Search

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophies and the most frequent cause of congenital blindness in children. To date, 25 genes have been implicated in the pathogenesis of this rare disorder. Performing an accurate molecular diagnosis is crucial as gene therapy is becoming available. This study aimed to report the molecular basis of Leber congenital amaurosis, especially novel and rare variants in 27 Polish families with a clinical diagnosis of LCA fully confirmed by molecular analyses. Whole exome sequencing or targeted next-generation sequencing (NGS) of inherited retinal dystrophies-associated (IRD) genes was applied to identify potentially pathogenic variants. Bidirectional Sanger sequencing and quantitative PCR (qPCR) were carried out for validation and segregation analysis of the variants identified within the families. We identified 28 potentially pathogenic variants, including 11 novel, in 8 LCA genes: CEP290, CRB1, GUCY2D, NMNAT1, RPGRIP1, CRX, LRAT1, and LCA5. This study expands the mutational spectrum of the LCA genes. Moreover, these results, together with the conclusions from our previous studies, allow us to point to the most frequently mutated genes and variants in the Polish cohort of LCA patients.

Aniridia is usually an autosomal dominant, rare disorder characterized by a variable degree of hypoplasia or the absence of iris tissue, with additional ocular abnormalities. Pathogenic variants in the PAX6 gene are associated with aniridia in most patients. However, in up to 30% of individuals, disease results from 11p13 chromosomal rearrangements. Here we present a patient with a clinical diagnosis of partial aniridia born to consanguineous Polish parents. The parents were asymptomatic and ophthalmologically normal. We performed PAX6 sequencing, array comparative genomic hybridization, quantitative real-time PCR, and whole genome sequencing. aCGH revealed a homozygous deletion of the DCDC1 gene fragment in the patient. The same, but heterozygous deletion, was detected in each of the patient's asymptomatic parents and brother. In the presented family, the signs and symptoms of aniridia are observed only in the homozygous proband. Whole genome sequencing analysis was performed to determine other possible causes of the disease and did not detect any additional or alternative potentially pathogenic variant. We report a novel homozygous deletion located in the 11p13 region, which does not include the PAX6 gene or any known PAX6 enhancers. To our best knowledge, this is the first reported case of a patient presented with isolated aniridia carrying a homozygous microdeletion downstream of the PAX6 gene.

Ciliopathies are rare congenital disorders, caused by defects in the cilium, that cover a broad clinical spectrum. A subgroup of ciliopathies showing significant phenotypic overlap are known as skeletal ciliopathies and include Jeune asphyxiating thoracic dysplasia (JATD), Mainzer-Saldino syndrome (MZSDS), cranioectodermal dysplasia (CED), and short-rib polydactyly (SRP). Ciliopathies are heterogeneous disorders with187 associated genes, of which some genes are described to cause more than one ciliopathy phenotype. Both the clinical and molecular overlap make accurate diagnosing of these disorders challenging. We describe two unrelated Polish patients presenting with a skeletal ciliopathy who share the same compound heterozygous variants in

Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations, corresponding, respectively, to absent eyeball or reduced size of the eye. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome. Genetic heterogeneity has been demonstrated, and many genes have been reported to be associated with A/M. The advances in high-throughput sequencing have proven highly effective in defining the molecular basis of A/M. Nevertheless, there are still many patients with unsolved genetic background of the disease, who pose a significant challenge in the molecular diagnostics of A/M. Here we describe a family, with three males affected with the non-syndromic A/M. Whole exome-sequencing performed in Patient 1, revealed the presence of a novel probably pathogenic variant c.734A>G, (p.[Tyr245Cys]) in the PORCN gene. Pedigree analysis and segregation of the identified variant in the family confirmed the X-linked recessive pattern of inheritance. This is the first report of X-linked recessive non-syndromic A/M. Until now, pathogenic variants in the PORCN gene have been identified in the patients with Goltz syndrome, but they were inherited in X-linked dominant mode. The ocular phenotype is the only finding observed in the patients, which allows to exclude the diagnosis of Goltz syndrome.

The ciliary chondrodysplasias represent a group of clinically and genetically heterogeneous disorders that affect skeleton development. Cilia are organelles that project from the surface of many cell types and play an important role during prenatal and postnatal human development. Cranioectodermal dysplasia (Sensenbrenner syndrome, CED) is a ciliopathy primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. To date six genes have been associated with CED: IFT122, WDR35, WDR19, IFT140, IFT43, and IFT52. Prenatal diagnosis of CED is challenging, and genetic testing can facilitate making a correct diagnosis. Here, we report on a family with two male siblings affected by CED: a 3.5 year-old patient and his 2 year-old brother. Molecular analysis of the proband at 1 year of age revealed compound heterozygous variants in WDR35: c.3G>A [p.(Met1-Ala30delinsMetfsTer4)] and c.2522A>T [p.(Asp841Val)]. Ultrasound examination during the second pregnancy revealed an increased nuchal translucency of 4.5 mm and a hypoplastic nasal bone at 12 weeks of gestation. Prenatal diagnostic testing was offered because of an increased risk for chromosomal abnormalities and recurrence risk for CED. Prenatal genetic analysis of a chorionic villus sample detected the WDR35 variants previously identified in the elder brother. This is the first report of a prenatal genetic diagnosis in CED.

Objective Craniosynostosis (CS) is the premature fusion of the cranial sutures, occurring either in isolated or syndromic form. Syndromic CS, which was described in over 180 genetic syndromes, accounts for 15-30% of all CS cases and usually originates from mutations within the FGFR1, FGFR2, FGFR3, and TWIST1 genes. However, causative alterations in other genes, or rarely copy number variations (CNVs) were also reported. In this article, we describe a patient with Noonan-like facial dysmorphism accompanied by intellectual disability and compound CS, involving coronal, sagittal, and squamous sutures. Methods We applied karyotyping, copy number variations analysis using array comparative genomic hybridization, and microarray-based genes expresion analysis. Results We have shown that the index carried a large and rare heterozygous deletion, which encompassed 12.782 Mb and mapped to a chromosomal region of 7q32.3-q35 (HG38 - chr7:131837067-144607071). The aberration comprised 109 protein-coding genes, including BRAF, that encodes serine/threonine-protein kinase B-Raf, being a part of the RAS/MAPK signaling pathway. Discussion The RAS/MAPK pathway plays an essential role in human development; hence, its dysregulation not surprisingly results in severe congenital anomalies, such as phenotypically overlapping syndromes termed RASopathies. To our best knowledge, we report here the first CNV causing haploinsufficiency of BRAF, resulting in dysregulation of the RAS/MAPK cascade, and consequently, in the phenotype observed in our patient. To conclude, with this report, we have pointed to the involvement of the RAS/MAPK signaling pathway in CS development. Moreover, we have shown that the molecular analysis based on both DNA and RNA profiling, undoubtedly constitutes a comprehensive diagnostic and research strategy for elucidating a cause of genetic diseases.

Genetic analysis of two siblings with complex microphthalmia, with clinically healthy parents. Clinical and experimental. The patients underwent a detailed ophthalmic evaluation, including visual acuity, fundus examination, gonioscopy, ultrasound examination, and optical coherence tomography. Lensectomy with anterior vitrectomy was conducted in both patients. Additionally, in patient p1, electroencephalography analysis was performed. Genetic analysis was carried out using array comparative genomic hybridization (aCGH) and whole exome sequencing (WES). Bidirectional Sanger sequencing was conducted for validation and segregation analysis of the identified variant in the family. The aCGH results were normal. The heterozygous PAX6 variant c.52G>C (p.Gly18Arg) was identified in the proband (p1) through WES analysis. Sanger sequencing of exon 5 of PAX6 confirmed the presence of the variant in the other affected sibling (patient p2) but did not allow for identification of the variant in the parents’ DNA isolated from leukocytes and buccal cells. The description of the variant in PAX6 in two siblings with clinically healthy parents who are negative for the mutation in DNA from leukocytes and buccal cells represents the possibility of parental gonadal mosaicism. Detection of germ cell mosaicism in the parents is essential to provide genetic counseling to the family regarding the risk of reoccurrence. Furthermore, we also report a pathogenic variant in PAX6 that to our knowledge has not so far been reported in patients with partial aniridia and therefore broadens the spectrum of the variants associated with aniridia.

Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.

Cranioectodermal dysplasia (CED) is a rare autosomal recessive disorder primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. CED is a chondrodysplasia, which is part of a spectrum of clinically and genetically heterogeneous diseases that result from disruptions in cilia. Pathogenic variants in genes encoding components of the ciliary transport machinery are known to cause CED. Intra- and interfamilial clinical variability has been reported in a few CED studies and the findings of this study align with these observations. Here, we report on five CED patients from four Polish families with identical compound heterozygous variants [c.1922T>G p.(Leu641Ter) and c.2522A>T; p.(Asp841Val)] in WDR35. The frequent occurrence of both identified changes in Polish CED families suggests that these variants may be founder mutations. Clinical evaluation of the CED patients revealed interfamilial clinical variability among the patients. This includes differences in skeletal and ectodermal features as well as variability in development, progression, and severity of renal and liver insufficiency. This is the first report showing significant interfamilial clinical variability in a series of CED patients from unrelated families with identical compound heterozygous variants in WDR35. Our findings strongly indicate that other genetic and non-genetic factors may modulate the progression and expression of the patients' phenotypes.

Auriculocondylar syndrome (ACS) is an ultra-rare disorder that arises from developmental defects of the first and second pharyngeal arches. Three subtypes of ACS have been described so far, i.e., ACS1 (MIM: 602483), ACS2 (MIM: 600810), and ACS3 (MIM: 131240). The majority of patients, however, are affected by ACS2, which results from the mutations in the PLCB4 gene. Herein, we have described an 8-year-old male patient presenting with ACS2 and summarized the molecular and phenotypic spectrum of the syndrome. We have also compared the clinical features of our case to three other previously described cases (one sporadic and two familial) harboring the same heterozygous missense variant c.1862G>A, p.Arg621His in the PLCB4 gene. The mutation was detected using whole-exome sequencing (WES). Due to low coverage of WES and suspicion of somatic mosaicism, the variant was additionally reassessed by deep targeted next-generation sequencing panel of genes related to the craniofacial disorders, and next confirmed by Sanger sequencing. ACS2 presents high intra- and interfamilial phenotypic heterogeneity that impedes reaching an exact clinical and molecular diagnosis. Thus, describing additional cases, carrying even the known mutation, but resulting in variable phenotypes, is essential for better understanding of such orphan Mendelian diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s13353-020-00591-3.

Introduction. Cough is the most common symptom of respiratory diseases. It has a significant impact on the quality of life of patients. Aim. Examination and comparison of cough intensity, symptoms associated with cough, head and neck muscle’s tonus, breathing type and maximum phonation time in patients with chronic cough before and after speech therapy. Material and methods. The study comprised 10 patients, including 8 women and 2 men from 30 to 73 years of age. All participants completed The Visual Analogue Scale (VAS), Reflux Symptoms Index (RSI), Voice Tract Discomfort (VTD), Voice Handicap Index (VHI). Additionally, the breathing track, muscle tension within the head and neck, maximum time of phonation were evaluated. Results. The results Visual Analogue Scale, Voice Handicap Index and the maximum phonation time after speech therapy were statistically significant (p 0.05) Conclusions. Speech therapy therapy has a significant impact on the severity of chronic cough, symptoms associated with cough, the normalization of head muscle tension, improvement of the breathing track and the elongation of the maximum time of phonation. It is the future direction in the therapy of patients with chronic cough.

Aim: The aim of the study was to determine the prevalence of dysphagia in patients with chronic cough. Material and methods: Thirty four consecutive patients. All patients underwent physical examination, ENT assessment, functional phoniatric assessment at rest and speech, Water-Swallow Test (WST), and Fiberoptic Endoscopic Evaluation of Swallowing disorders (FEES) Reflux Symptom Index (RSI) questionnaire and Eating Assestment Tool 10 (EAT 10) questionnaire were performed. Results: The results of the RSI and EAT 10 questionnaires showed the risk of reflux and dysphagia in participating patients. WST positive results increase with water volume. The patients presented episodes of spillage, double swallows, penetration, aspiration and residue of food at the hypopharynx. Functional examination showed decrease of laryngeal elevation (33%) and hypertension of external larynges muscles. Conclusions: The results of the study showed prevalence of dysphagia in most patients with chronic chough. It seems that phoniatric assessment in those cases should be expanded and the FEES examination should be their important part. Key words: dysphagia, FEES, chronic cough, water swallowing test, aspiration, penetration.

The endoscopic examination of swallowing FEES (fiberoptic endoscopic examination of swallowing) belongs to the basic instrumental examinations used in diagnostics of oropharyngeal dysphagia. It consists of three parts: I. Evaluation of the anatomy and physiology of the throat and larynx; II. Assessment of drinking and eating liquids and foods with different consistencies; III. Evaluation of the effectiveness of therapeutic maneuvers. The purpose of the work is to present the test procedure and the form used to describe it.

Shape-memory materials have recently gained significant attention from scientists and industries around the world. Their useful properties and ability to change their shape when triggered by different stimuli have encouraged researchers to develop this area of science. The examinations conducted herein concern a nonwoven material with thermally induced shape-memory properties, produced by the melt-blown technique. The subject of the research was a nonwoven fabric made from biodegradable poly(L-lactide) (PLLA) blended with atactic polyhydroxybutyrate (a-PHB). The main aim of the presented research was to determine the technological parameters of the melt-blown process and investigate the shape fixing and recovery mechanisms in the obtained material. Thermal, mechanical, and structural analyses were conducted to describe the properties of the smart fabric. The results obtained for the nonwoven fabric produced under specific conditions and selected process parameters showed that it possesses a controllable, thermally induced shape-memory effect. Shape-memory textiles have great potential for diverse applications, in particular in medical science.

Background The aim of this study was to evaluate the effect of sleeve gastrectomy (SG) and Roux-en-Y-bypass (RYGB) on anthropometric and biochemical parameters, including changes in glucose levels, lipid profile and liver function. Drastic decrease in all lipid fractions a few weeks or months after the surgery could be regarded as favourable, but low level of HDL is an independent risk factor for heart diseases. Extreme load on the liver without preparation of the patient to the surgery can have negative consequences. Methods The test group comprised of 40 female patients at the age of 42.96 with average body weight of 131.56 kg and BMI 46.49. Biochemical analyses were performed using calorimetric method. Results No statistically significant differences were observed in glucose levels between the two types of procedures. The highest differences were noted for triglycerides levels, which decreased, as well as all cholesterol fractions, after RYGB, but were increasing during the first months after SG procedure. Changes in lipid profile, caused by the reduction of all lipid fractions, were more visible after RYGB. The decrease in total cholesterol directly and activity of liver enzymes after the procedure was as higher after RYGB as after SG. Increased activity of transaminases indicates significant liver overload. Conclusions With the selection of groups of patients with similar initial parameters, it is not clear whether the differences between the two procedures when assessing the improvement of glycaemia are significant. However, due to invasive character of RYGB, liver overload lasting several months and lifelong limited absorption of nutrients, the possibility of SG procedure should be considered as a first option.

The original article contains an error. In the Introduction section, after MIM should have a colon as follows; ACS1 (MIM: 602483), ACS2 (MIM: 600810), and ACS3 (MIM: 131240).

Background Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Case We report a on 2-year-old male patient affected by Sensenbrenner syndrome. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, narrow chest, high forehead, epicanthal folds, telecanthus, broad nasal bridge, low-set ears, sparse hair, and widely space teeth. Craniosynostosis was surgically corrected at the age of 4 months. The patient presented chronic renal disease. Nephrologic picture showed early stages of nephronophthisis. Psychomotor development was apparently normal. Molecular analysis of the affected individual revealed compound heterozygosity for a novel nonsense p.(Arg113*) and a missense p.(Asp841Val) variant in the WDR35 gene. Conclusions The observations of the CED patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome.

The presented paper concerns scientific research on processing a poly(lactide-co-glycolide-co-trimethylene carbonate) copolymer (PLLAGLTMC) with thermally induced shape memory and a transition temperature around human body temperature. The material in the literature called terpolymer was used to produce smart, nonwoven fabric with the melt blowing technique. Bioresorbable and biocompatible terpolymers with shape memory have been investigated for its medical applications, such as cardiovascular stents. There are several research studies on shape memory in polymers, but this phenomenon has not been widely studied in textile products made from shape memory polymers (SMPs). The current research aims to explore the characteristics of the PLLAGLTMC nonwoven fabric in detail and the mechanism of its shape memory behavior. In this study, the nonwoven fabric was subjected to thermo-mechanical, morphological, and shape memory analysis. The thermo-mechanical and structural properties were investigated by means of differential scanning calorimetry, dynamic mechanical analysis, scanning electron microscopic examination, and mercury porosimetry measurements. Eventually, the gathered results confirmed that the nonwoven fabric possessed characteristics that classified it as a smart material with potential applications in medicine.

Jalili syndrome is a rare disorder inherited in an autosomal recessive pattern manifesting as a combination of cone-rod dystrophy including progressive loss of visual acuity, color blindness, photophobia, and amelogenesis imperfecta with hypoplastic, immature, or hypocalcified dental enamel. It is caused by mutations in CNNM4, which encodes the ancient conserved domain protein 4. Here we report three brothers with Jalili syndrome and muscle overgrowth of the legs. Myopathic changes were found in needle electromyography. Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant. In order to exclude other causative variants that could modify the patients' phenotype we performed exome sequencing and MLPA analysis of the DMD gene in Patient 1. These analyses did not identify any additional variants. Our results expand the mutational spectrum associated with Jalili syndrome and suggest that mild myopathy with muscle overgrowth of the legs could be a newly identified manifestation of the disorder.

Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy. Cranioectodermal dysplasia is characterized by craniofacial, skeletal, and ectodermal abnormalities. About 50 patients have been described to date. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disorder. Mutations in five genes: IFT122, WDR35, IFT43, WDR19, and IFT52 have been associated with CED. All known genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Here, we report a family with two children affected by Sensenbrenner syndrome, a 9-year-old girl and her older sister who died in infancy due to respiratory, liver, and renal insufficiency. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, preaxial polydactyly of left hand, narrow chest, craniosynostosis, dolichocephaly, high anterior hairline, epicanthal folds and telecanthus, depressed nasal bridge, low-set ears, and additional ectodermal abnormalities. The patient presented with chronic tubulointerstitial renal disease. She had abnormal echogenicity on renal ultrasound, reduced glomerular filtration, albuminuria and tubular proteinuria, hypocalciuria and hypocitraturia, accompanied by pre-hypertensive state. This pattern of renal abnormality was regarded as nephronophthisis. Psychomotor development was apparently normal. Molecular analysis in one of the affected individuals identified compound heterozygosity for a nonsense (c.1922T>G, p.(Leu641*)) and missense (c.2522A>T, p.(Asp841Val)) variants in WDR35. We present a detailed clinical descriptions of two female siblings showing an intrafamilial phenotypic variability of the disease, and illustrating the potential lethality of CED.

Deletions of chromosome bands 13q33-34 are rare. Patients with such deletions have mental retardation, microcephaly, and distinct facial features. Male patients frequently also have genital malformations. We report on four patients with three overlapping deletions of 13q33-34 that have been characterized by tiling-path array-CGH. Patient 1 had mental retardation and microcephaly with an interstitial 4.7 Mb deletion and a translocation t(12;13)(q13.3;q32.3). His mother (Patient 2), who also had mental retardation and microcephaly, carried the identical chromosome aberration. Patient 3 was a girl with a de novo insertion ins(7;13)(p15.1;q22q31) and interstitial 4.5 Mb deletion in 13q33-34. She had mental retardation and microcephaly. Patient 4 was a newborn boy with severe genital malformation (penoscrotal transposition and hypospadias) and microcephaly. He had a de novo ring chromosome 13 lacking the terminal 9.3 Mb of 13q. Karyotype-phenotype comparisons of these and eight previously published del13q33-34 patients suggest EFNB2 as a candidate gene for genital malformations in males. Molecular cytogenetic definition of a common deleted region in all patients suggests ARHGEF7 as a candidate gene for mental retardation and microcephaly.

A major risk faced by bone-marrow and solid organ transplant patients is the development of post-transplant lymphoproliferative disease or post-transplant lymphoma (PTLD). In pediatric transplantation, PTLD onset is often associated with a rapid rise in Epstein-Barr virus (EBV) load in peripheral blood mononuclear cells (PBMC). We have analyzed EBV viral loads in PBMC over time using real-time quantitative PCR in 56 patients, 19 of which have been followed for more than 1 year. In nine patients; eight bone marrow (BMT) and one kidney transplant, PTLD was associated with a rapid rise in viral load, exceeding 1 x 10(5) EBV genomes/microg of PBMC-derived DNA. Four of these patients exceeded 1 x 10(6) EBV genomes/microg PBMC DNA. All patients with viral loads exceeding 1 x 10(5) EBV genomes/microg PBMC DNA were clearly at high risk for transplant-associated mortality, with only six of nine surviving. Importantly, only one of these deaths was directly attributable to EBV. A second elevated state of EBV load, defined as exceeding 2 x 10(4) EBV genomes/microg PBMC, was seen in a total of 12 BMT, kidney, heart, and liver transplant patients. These patients did not appear to be at immediate lethal risk for PTLD and one EBV-attributable death was found in this group as well. Thirty-four transplant patients whose EBV viral load oscillated from undetectable to 10 000 EBV genomes/microg PBMC DNA are reported as well. The threshold for normal EBV viral load based on our combined experience with viral load analysis is defined as 1 x 10(4) EBV genomes/microg PBMC DNA. The ability to rapidly analyze EBV load allows rapid changes in viral load, such as those that occur with PTLD onset, and the impact of anti-CD20 antibody therapy to be rapidly detected.

Purpose To identify the genetic basis of achromatopsia (ACHM) in four patients from four unrelated Polish families. Methods In this study, we investigated probands with a clinical diagnosis of ACHM. Ophthalmologic examinations, including visual acuity testing, color vision testing, and full-field electroretinography (ERG), were performed in all patients (with the exception of patient p4, who had no ERG). Direct DNA sequencing encompassing the entire coding region of the CNGB3 gene, eight exons of the GNAT2 gene, and exons 5–7 of the CNGA3 gene was performed. Segregation analysis for the presence and independent inheritance of two mutant alleles was performed in the three families available for study. Results All patients showed typical achromatopsia signs and symptoms. Sequencing helped detect causative changes in the CNGB3 gene in all probands. Eight different mutations were detected in the CNGB3 gene, including five novel mutations: two splice site mutations (c.1579–1G>A and c.494–2A>T), one nonsense substitution (c.1194T>G), and two frame-shift mutations (c.393_394delGCinsTCCTGGTGA and c.1366delC). We also found three mutations: one splice site (c.1578+1G>A) and two frame-shift deletions that had been previously described (c.819_826del and c.1148delC). All respective parents were shown to be heterozygous carriers for the mutation detected in their children. Conclusions The present study reports five novel mutations in the CNGB3 gene, and thus broadens the spectrum of probably pathogenic mutations associated with ACHM. Together with molecular data, we provide a brief clinical description of the affected individuals.

Vaginal birth after cesarean delivery has recently become a significant problem in obstetrics. The purpose of this paper was to present current expert knowledge about vaginal birth after cesarean delivery (VBAC), taking into account advantages and disadvantages mentioned in literature.

Cranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support an autosomal-recessive inheritance pattern. Aiming at the elucidation of the genetic basis of CED, we collected 13 patients with CED symptoms from 12 independent families. In one family with consanguineous parents two siblings were affected, permitting linkage analysis and homozygosity mapping. This revealed a single region of homozygosity with a significant LOD score (3.57) on chromosome 3q21-3q24. By sequencing candidate genes from this interval we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with the disease. Examination of IFT122 in our patient cohort revealed one additional homozygous missense change in the patient from a second consanguineous family. In addition, we found compound heterozygosity for a donor splice-site change and a missense change in one sporadic patient. All mutations were absent in 340 control chromosomes. Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls. Furthermore, we transiently knocked down ift122 in zebrafish embryos and observed the typical phenotype found in other models of ciliopathies. Because not all of our patients harbored mutations in IFT122, CED seems to be genetically heterogeneous. Still, by identifying CED as a ciliary disorder, our study suggests that the causative mutations in the unresolved cases most likely affect primary cilia function too.