Extended genetic testing in fetuses with sonographic skeletal system abnormalities.

OBJECTIVES: To analyze genetic causes of skeletal system abnormalities diagnosed by prenatal sonography and to establish a diagnostic protocol with regard to extended genetic testing in this group of patients. METHODS: This prospective observational cohort study included all singleton pregnancies with a sonographic abnormality of the skeletal system evaluated in a single ultrasound department during a 1-year period (2019). Fetuses underwent routine genetic testing by chromosomal microarray analysis (CMA) supplemented with polyploidy testing, and those with either a normal result or an abnormal result not consistent with the observed phenotype underwent exome sequencing (ES). Interpretation of variants was discussed by a panel of specialists to identify pathogenic/likely pathogenic variants. RESULTS: The study group comprised 55 fetuses. A chromosomal abnormality consistent with the observed phenotype was detected in 24 (43.6%) cases. After exclusions, 26 (47.3%) cases underwent further molecular testing by ES, of which 18 (69.2%) were classified as having abnormal ES results, thus increasing the diagnostic yield by a further 18 (32.7%) cases and giving an abnormal genetic test result in 42/55 (76.4%) fetuses overall. Pathogenic or likely pathogenic sequence variants in 14 different genes were detected across 18 fetuses. Seven genes are already listed in the International Skeletal Dysplasia Society Nosology and seven are not typically found to be causal for skeletal dysplasias and are not listed in the Nosology. CONCLUSIONS: In fetuses with skeletal system anomalies, chromosomal abnormality was the most common genetic diagnosis. Exome sequencing increased the diagnostic yield over that of CMA and polyploidy testing. Fetuses with skeletal abnormalities should undergo extended genetic testing following routine testing, as many genetic anomalies responsible for skeletal defects may otherwise be missed. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Higher serum levels of pro-hepcidin in patients with Parkinson's disease treated with deep brain stimulation.

Hepcidin is an essential hormone responsible for the systemic metabolism of iron and simultaneously belongs to the family of the protein mediators of the acute inflammatory response, primarily induced in response to interleukin 6. It can therefore be regarded as a link between the oxidative stress processes, where iron plays an important role, and the processes of neuroinflammation - both considered to be responsible for the neurodegeneration in Parkinson's disease. We assessed the serum level of pro-hepcidin in patients with Parkinson's disease treated only pharmacologically and those treated additionally with deep brain stimulation (DBS) as compared to the control group. Thirty-seven patients with Parkinson's disease (18 females, 19 males, mean age: 57 years) were treated only pharmacologically with optimal, individualized therapy for each patient, whereas 15 (7 females, 8 males, mean age: 54 years) were treated additionally with DBS. The control group consisted of 31 healthy volunteers (15 females, 16 males, mean age: 58 years). In the subgroup of patients with Parkinson's disease treated with DBS the serum concentration of pro-hepcidin was significantly higher and the result was statistically significantly higher than in the control group (p = 0.0003) and in patients with Parkinson's disease treated only pharmacologically (p = 0.025). The results suggested the possible immunomodulatory effect of prolonged high-frequency stimulation and the implantation of the electrodes into the brain tissue of the host, most likely in the form of the increasaed production of inflammatory mediators, associated with the activation of the astroglia and microglia. The rational justification for the purpose of our study was the evidences and hypothesis from studies on the potential immunomodulatory and neuroprotective effect of DBS in patients with Parkinson's disease, the systemic influence of the DBS procedure on the improvement of motor function, reduction of dopaminergic drugs, improvement of the quality of life of patients, and animal studies, which have proven the presence of regional neuroinflammation around implanted electrodes.

Linkage analysis localises a Kartagener syndrome gene to a 3.5 cM region on chromosome 15q24-25.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a genetic disorder caused by ciliary immotility/dysmotility due to ultrastructural defects of the cilia. Kartagener syndrome (KS), a subtype of PCD, is characterised by situs inversus accompanying the typical PCD symptoms of bronchiectasis and chronic sinusitis. In most cases, PCD is transmitted as an autosomal recessive trait, but its genetic basis is unclear due to extensive genetic heterogeneity. METHODS: In a genome-wide search for PCD loci performed in 52 KS families and in 18 PCD families with no situs inversus present (CDO, ciliary dysfunction-only), the maximal pairwise LOD score of 3.36 with D15S205 in the KS families indicated linkage of a KS locus to the long arm of chromosome 15. In the follow-up study, 65 additional microsatellite markers encompassing D15S205 were analysed. RESULTS: A maximal pairwise LOD score of 4.34 was observed with D15S154, further supporting linkage of the KS, but not the CDO, families to 15q24-25. Analysis of heterogeneity and haplotypes suggested linkage to this region in 60% of KS families. CONCLUSIONS: Reinforced by the results of multipoint linkage, our analyses indicate that a major KS locus is localised within a 3.5 cM region on 15q, between D15S973 and D15S1037.

RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. RESULTS: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene (RPGR) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. CONCLUSION: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.

A5814G mutation in mitochondrial DNA can cause mitochondrial myopathy and cardiomyopathy.

We describe a 5-year-old child with hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis. Mitochondrial DNA analysis showed a heteroplasmic A5814G point mutation in the tRNA(Cys) gene. The mutational load was extremely high (>95%) in muscle, fibroblasts, and blood. This report expands the clinical heterogeneity of the A5814G mutation, which should be considered in the differential diagnosis of hypertrophic cardiomyopathy in childhood.

Evaluating the competence of venous valves preserved with denaturation in cold ischaemia.

AIM OF STUDY: The aim of this study was to evaluate the competence of venous valves preserved with denaturation in cold ischaemia. MATERIAL AND METHOD: Eight segments of saphenous veins with 20 competent valves were analysed in the study. The material was collected during multiorgan retrievals. After harvesting, 15 cm long venous fragments were assessed with respect to valve presence. A 4-cm fragment with a valve was used for the analysis. Valve competence was assessed twice: after sampling and after 21 days of preservation. The valves were subjected to 136 cm water column pressure test. Denaturation in cold ischaemia consists of preservation of vessels at 4_C in a preservation medium containing antibiotics. Bacteriological and morphological examinations by light microscopy were performed. RESULTS: After the preservation period, all the valves retained their mechanical properties. Well-preserved elastic elements of vascular wall were maintained in all vessels. Minor fragmentation of elastic fibres was observed and the structure of vascular wall was usually regular. CONCLUSIONS: Our study indicates that denaturation in cold ischaemia allows for the maintenance of the properties and physiological functions of the valves after preservation. This effect is related to the good condition of elastic fibres, venous wall structure and the valve itself.