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Marfan syndrome (MFS) is a complex connective tissue disorder characterized by considerable clinical variability. The diagnosis of MFS is based on the Ghent criteria, which require the presence of both clinical and genetic features. MFS is primarily caused by pathogenic alterations in FBN1, which encodes the fibrillin-1 protein. Fibrillin-1 comprises multiple domains rich in cysteine residues, with disulfide bonds formed between these residues. It has long been recognized that variants that alter or introduce cysteine residues damage protein function, leading to the development of MFS. In this study, we report a cysteine-introducing variant: FBN1 variant, c.6724C>T (p.[Arg2242Cys]). We have observed this variant in several individuals without MFS, challenging our previous understanding of the underlying mechanism of MFS. This finding emphasizes the importance of revisiting and reevaluating our current knowledge in light of new and unexpected observations. Moreover, our study highlights the significance of incorporating local and national data on allele frequencies, as well as employing multidisciplinary phenotyping approaches, in the classification of genetic variants. By considering a wide range of information, we can enhance the accuracy and reliability of variant classification, ultimately improving the diagnosis and management of individuals with genetic disorders like MFS., (© 2024 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Objectives: We aimed to compare cell-based NIPT (cbNIPT) to chorionic villus sampling (CVS) and to examine the test characteristics of cbNIPT in the first clinical validation study of cbNIPT compared to cell-free NIPT (cfNIPT)., Material and Methods: Study 1: Women (N = 92) who accepted CVS were recruited for cbNIPT (53 normal and 39 abnormal). Samples were analyzed with chromosomal microarray (CMA). Study 2: Women (N = 282) who accepted cfNIPT were recruited for cbNIPT. cfNIPT was analyzed using sequencing and cbNIPT by CMA., Results: Study 1: cbNIPT detected all aberrations (32/32) found in CVS: trisomies 13, 18 and 21 (23/23), pathogenic copy number variations (CNVs) (6/6) and sex chromosome aberrations (3/3). cbNIPT detected 3/8 cases of mosaicism in the placenta. Study 2: cbNIPT detected all trisomies found with cfNIPT (6/6) and had no false positive (0/246). One of the three CNVs called by cbNIPT was confirmed by CVS but was undetected by cfNIPT, two were false positives. cbNIPT detected mosaicism in five samples, of which two were not detected by cfNIPT. cbNIPT failed in 7.8% compared to 2.8% in cfNIPT., Conclusion: Circulating trophoblasts in the maternal circulation provide the potential of screening for aneuploidies and pathogenic CNVs covering the entire fetal genome., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Noonan syndrome is characterized by variable phenotypic expressivity with characteristic dysmorphic facial features, varying degrees of intellectual disability, developmental delay, short stature, and congenital heart defects in 50-80%. Other findings include a webbed neck, cryptorchidism, coagulation defects and eye abnormalities. Thus far, Noonan syndrome has mainly been attributed to heterozygous pathogenic variants in 10+ different genes, with the rare exception of cases due to biallelic pathogenic variants in LZTR1. Recently, homozygous loss-of-function variants in SPRED2 have been identified as a cause of a recessive Noonan syndrome-like phenotype. We present the phenotypes of two additional patients with homozygosity for a previously unreported loss-of-function variant in SPRED2, thereby adding relevant clinical information about the recently described Noonan syndrome-like SPRED2-related phenotype., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The genetic background of familial, late-onset colorectal cancer (CRC) (i.e., onset > age 50 years) has not been studied as thoroughly as other subgroups of familial CRC, and the proportion of families with a germline genetic predisposition to CRC remains to be defined. To define the contribution of known or suggested CRC predisposition genes to familial late-onset CRC, we analyzed 32 well-established or candidate CRC predisposition genes in 75 families with late-onset CRC. We identified pathogenic or likely pathogenic variants in five patients in MSH6 (n = 1), MUTYH (monoallelic; n = 2) and NTHL1 (monoallelic; n = 2). In addition, we identified a number of variants of unknown significance in particular in the lower penetrant Lynch syndrome-associated mismatch repair (MMR) gene MSH6 (n = 6). In conclusion, screening using a comprehensive cancer gene panel in families with accumulation of late-onset CRC appears not to have a significant clinical value due to the low level of high-risk pathogenic variants detected. Our data suggest that only patients with abnormal MMR immunohistochemistry (IHC) or microsatellite instability (MSI) analyses, suggestive of Lynch syndrome, or a family history indicating another cancer predisposition syndrome should be prioritized for such genetic evaluations. Variants in MSH6 and MUTYH have previously been proposed to be involved in digenic or oligogenic hereditary predisposition to CRC. Accumulation of variants in MSH6 and monoallelic, pathogenic variants in MUTYH in our study indicates that digenic or oligogenic inheritance might be involved in late-onset CRC and warrants further studies of complex types of inheritance., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Cell-free NIPT and cell-based NIPT are risk-free testing options using maternal blood samples to screen for fetal aneuploidies, but the methods differ. For cell-free NIPT, the fetal fraction of cell-free DNA in plasma is analyzed with a high background of maternal DNA. In contrast, for cell-based NIPT, a limited number of the rare, intact fetal cells are isolated for the genetic analysis. This case demonstrates the differences regarding testing for fetal sex-chromosomes anomalies (SCAs) between these two tests. Materials and Methods: A pregnant woman with mosaicism for Turner syndrome opted for NIPT in first trimester. For the cell-free NIPT analysis, DNA extraction, genome-wide massive parallel sequencing, and data analysis were carried out as described by the kit manufacturer (Illumina©, San Diego, CA, USA). For cell-based NIPT, the first sample gave no result, but the woman consented to repeat cell-based NIPT. After whole genome amplification and STR analysis, fetal DNA from three individual fetal cells was subjected to chromosomal microarray (aCGH, Agilent oligoarray, 180 kb). Results: Fetal fraction was 7%, and cell-free NIPT showed 2 copies of chromosomes 13, 18, and 21 and a decreased proportion of chromosome X, suggestive of fetal Turner syndrome. In contrast, the cell-based NIPT result showed no aneuploidy and two X-chromosomes in the fetus. Conclusion: cell-based NIPT may provide a non-invasive testing option to screen for SCAs in women with mosaicism for monosomy-X in blood, where cell-free NIPT cannot discriminate whether the X-loss is maternal or fetal., Competing Interests: LJ, LH, RS, and PS are all employed by the Danish biotech company ARCEDI Biotech that has launched a commercial cell-based non-invasive prenatal test (www.evitatest.com). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jeppesen, Hatt, Singh, Schelde, Andreasen, Markholt, Lildballe and Vogel.)

Background: Musculocontractural Ehlers-Danlos Syndrome (mcEDS) is a rare connective tissue disorder caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE), both of which result in defective dermatan sulfate biosynthesis. Forty-one patients with mcEDS-CHST14 and three patients with mcEDS-DSE have been described in the literature., Methods: Clinical, molecular, and glycobiological findings in three additional patients with mcEDS-DSE were investigated., Results: Three patients from two families shared craniofacial characteristics (hypertelorism, blue sclera, midfacial hypoplasia), skeletal features (pectus and spinal deformities, characteristic finger shapes, progressive talipes deformities), skin features (fine or acrogeria-like palmar creases), and ocular refractive errors. Homozygous pathogenic variants in DSE were found: c.960T>A/p.Tyr320* in patient 1 and c.996dupT/p.Val333Cysfs*4 in patients 2 and 3. No dermatan sulfate was detected in the urine sample from patient 1, suggesting a complete depletion of DS., Conclusion: McEDS-DSE is a congenital multisystem disorder with progressive symptoms involving craniofacial, skeletal, cutaneous, and cardiovascular systems, similar to the symptoms of mcEDS-CHST14. However, the burden of symptoms seems lower in patients with mcEDS-DSE., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Secondary inflammatory reactions to stroke or trauma contribute to irreplaceable loss of brain tissue of the affected patients. Likewise, neuroinflammatory processes are the main pathophysiological feature in Multiple Sclerosis (MS), a common neurodegenerative disease among young adults. In the search for safe and efficient ways to reduce inflammation within nervous tissue older immunosuppressive remedies have been re-investigated. The anti-inflammatory properties of gold salts are well known but result in uncontrollable systemic spread of gold ions, generating side effects such as nephrotoxicity, limiting their use. Recent studies have circumvented this obstacle by introducing metallic gold implants as a localized source of immune-modulating gold ions and suspension in hyaluronic acid (HA) enables injection of small amounts of gold in the natural spaces of the brain. By injecting >25 μm gold beads in HA intracerebrally we recently showed a slowing of disease progression in a rodent model of MS. The toxicological aspects were, however, not assessed. The present study investigates the viability of neuronal and macrophage cell cultures exposed to the gold/HA combination and the possible risk associated with unilateral gold/HA injection in young Balb/CA mice in the first 7 to 21 days of gold-exposure. Tracing by autometallography of gold accumulations throughout the brain exhibited sparse gold uptake in glia and neurons of hippocampus and cortex, and striatum and cerebellum were void of staining. No systemic spread of gold was seen in liver or kidney, nor were there signs of obstruction of the ventricular system. Both cell cultures of J774 macrophages and CCL neurons accumulated gold from gold/HA-exposure with no signs of reduced viability. In conclusion, our findings indicate that gold/HA is not overtly neuro- or cytotoxic, nor does intraventricular exposure result in widespread gold accumulation or tissue damage, warranting further studies into the pharmacological properties of this novel form of gold treatment.

Silver is a metal with well-known antibacterial effects. This makes silver an attractive coating material for medical devices for use inside the body, e.g. orthopaedic prostheses and catheters used in neurosurgery as it has been found to reduce the high risk of infections. Lately, the use of nano-silver particles in the industry, e.g. woven into fabrics and furniture has increased, and thus the exposure to silver particles in daily life increases. To study the effect of metallic silver particles on nervous tissue, we injected micron-sized silver particles into the mouse brain by stereotactic procedures. After 7, 14 days and 9 months, the silver-exposed animals had considerable brain damage seen as cavity formation and inflammation adjacent to the injected metallic silver particles. The tissue loss involved both cortical and hippocampal structures and resulted in enlargement of the lateral ventricles. Autometallographic silver enhancement showed silver uptake in lysosomes of glia cells and neurons in the ipsilateral cortex and hippocampus alongside a minor uptake on the contralateral side. Silver was also detected in ependymal cells and the choroid plexus. After 9 months, spreading of silver to the kidneys was seen. Cell counts of immunostained sections showed that metallic silver induced a statistically significant inflammatory response, i.e. increased microgliosis (7 days: p < 0.0001; 14 days: p < 0.01; 9 months: p < 0.0001) and TNF-α expression (7 and 14 days: p < 0.0001; 9 months: p = 0.91). Significant astrogliosis (7, 14 days and 9 months: p < 0.0001) and increased metallothionein (MT I + II) expression (7 and 14 days: p < 0.0001; 9 months: p < 0.001) were also seen in silver-exposed brain tissue. We conclude that metallic silver implants release silver ions causing neuroinflammation and a progressive tissue loss in the brain., (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)

Cryopreservation of ovarian tissue is a promising new technique for fertility preservation in patients facing gonadotoxic treatment. Ovarian tissue is extracted and cryo-stored at low temperature prior to treatment. If the woman becomes menopausal, the tissue can be transplanted and a few months later the woman will start to ovulate and be able to conceive, naturally or with assisted reproduction treatment. Currently, 12 healthy children have been born worldwide as a result of transplanting frozen/thawed ovarian tissue. Of these children 3 are Danish and a number of other Danish women are currently attempting to become pregnant. One of these women conceived naturally and had a normal intrauterine pregnancy following transplantation of cryopreserved ovarian tissue. However, the woman decided to terminate the pregnancy within the legal time frame. This pregnancy imposes cryopreservation of ovarian tissue for fertility preservation as a valid method and illustrates that personal life circumstances may rapidly change.