Search

Abstract Background Myotonic dystrophy type 1 (DM1) is the most common muscle dystrophy in adults. The disease is caused by a triplet expansion in the 3'end of the myotonic dystrophy protein kinase (DMPK) gene. In order to develop a human cell model for investigation of possible effects of antisense and RNAi effector molecules we have used lentiviral mediated myoD-forced myogenesis of DM1 patient fibroblasts. Findings Transduced fibroblasts show a multinuclear phenotype and express the differentiation marker myogenin. Furthermore, fluorescence in situ hybridization (FISH) analysis revealed a statistical significant increase in the amount of nuclear foci in DM1 patient fibroblasts after myogenesis. Finally, no nuclear foci were found after treatment with oligonucleotides targeting the repeat expansions. Conclusions The abundance of nuclear foci in DM1 patient fibroblasts increase following myogenesis, as visualized by FISH analysis. Foci were eradicated after treatment with antisense oligonucleotides. Thus, we propose that the current cell model is suitable for testing of novel treatment modalities.

Introduction: Previous studies indicate a familial predisposition for developmental dysplasia of the hip (DDH), especially among first-degree relatives. This study investigated the association between unilateral or bilateral periacetabular osteotomy (PAO), family history of DDH and the degree of relationship with relatives with DDH. Material and methods: This cross-sectional study consisted of 815 consecutive patients undergoing PAO from 1998 to 2016. Information regarding unilateral or bilateral PAO, gender and age at the time of surgery was obtained from the clinical PAO database at Aarhus University Hospital, Denmark. A questionnaire was used to collect information about the family history of DDH. The association was assessed by logistic regression analysis, and divided into 615 unilateral and 200 bilateral PAO patients. Results: PAO patients with a first-degree relative with DDH had a 72% (odds ratio [OR] = 1.72, 95% confidence interval [CI] 1.17; 2.50) higher occurrence of bilateral PAO than patients without family relatives with DDH. This association was statistically significant (p = 0.005), even when adjusting for gender and age at the time of surgery. A similar association was not demonstrated among any other degrees of relationship. Conclusion: Danish patients with DDH and a first-degree relative with DDH have an increased risk of being surgically treated with bilateral PAO compared to patients without a family history of DDH. Patients undergoing bilateral PAO may therefore have a strong genetic predisposition for DDH. This study reveals a potential group of patients with DDH where genetic analysis may identify relatives with a higher risk of the disease. [ABSTRACT FROM AUTHOR]

The development of hip dysplasia is associated with several risk factors. 1 of these risk factors is gender, since 80% of patients with symptomatic hip dysplasia are females. Another risk factor for hip dysplasia is familial predisposition of hip dysplasia. Several studies indicate that the risk of hip dysplasia is increased with familial prevalence of hip dysplasia. However, little is known about the association between the familial prevalence and gender and the development of hip dysplasia.~Background~Background~The aim of the study was to estimate the prevalence of hip dysplasia among relatives to Danish patients with hip dysplasia operated with periacetabular osteotomy (PAO), and the degree of relationship of affected family members. Furthermore, to assess the association between gender and family predisposition in the same group of patients.~Purpose~Objective~The study is a cross-sectional study, with a descriptive and an analytical part. The study population consists of 676 patients drawn from a clinical database of patients operated with PAO at Aarhus University hospital from 1998 to 2014. Information about gender, operated hip side and age was collected from the clinical PAO database, while information about familial prevalence was collected through questionnaires. The association between gender and familial prevalence of hip dysplasia was presented as the prevalence proportions ratio (PPR), tested by ¿2 test. Stratification was conducted for the variables age and operated hip side, with the Mantel-Haenszels analytical method, and tested for statistical significance by ¿2.~Method~Methods~The familial prevalence of hip dysplasia in the study population was 30% (95% CI, 27%-34%), with 73% reporting affected first-degree relatives. Females have 32% increased risk of familial prevalence of hip dysplasia compared to males, but this difference in risk was not statistically significant (p = 0.10).~Results~Results~The study shows that females have 32% increased familial prevalence of hip dysplasia compared to males, but the increased prevalence was not statistically significant probably due to the low power of the study.~Conclusions~Conclusions [ABSTRACT FROM AUTHOR]

A previously unknown α0deletion, designated – –DANE, was found in three generations of a Danish family of Palestinian origin. Six patients were heterozygous and three patients had deletional Hb H (β4) disease with a compound heterozygosity for the common −α3.7(rightward) deletion. Multiplex ligation-dependent probe amplification (MLPA) supplemented by repeated polymerase chain reaction (PCR) amplification identified the 5′ and 3′ breakpoints in the α-globin gene cluster. This novel 31.2 kb deletion (NG_000006.1: g.8800_40007del31208) leads to the removal of theHBZ, HBA2andHBA1genes. [ABSTRACT FROM AUTHOR]

We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p = 6.81×10−6) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk. [ABSTRACT FROM AUTHOR]