Cancer-prone syndrome of mosaic variegated aneuploidy and total premature chromatid separation: Report of five infants

Five infants (two girls and three boys) from four families all had severe pre- and post-natal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%-83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%-41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2-16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483-486]), was discussed in connection with tumor development and progression

Extensive Phenotyping for Potential Weight-Inducing Factors in an Outpatient Population with Obesity

Background: Obesity has been associated with miscellaneous weight-inducing determinants. A comprehensive assessment of known obesity-related factors other than diet and physical activity within one cohort is currently lacking. Objectives: To assess the prevalence of potential contributors to obesity and self-reported triggers for marked weight gain in an adult population with obesity and between obesity classes. Methods: In this observational cohort study, we assessed 408 persons with obesity (aged 41.3 ± 14.2 years, BMI 40.5 ± 6.2) visiting our obesity clinic. They were evaluated for use of weight-inducing drugs, hormonal abnormalities, menarcheal age, (high) birth weight, sleep deprivation, and obstructive sleep apnea syndrome (OSAS). We additionally assessed self-reported triggers for marked weight gain and performed genetic testing in patients suspected of genetic obesity. Results: Nearly half of the patients were using a potentially weight-inducing drug, which was also the most reported trigger for marked weight gain. For the assessed hormonal conditions, a relatively high prevalence was found for hypothyroidism (14.1%), polycystic ovary syndrome (12.0%), and male hypogonadism (41.7%). A relatively low average menarcheal age (12.6 ± 1.8 years) was reported, whereas there was a high prevalence of a high birth weight (19.5%). Sleep deprivation and OSAS were reported in, respectively, 14.5 and 13.7% of the examined patients. Obesity class appeared to have no influence on the majority of the assessed factors. Of the genetically analyzed patients, a definitive genetic diagnosis was made in 3 patients (1.9%). Conclusions: A thorough evaluation of patients with obesity yields a relatively high prevalence of various potentially weight-inducing factors. Diagnostic screening of patients with obesi

Health as a Symbolic Media Interchanging between Body and Social System

Genetics of disease, diagnosis and treatmen

Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood (vol 6, 92, 2021)

Genetics of disease, diagnosis and treatmen

DLG4-related synaptopathy: a new rare brain disorder

PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.Genetics of disease, diagnosis and treatmen

To STOPP or to START? Potentially inappropriate prescribing in older patients with falls and syncope

Objectives: To investigate the prevalence of potentially inappropriate prescribing (PIP) according to the revised STOPP/START criteria in older patients with falls and syncope. Study design: We included consecutive patients with falls and syncope aged ≥65 years at the day clinic of the Northwest Clinics, the Netherlands, from 2011 to 2016. All medication use before and after the visit was retrospectively investigated using the revised STOPP/START criteria. Main outcome measures: The prevalence/occurrence of PIP before the visit, persistent PIP after the visit, and unaddressed persistent PIP not explained in the patient's chart. Results: PIP was present in 98 % of 374 patients (mean age 80 (SD ± 7) years; 69 % females). 1564 PIP occurrences were identified. 1015 occurrences persisted (in 91 % of patients). 690 occurrences (in 80 % of patients) were not explained in the patient's chart. The most frequent unaddressed persistent forms of PIP were prescriptions of vasodilator drugs for patients with orthostatic hypotension (16 %), and benzodiazepines for >4 weeks (10 %) or in fall patients (8 %), and omission of vitamin D (28 %), antihypertensive drugs (24 %), and antidepressants (17 %). 54 % of all medication changes were initiated for reasons beyond the scope of the STOPP/START criteria. Conclusions: Almost every patient in our study population suffered from PIP. In 80 %, PIP continued after the clinical visit, without an explanation in the patient's chart. The most frequent PIP concerned medication that increased the risk of falls or syncope, specifically vasodilator drugs and benzodiazepines. Physicians should be aware of PIP in older patients with falls and syncope. Further studies should investigate whether a structured medication review may improve clinical outcomes

Non-invasive sources of cells with primary cilia from pediatric and adult patients

Contains fulltext : 153513.pdf (publisher's version ) (Open Access)BACKGROUND: Ciliopathies give rise to a multitude of organ-specific pathologies; obtaining relevant primary patient material is useful for both diagnostics and research. However, acquisition of primary ciliated cells from patients, particularly pediatric patients, presents multiple difficulties. Biopsies and blood samples are invasive, and patients (and their parents) may be reluctant to travel to medical centers, especially for research purposes. We sought to develop non-invasive methods of obtaining viable and ciliated primary cells from ciliopathy patients which could be obtained in the home environment. FINDINGS: We introduce two methods for the non-invasive acquisition of primary ciliated cells. In one approach, we collected spontaneously shed deciduous (milk) teeth from children. Fibroblast-like cells were observed after approximately 2 weeks of culture of fragmented teeth. Secondly, urine samples were collected from children or adults. Cellular content was isolated and after approximately 1 week, renal epithelial cells were observed. Both urine and tooth-derived cells ciliate and express ciliary proteins visible with immunofluorescence. Urine-derived renal epithelial cells (URECs) are amenable to 3D culturing, siRNA knockdown, and ex vivo drug testing. CONCLUSIONS: As evidence continues to accumulate showing that the primary cilium has a central role in development and disease, the need for readily available and ciliated patient cells will increase. Here, we introduce two methods for the non-invasive acquisition of cells with primary cilia. We believe that these cells can be used for further ex vivo study of ciliopathies and in the future, for personalized medicine

Effect of vertical sleeve gastrectomy in melanocortin receptor 4-deficient rats

Bariatric surgery is currently the most effective treatment for obesity. Vertical sleeve gastrectomy (VSG), a commonly applied bariatric procedure, involves surgically incising most of the volume of the stomach. In humans, partial loss of melanocortin receptor-4 (MC4R) activity is the most common monogenic correlate of obesity regardless of lifestyle. At present it is unclear whether genetic alteration of MC4R signaling modulates the beneficial effects of VSG. Following VSG, we analyzed body weight, food intake, glucose sensitivity, and macronutrient preference of wild-type and MC4R-deficient (Mc4r(+/-) and Mc4r(-/-)) rats compared with sham-operated controls. VSG reduced body weight and fat mass and improved glucose metabolism and also shifted preference toward carbohydrates and away from fat. All of this occurred independently of MC4R activity. In addition, MC4R was resequenced in 46 human subjects who underwent VSG. We observed common genetic variations in the coding sequence of MC4R in five subjects. However, none of those variations appeared to affect the outcome of VSG. Taken together, these data suggest that the beneficial effect of VSG on body weight and glucose metabolism is not mediated by alterations in MC4R activity

Den osynlige fotbollsspelaren : Redovisning av fotbollsspelare på balansräkningen

Problem: Genom Svenska Fotbollförbundets införande av elitlicensen får fotbollsklubbar redovisa inköpta spelare som en tillgång eller kostnadsföra utgiften direkt. Dock får ej icke förvärvade spelare aktiveras på balansräkningen. Syfte: Undersöka möjligheten att redovisa alla spelare i en fotbollsklubb ekonomiskt samt undersöka sätt att värdera spelare vilka saknar anskaffningspris. Även utreda om en sådan redovisning leder till en mer ekonomisk rättvisande bild av klubbarna och hur jämförbarheten mellan klubbarna påverkas. Vill väcka intresse kring problemen med spelarvärdering på balansräkningen. Genomförande: Studie av litteratur i ämnet, gällande lagar och Svenska Fotbollförbundets elitlicens. Material insamlades genom en kvalitativ undersökning i form av intervjuer av kunniga personer inom elitfotboll och redovisning. Materialet från litteratur och intervjuer sammankopplas och diskuteras. Slutsatser: Undersökningen visar att rådande regler för fotbollsklubbarnas redovisning är efter de möjligheter som finns utformade på ett bra sätt och att därmed endast förvärvade spelare kan aktiveras. Detta då objektiva värderingsmodeller för ej köpta spelare saknas och att detta krävs för att få ett korrekt värde på spelaren. Dagens regler ger inte en helt rättvisande bild av fotbollsklubbarna men dock så väl som är möjligt idag

Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease

Infantile-onset inflammatory bowel disease (IO IBD) is an invalidating illness with an onset before 2 years of age and has a complex pathophysiology in which genetic factors are important. Homozygosity mapping and whole-exome sequencing in an IO IBD patient and subsequent sequencing of the candidate gene in 12 additional IO IBD patients revealed two patients with two mutated ankyrin repeat and zinc-finger domain-containing 1 (ANKZF1) alleles (homozygous ANKZF1 R585Q mutation and compound heterozygous ANKZF1 E152K and V32-Q87del mutations, respectively) and two patients with one mutated ANKZF1 allele. Although the function of ANKZF1 in mammals had not been previously evaluated, we show that ANKZF1 has an indispensable role in the mitochondrial response to cellular stress. ANKZF1 is located diffusely in the cytoplasm and translocates to the mitochondria upon cellular stress. ANKZF1 depletion reduces mitochondrial integrity and mitochondrial respiration under conditions of cellular stress. The ANKZF1 mutations identified in IO IBD patients with two mutated ANKZF1 alleles result in dysfunctional ANKZF1, as shown by an increased level of apoptosis in patients' lymphocytes, a decrease in mitochondrial respiration in patient fibroblasts with a homozygous ANKZF1 R585Q mutation, and an inability of ANKZF1 R585Q and E152K to rescue the phenotype of yeast deficient in Vms1, the yeast homologue of ANKZF1. These data indicate that loss-of-function mutations in ANKZF1 result in deregulation of mitochondrial integrity, and this may play a pathogenic role in the development of IO IBD