X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4−/− mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases

A new experimental approach to develop unilocular cystic echinococcosis in rabbit livers

Cystic echinococcosis is a parasitic disease that is endemic in many parts of the world. Besides surgical and percutaneous interventional methods, new experimental therapeutic modalities with the use of antiparasitic drugs are still under investigation. The aim of this study is to present a new practical and time saving experimental model for treatment of cystic echinococcosis. Daughter cysts obtained from naturally infected cattle liver with cystic echinococcosis were implanted into the rabbit liver under sterile conditions. Cysts were evaluated with ultrasonography and computed tomography for six months. Volumes were significantly increased in seven survived cysts at the end of the sixth month (P < 0.05). The main advantage of this method over the known classical intraperitoneal protoscoleces injection methods is to be able to form a successful unilocular liver cyst. This method proved to be an applicable approach with a short cyst development time and high inoculation rate of cysts into the liver

Results of alcohol and albendazole injections in hepatic hydatidosis: Experimental study

Background: Percutaneous drainage with alcohol injection for hydatid cysts has been commonly used in the last two decades. Albendazole is the drug of choice in the medical treatment of hydatidosis, and has also been used as an intraoperative scolicidal solution. The side-effects of its local application are not well known and have not been investigated. The purpose of the present study was to investigate the effects of the intracystic injections of alcohol and albendazole solutions on the hydatid cysts and hepatobiliary system of rabbits

Epididymal Cysts in Childhood - Conservative or Surgical Approach?

The aim of the study. To decide on the accurate way of treatment and to establish criteria for operation in boys with pubertal epididymal cysts (ECs).Material and methods. Results of scrotal ultrasound of 363 boys and adolescents, aged 2 months to 18 years, were reviewed retrospectively.Results. Of all 363 patients with scrotal ultrasound 59 (16.2%) at mean age of 14.03 yrs had ECs. The EC incidence increased with age and 42 out of 124 boys (33.8%) older than 14 yrs had cysts (chi2=27.627, p=0.000). Out of 59 patients, in 30 (50.8%) cysts were diagnosed incidentally at the time of scrotal US, 29 boys (49.2%) presented with scrotal mass and/or pain. 31 patients with ECs (52.5%) underwent elective surgery and the remaining 28 boys (47.5%) received conservative treatment. The age of boys with ECs who underwent surgery ranged from 8 to 18 years (mean 14.32). The age range of patients treated conservatively was 7-18 (mean 13.71). There was no statistical difference in age between boys treated surgically and conservatively (t=0.924, p=0.36). ECs resolved in 17 patients out of 28 boys treated conservatively, in remaining 11 boys the size of cysts was stabile and they remain asymptomatic. Clinical and ultrasonographic follow-up were carried out from 11 months to 5 years.Conclusions. ECs are more common in older boys (over 14 years). Management of ECs smaller than 10 mm should be conservative with clinical and ultrasound controls, leaving surgery for cysts increasing in size over 10 mm which did not involute with time

The epidemiology and economic impact of varicella-related hospitalizations in Turkey from 2008 to 2010: A nationwide survey during the pre-vaccine era (VARICOMP study)

PubMed ID: 22170238Varicella can cause complications that are potentially serious and require hospitalization. Our current understanding of the causes and incidence of varicella-related hospitalization in Turkey is limited and sufficiently accurate epidemiological and economical information is lacking. The aim of this study was to estimate the annual incidence of varicella-related hospitalizations, describe the complications, and estimate the annual mortality and cost of varicella in children. VARICOMP is a multi-center study that was performed to provide epidemiological and economic data on hospitalization for varicella in children between 0 and 15 years of age from October 2008 to September 2010 in Turkey. According to medical records from 27 health care centers in 14 cities (representing 49.3% of the childhood population in Turkey), 824 children (73% previously healthy) were hospitalized for varicella over the 2-year period. Most cases occurred in the spring and early summer months. Most cases were in children under 5 years of age, and 29.5% were in children under 1 year of age. The estimated incidence of varicella-related hospitalization was 5.29-6.89 per 100,000 in all children between 0-15 years of age in Turkey, 21.7 to 28 per 100,000 children under 1 year of age, 9.8-13.8 per 100,000 children under 5 years of age, 3.96-6.52 per 100,000 children between 5 and 10 years of age and 0.42 to 0.71 per 100,000 children between 10 and 15 years of age. Among the 824 children, 212 (25.7%) were hospitalized because of primary varicella infection. The most common complications in children were secondary bacterial infection (23%), neurological (19.1%), and respiratory (17.5%) complications. Secondary bacterial infections (p<0.001) and neurological complications (p<0.001) were significantly more common in previously healthy children, whereas hematological complications (p<0.001) were more commonly observed in children with underlying conditions. The median length of the hospital stay was 6 days, and it was longer in children with underlying conditions (<0.001). The median cost of hospitalization per patient was $338 and was significantly higher in children with underlying conditions (p<0.001). The estimated direct annual cost (not including the loss of parental work time and school absence) of varicella-related hospitalization in children under the age of 15 years in Turkey was$856,190 to $1,407,006. According to our estimates, 882 to 1,450 children are hospitalized for varicella each year, reflecting a population-wide occurrence of 466-768 varicella cases per 100,000 children. In conclusion, this study confirms that varicella-related hospitalizations are not uncommon in children, and two thirds of these children are otherwise healthy. The annual cost of hospitalization for varicella reflects only a small part of the overall cost of this disease, as only a very few cases require hospital admission. The incidence of this disease was higher in children <1 year of age, and there are no prevention strategies for these children other than population-wide vaccination. Universal vaccination is therefore the only realistic option for the prevention of severe complications and deaths. The surveillance of varicellaassociated complications is essential for monitoring of the impact of varicella immunization. © Springer-Verlag 2011

De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation

Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X-inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics