDA is a useful alternative for the diagnosis of FA patients' hypersensitivity to ICL agents.

The recently reported cell division assay (CDA) was optimized to measure the relative sensitivity of cells to cytotoxic drugs in vitro. Here, we investigated the in vitro hypersensitivity of lymphocytes from Fanconi anemia (FA) patients, to cytotoxic drugs using CDA. Peripheral blood mononuclear cells (PBMC) as well as cell lines derived from FA patients were treated with two DNA interstrand crosslinking (ICL) agents, mitomycin C and cyclophosphamide. Our data indicate that the CDA detects hypersensitivity of cells from FA patients to mitomycin C. Further, cell lines derived from FA‐patients were also hypersensitive to mitomycin C as well as cyclophosphamide, when assayed by the CDA. This study suggests that the CDA is a useful alternative for the diagnosis of FA patients' hypersensitivity to ICL agents.