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Alport syndrome is the commonest inherited kidney disease and nearly half the pathogenic variants in the COL4A3–COL4A5 genes that cause Alport syndrome result in Gly substitutions. This study examined the molecular characteristics of Gly substitutions that determine the severity of clinical features. Pathogenic COL4A5 variants affecting Gly in the Leiden Open Variation Database in males with X-linked Alport syndrome were correlated with age at kidney failure (n = 157) and hearing loss diagnosis (n = 80). Heterozygous pathogenic COL4A3 and COL4A4 variants affecting Gly (n = 304) in autosomal dominant Alport syndrome were correlated with the risk of haematuria in the UK 100,000 Genomes Project. Gly substitutions were stratified by exon location (1 to 20 or 21 to carboxyl terminus), being adjacent to a non-collagenous region (interruption or terminus), and the degree of instability caused by the replacement residue. Pathogenic COL4A5 variants that resulted in a Gly substitution with a highly destabilising residue reduced the median age at kidney failure by 7 years (p = 0.002), and age at hearing loss diagnosis by 21 years (p = 0.004). Substitutions adjacent to a non-collagenous region delayed kidney failure by 19 years (p = 0.014). Heterozygous pathogenic COL4A3 and COL4A4 variants that resulted in a Gly substitution with a highly destabilising residue (Arg, Val, Glu, Asp, Trp) were associated with an increased risk of haematuria (p = 0.018), and those adjacent to a non-collagenous region were associated with a reduced risk (p = 0.046). Exon location had no effect. In addition, COL4A5 variants adjacent to non-collagenous regions were over-represented in the normal population in gnomAD (p < 0.001). The nature of the substitution and of nearby residues determine the risk of haematuria, early onset kidney failure and hearing loss for Gly substitutions in X-linked and autosomal dominant Alport syndrome. [ABSTRACT FROM AUTHOR]

Purpose: No rapid diagnostic test exists to screen individuals for primary antibody deficiencies (PAD) at or near the point of care. In settings at risk for polio where live oral polio vaccine is utilized, undiagnosed PAD patients and cases with delayed diagnosis constitute a potential reservoir for neurovirulent polioviruses, undermining polio eradication. This research aimed to develop a rapid screening test suited for use in resource-limited settings to identify individuals with low immunoglobulin G (IgG) levels, enabling early diagnosis and appropriate treatment. Methods: Three prototype tests distinguishing low and normal IgG levels were evaluated with a blinded panel of serum/plasma specimens from 32 healthy controls and 86 primary immunodeficiency-confirmed patients with agammaglobulinemia, common variable immunodeficiency, and hyper-IgM syndrome, including 57 not receiving IgG therapy. Prototype tests were compared to laboratory reference and clinical case definition. Results: The leading prototype correctly identified 32 of 32 healthy controls. Among primary antibody deficiency patients not receiving IgG treatment, 17 of 19 agammaglobulinemia, 7 of 24 common variable immunodeficiency, and 5 of 14 hyper-IgM were correctly identified by the prototype, with 67% agreement with the reference assay. Conclusion: The Rapid IgG Screen (RIgGS) test can differentiate between low IgG levels associated with agammaglobulinemia and normal IgG antibody levels. Differentiating CVID and hyper IgM was challenging due to the wide range in IgG levels and influence of high IgM. This test can facilitate the identification of patients with primary antibody deficiencies and support polio surveillance initiatives. [ABSTRACT FROM AUTHOR]

Background: Soil-transmitted helminths (STHs) are parasitic nematodes that inhabit the human intestine. They affect more than 1.5 billion people worldwide, causing physical and cognitive impairment in children. The global strategy to control STH infection includes periodic mass drug administration (MDA) based on the results of diagnostic testing among populations at risk, but the current microscopy method for detecting infection has diminished sensitivity as the intensity of infection decreases. Thus, improved diagnostic tools are needed to support decision-making for STH control programs. Methodology: We developed a nucleic acid amplification test based on recombinase polymerase amplification (RPA) technology to detect STH in stool. We designed primers and probes for each of the four STH species, optimized the assay, and then verified its performance using clinical stool samples. Principal findings: Each RPA assay was as sensitive as a real-time polymerase chain reaction (PCR) assay in detecting copies of cloned target DNA sequences. The RPA assay amplified the target in DNA extracted from human stool samples that were positive for STH based on the Kato-Katz method, with no cross-reactivity of the non-target genomic DNA. When tested with clinical stool samples from patients with infections of light, moderate, and heavy intensity, the RPA assays demonstrated performance comparable to that of real-time PCR, with better results than Kato-Katz. This new rapid, sensitive and field-deployable method for detecting STH infections can help STH control programs achieve their goals. Conclusions: Semi-quantitation of target by RPA assay is possible and is comparable to real-time PCR. With proper instrumentation, RPA assays can provide robust, semi-quantification of STH DNA targets as an alternative field-deployable indicator to counts of helminth eggs for assessing infection intensity. Author summary: More than 1.5 billion people are infected with parasitic intestinal worms called soil-transmitted helminths. Infection is transmitted by helminth eggs in human feces, which contaminate soil in areas with poor sanitation. Adverse health effects include physical and cognitive impairment in children. A key strategy to control infection is periodic mass drug administration for populations with a high prevalence of disease based on the results of diagnostic testing. The current microscopy method for detecting infection, however, has limited ability to detect disease as the intensity of infection decreases with repeated mass drug administration. To address limitations of current diagnostic methods, we developed a novel technique to diagnose infections, including those at very low levels of intensity, by detecting helminth DNA in stool samples. Our initial studies suggest that the new diagnostic technique reliably detects the presence of intestinal worms, even at low intensities of infection, and may be more useful than currently available diagnostic tools for guiding the use of periodic mass drug administration to eliminate disease in low-resource settings. [ABSTRACT FROM AUTHOR]

Recent expert guidelines recommend genetic testing for the diagnosis of Alport syndrome. Here, we describe current best practice and likely future developments. In individuals with suspected Alport syndrome, all three COL4A5, COL4A3 and COL4A4 genes should be examined for pathogenic variants, probably by high throughput-targeted next generation sequencing (NGS) technologies, with a customised panel for simultaneous testing of the three Alport genes. These techniques identify up to 95% of pathogenic COL4A variants. Where causative pathogenic variants cannot be demonstrated, the DNA should be examined for deletions or insertions by re-examining the NGS sequencing data or with multiplex ligation-dependent probe amplification (MLPA). These techniques identify a further 5% of variants, and the remaining few changes include deep intronic splicing variants or cases of somatic mosaicism. Where no pathogenic variants are found, the basis for the clinical diagnosis should be reviewed. Genes in which mutations produce similar clinical features to Alport syndrome (resulting in focal and segmental glomerulosclerosis, complement pathway disorders, MYH9-related disorders, etc.) should be examined. NGS approaches have identified novel combinations of pathogenic variants in Alport syndrome. Two variants, with one in COL4A3 and another in COL4A4, produce a more severe phenotype than an uncomplicated heterozygous change. NGS may also identify further coincidental pathogenic variants in genes for podocyte-expressed proteins that also modify the phenotype. Our understanding of the genetics of Alport syndrome is evolving rapidly, and both genetic and non-genetic factors are likely to contribute to the observed phenotypic variability. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminths (STHs) affect more than 1.5 billion people. The global strategy to control STH infections requires periodic mass drug administration (MDA) based on prevalence among populations at risk determined by diagnostic testing. Widely used copromicroscopy methods to detect infection, however, have low sensitivity as the prevalence and intensity of STH infections decline with repeated MDA. More sensitive diagnostic tools are needed to inform program decision-making. Using an integrated product development process, PATH conducted qualitative and quantitative formative research to inform the design and development of a more sensitive test for STH infections. The research, grounded in a conceptual framework for ensuring access to health products, involved stakeholder analysis, key opinion leader interviews, observational site visits of ongoing STH surveillance programs, and market research including market sizing, costing and willingness-to-pay analyses. Stakeholder analysis identified key groups and proposed strategic engagement of stakeholders during product development. Interviews highlighted features, motivations and concerns that are important for guiding design and implementation of new STH diagnostics. Process mapping outlined current STH surveillance workflows in Kenya and the Philippines. Market sizing in 2016 was estimated around half a million tests for lower STH burden countries, and 1–2 million tests for higher STH burden countries. The cost of commodities per patient for a molecular STH diagnostic may be around $10, 3–4 times higher than copromicroscopy methods, though savings may be possible in time and staffing requirements. The market is highly price sensitive as even at $5 per test, only 27% of respondents thought the test would be used by surveillance programs. A largely subsidized STH control strategy and a semi-functional Kato-Katz test may have created few incentives for manufacturers to innovate in STH diagnostics. Diverse partnerships, as well as balancing needs and expectations for new STH diagnostics are necessary to ensure access to needed products. [ABSTRACT FROM AUTHOR]

Background: Mapping of lymphatic filariasis (LF) caused by Wuchereria bancrofti largely relies on the detection of circulating antigen using ICT cards. Several studies have recently shown that this test can be cross-reactive with sera of subjects heavily infected with Loa loa and thus mapping results in loiasis endemic areas may be inaccurate. Methodology/Principal findings: In order to develop an LF mapping strategy for areas with high loiasis prevalence, we collected day blood samples from 5,001 subjects residing in 50 villages that make up 6 health districts throughout Cameroon. Antigen testing using Filarial Test Strip (FTS, a novel platform that uses the same reagents as ICT) revealed an overall positivity rate of 1.1% and L. loa microfilaria (Mf) rates of up to 46%. Among the subjects with 0 to 8,000 Mf/ml in day blood, only 0.4% were FTS positive, while 29% of subjects with >8,000 Mf/ml were FTS positive. A Mf density of >8,200 Mf/ml was determined as the cut point at which positive FTS results should be excluded from the analysis. No FTS positive samples were also positive for W. bancrofti antibodies as measured by two different point of care tests that use the Wb123 antigen not found in L. loa. Night blood examination of the FTS positive subjects showed a high prevalence of L. loa Mf with densities up to 12,710 Mf/ml. No W. bancrofti Mf were identified, as confirmed by qPCR. Our results show that high loads of L. loa Mf in day blood are a reliable indicator of FTS positivity, and Wb123 rapid test proved to be relatively specific. Conclusions/Significance: Our study provides a simple day blood-based algorithm for LF mapping in loiasis areas. The results indicate that many districts that were formerly classified as endemic for LF in Cameroon are non-endemic and do not require mass drug administration for elimination of LF. [ABSTRACT FROM AUTHOR]

Aims/Purpose: Alport syndrome can have ocular features, including anterior lenticonus, which affects vision and quality of life. We explored visual acuities and vision‐related quality of life, as quantified using the National Eye Institute 25 item Visual Functioning Questionnaire (VFQ‐25), in a cohort of patients before and after lens exchange surgery. Methods: Patients with genetically confirmed Alport syndrome were recruited for an ocular phenotyping study, and completed the NEI‐VFQ25 (a validated visual function questionnaire, yielding a total score out of 100). Patients with lenticonus were offered lens exchange surgery. Best recorded visual acuities before and after surgery were collated, and converted to logMAR for analysis. Changes in quality of life were ascertained by comparing scores obtained before, and some time after, surgery. Results: Five patients (10 eyes) underwent lens exchange surgery for lenticonus. All were male; mean (SD) age at first eye surgery was 43 (8.5) years. For right eyes, mean (SD) pre‐ and post‐operative logMAR visual acuities were 0.31 (0.28) and 0.05 (0.10), respectively. For left eyes, these were 0.23 (0.11) and 0.02 (0.10), respectively. Median pre‐op acuities were 0.30 and 0.18 for right and left eyes, respectively; median post‐operative acuities were 0.03 and 0.00, respectively. Median improvements were 0.2 and 0.18 for right and left eyes, respectively. Taking all eyes together, the improvement seen following surgery was significant (p = 0.001). Four of the five patients completed the VFQ25 before and after surgery. Initial and final mean (SD) scores were 68.5 (13.7) and 94.1 (4.9), respectively, with a significant difference seen (p < 0.05). Conclusions: Objective improvement in best‐recorded visual acuity was seen in this cohort of patients. Anterior lenticonus was shown to have an adverse effect of vision‐specific quality of life, with improvement demonstrated following lens exchange surgery. [ABSTRACT FROM AUTHOR]

With moves towards improving sustainability within the retail sector and a growing requirement to conform to existing and emerging legislation, retailers from ostensibly disparate sectors face the common challenge of encouraging the reduced consumption of saleable products, while simultaneously maintaining their prosperity. Project transfer was initiated to investigate how efforts to promote sustainable consumption within retail is received and responded to by consumers. Consumers and partners in the retail sector were engaged with throughout the research which culminated in three consumer facing outputs; a workshop ('Put a Better Foot Forward', The Moor retail destination, Sheffield, UK), installation ('Making in Real', pop- up T- Shirt factory, Trinity Shopping Centre, Leeds, UK) and animated short film (Nothing to Wear? available via YouTube and launched at the Sheffield Shorts film screening, Sheffield, UK). Each of the outputs were designed to allow consumers to reflect on their shopping and consumption habits in an engaging, stimulating environment. The key aim was to promote mindfulness and engage consumers in discussion and debate. All the output events were free for the general public to attend/participate in. This paper will discuss the role of engaging the consumer in sustainable fashion research and the impact of consumer facing outputs in education and awareness of sustainable issues in shopping and consumption. [ABSTRACT FROM AUTHOR]

As effective onchocerciasis control efforts in Africa transition to elimination efforts, different diagnostic tools are required to support country programs. Senegal, with its long standing, successful control program, is transitioning to using the SD BIOLINE Onchocerciasis IgG4 (Ov16) rapid test over traditional skin snip microscopy. The aim of this study is to demonstrate the feasibility of integrating the Ov16 rapid test into onchocerciasis surveillance activities in Senegal, based on the following attributes of acceptability, usability, and cost. A cross-sectional study was conducted in 13 villages in southeastern Senegal in May 2016. Individuals 5 years and older were invited to participate in a demographic questionnaire, an Ov16 rapid test, a skin snip biopsy, and an acceptability interview. Rapid test technicians were interviewed and a costing analysis was conducted. Of 1,173 participants, 1,169 (99.7%) agreed to the rapid test while 383 (32.7%) agreed to skin snip microscopy. The sero-positivity rate of the rapid test among those tested was 2.6% with zero positives 10 years and younger. None of the 383 skin snips were positive for Ov microfilaria. Community members appreciated that the rapid test was performed quickly, was not painful, and provided reliable results. The total costs for this surveillance activity was $22,272.83, with a cost per test conducted at $3.14 for rapid test, $7.58 for skin snip microscopy, and $13.43 for shared costs. If no participants had refused skin snip microscopy, the total cost per method with shared costs would have been around $16 per person tested. In this area with low onchocerciasis sero-positivity, there was high acceptability and perceived value of the rapid test by community members and technicians. This study provides evidence of the feasibility of implementing the Ov16 rapid test in Senegal and may be informative to other country programs transitioning to Ov16 serologic tools. [ABSTRACT FROM AUTHOR]

Global efforts to address schistosomiasis and soil-transmitted helminthiases (STH) include deworming programs for school-aged children that are made possible by large-scale drug donations. Decisions on these mass drug administration (MDA) programs currently rely on microscopic examination of clinical specimens to determine the presence of parasite eggs. However, microscopy-based methods are not sensitive to the low-intensity infections that characterize populations that have undergone MDA. Thus, there has been increasing recognition within the schistosomiasis and STH communities of the need for improved diagnostic tools to support late-stage control program decisions, such as when to stop or reduce MDA. Failure to adequately address the need for new diagnostics could jeopardize achievement of the 2020 London Declaration goals. In this report, we assess diagnostic needs and landscape potential solutions and determine appropriate strategies to improve diagnostic testing to support control and elimination programs. Based upon literature reviews and previous input from experts in the schistosomiasis and STH communities, we prioritized two diagnostic use cases for further exploration: to inform MDA-stopping decisions and post-MDA surveillance. To this end, PATH has refined target product profiles (TPPs) for schistosomiasis and STH diagnostics that are applicable to these use cases. We evaluated the limitations of current diagnostic methods with regards to these use cases and identified candidate biomarkers and diagnostics with potential application as new tools. Based on this analysis, there is a need to develop antigen-detecting rapid diagnostic tests (RDTs) with simplified, field-deployable sample preparation for schistosomiasis. Additionally, there is a need for diagnostic tests that are more sensitive than the current methods for STH, which may include either a field-deployable molecular test or a simple, low-cost, rapid antigen-detecting test. [ABSTRACT FROM AUTHOR]

Alport syndrome results from mutations in the COL4A5 (X-linked) or COL4A3/COL4A4 (recessive) genes. This study examined 754 previously- unpublished variants in these genes from individuals referred for genetic testing in 12 accredited diagnostic laboratories worldwide, in addition to all published COL4A5, COL4A3 and COL4A4 variants in the LOVD databases. It also determined genotype-phenotype correlations for variants where clinical data were available. Individuals were referred for genetic testing where Alport syndrome was suspected clinically or on biopsy (renal failure, hearing loss, retinopathy, lamellated glomerular basement membrane), variant pathogenicity was assessed using currently-accepted criteria, and variants were examined for gene location, and age at renal failure onset. Results were compared using Fisher’s exact test (DNA Stata). Altogether 754 new DNA variants were identified, an increase of 25%, predominantly in people of European background. Of the 1168 COL4A5 variants, 504 (43%) were missense mutations, 273 (23%) splicing variants, 73 (6%) nonsense mutations, 169 (14%) short deletions and 76 (7%) complex or large deletions. Only 135 of the 432 Gly residues in the collagenous sequence were substituted (31%), which means that fewer than 10% of all possible variants have been identified. Both missense and nonsense mutations in COL4A5 were not randomly distributed but more common at the 70 CpG sequences (p<10−41 and p<0.001 respectively). Gly>Ala substitutions were underrepresented in all three genes (p< 0.0001) probably because of an association with a milder phenotype. The average age at end-stage renal failure was the same for all mutations in COL4A5 (24.4 ±7.8 years), COL4A3 (23.3 ± 9.3) and COL4A4 (25.4 ± 10.3) (COL4A5 and COL4A3, p = 0.45; COL4A5 and COL4A4, p = 0.55; COL4A3 and COL4A4, p = 0.41). For COL4A5, renal failure occurred sooner with non-missense than missense variants (p<0.01). For the COL4A3 and COL4A4 genes, age at renal failure occurred sooner with two non-missense variants (p = 0.08, and p = 0.01 respectively). Thus DNA variant characteristics that predict age at renal failure appeared to be the same for all three Alport genes. Founder mutations (with the pathogenic variant in at least 5 apparently- unrelated individuals) were not necessarily associated with a milder phenotype. This study illustrates the benefits when routine diagnostic laboratories share and analyse their data. [ABSTRACT FROM AUTHOR]

Novel typhoid diagnostics currently under development have the potential to improve clinical care, surveillance, and the disease burden estimates that support vaccine introduction. Blood culture is most often used as the reference method to evaluate the accuracy of new typhoid tests; however, it is recognized to be an imperfect gold standard. If no single gold standard test exists, use of a composite reference standard (CRS) can improve estimation of diagnostic accuracy. Numerous studies have used a CRS to evaluate new typhoid diagnostics; however, there is no consensus on an appropriate CRS. In order to evaluate existing tests for use as a reference test or inclusion in a CRS, we performed a systematic review of the typhoid literature to include all index/reference test combinations observed. We described the landscape of comparisons performed, showed results of a meta-analysis on the accuracy of the more common combinations, and evaluated sources of variability based on study quality. This wide-ranging meta-analysis suggests that no single test has sufficiently good performance but some existing diagnostics may be useful as part of a CRS. Additionally, based on findings from the meta-analysis and a constructed numerical example demonstrating the use of CRS, we proposed necessary criteria and potential components of a typhoid CRS to guide future recommendations. Agreement and adoption by all investigators of a standardized CRS is requisite, and would improve comparison of new diagnostics across independent studies, leading to the identification of a better reference test and improved confidence in prevalence estimates. [ABSTRACT FROM AUTHOR]

Background: Mutations in podocyte and basement membrane genes are associated with a growing spectrum of glomerular disease affecting adults and children. Investigation of familial cases has helped to build understanding of both normal physiology and disease. Methods: We investigated a consanguineous family with a wide clinical phenotype of glomerular disease using clinical, histological, and new genetic studies. Results: We report striking variability in severity of nephropathy within an X-linked Alport syndrome (XLAS) family. Four siblings each carried a mutant COL4A5 allele, p.(Gly953Val) and p.(Gly1033Arg). Two boys had signs limited to hematuria and mild/moderate proteinuria. In striking contrast, a sister presented with end-stage renal disease (ESRD) at 8 years of age and an infant brother presented with nephrotic syndrome, progressing to ESRD by 3 years of age. Both were subsequently found to have homozygous variants in MYO1E, p.(Lys118Glu) and p.(Thr876Arg). MYO1E is a gene implicated in focal segmental glomerulosclerosis and it encodes a podocyte-expressed non-muscle myosin. Bioinformatic modeling demonstrated that the collagen IV-alpha3,4,5 extracellular network connected via known protein-protein interactions to intracellular myosin 1E. Conclusions: COL4A5 and MYO1E mutations may summate to perturb common signaling pathways, resulting in more severe disease than anticipated independently. We suggest screening for MYO1E and other non- COL4 'podocyte gene' mutations in XLAS when clinical nephropathy is more severe than expected for an individual's age and sex. [ABSTRACT FROM AUTHOR]

Background Alport syndrome is a clinically heterogeneous, progressive nephropathy caused by mutations in collagen IV genes, namely COL4A3 and COL4A4 on chromosome 2 and COL4A5 on chromosome X. The wide phenotypic variability and the presence of incomplete penetrance suggest that a simple Mendelian model cannot completely explain the genetic control of this disease. Therefore, we explored the possibility that Alport syndrome is under digenic control. Methods Using massively parallel sequencing, we identified 11 patients who had pathogenic mutations in two collagen IV genes. For each proband, we ascertained the presence of the same mutations in up to 12 members of the extended family for a total of 56 persons studied. Results Overall, 23 mutations were found. Individuals with two pathogenic mutations in different genes had a mean age of renal function deterioration intermediate with respect to the autosomal-dominant form and the autosomal-recessive one, in line with molecule stoichiometry of the disruption of the type IV collagen triple helix. Conclusions Segregation analysis indicated three possible digenic segregation models: (i) autosomal inheritance with mutations on different chromosomes, resembling recessive inheritance (five families); (ii) autosomal inheritance with mutations on the same chromosome resembling dominant inheritance (two families) and (iii) unlinked autosomal and X-linked inheritance having a peculiar segregation (four families). This pedigree analysis provides evidence for digenic inheritance of Alport syndrome. Clinical geneticists and nephrologists should be aware of this possibility in order to more accurately assess inheritance probabilities, predict prognosis and identify other family members at risk. [ABSTRACT FROM AUTHOR]

X-linked Alport syndrome is a form of progressive renal failure caused by pathogenic variants in the COL4A5 gene. More than 700 variants have been described and a further 400 are estimated to be known to individual laboratories but are unpublished. The major genetic testing laboratories for X-linked Alport syndrome worldwide have established a Web-based database for published and unpublished COL4A5 variants (). This conforms with the recommendations of the Human Variome Project: it uses the Leiden Open Variation Database (LOVD) format, describes variants according to the human reference sequence with standardized nomenclature, indicates likely pathogenicity and associated clinical features, and credits the submitting laboratory. The database includes non-pathogenic and recurrent variants, and is linked to another COL4A5 mutation database and relevant bioinformatics sites. Access is free. Increasing the number of COL4A5 variants in the public domain helps patients, diagnostic laboratories, clinicians, and researchers. The database improves the accuracy and efficiency of genetic testing because its variants are already categorized for pathogenicity. The description of further COL4A5 variants and clinical associations will improve our ability to predict phenotype and our understanding of collagen IV biochemistry. The database for X-linked Alport syndrome represents a model for databases in other inherited renal diseases. [ABSTRACT FROM AUTHOR]

Background: This study determined the family history and clinical features that suggested autosomal recessive rather than X-linked Alport syndrome. Methods: All patients had the diagnosis of Alport syndrome and the mode of inheritance confirmed by genetic testing, and underwent examination at a single centre. Results: Patients comprised 9 males and 6 females with autosomal recessive Alport syndrome, and 18 males and 22 females with X-linked disease. Fourteen (93 %) individuals with autosomal recessive Alport syndrome developed early end-stage renal failure, all 15 had hearing loss, and most had lenticonus (12, 80 %), and a central (13, 87 %) or peripheral (13, 87 %) retinopathy. These features occurred as often as in males with X-linked disease. Females with autosomal recessive inheritance were less likely to have an affected family member in another generation ( p = 0.01) than females with X-linked disease. They were more likely to have renal failure ( p = 0.003), hearing loss ( p = 0.02) and lenticonus ( p < 0.001). Fifty percent had a central retinopathy compared with 18 % with X-linked disease ( p = 0.14), but peripheral retinopathy prevalence was not different ( p = 0.64). Nonsense mutations accounted for 67 % (8/12) of these disease-causing mutations. Conclusions: Autosomal recessive inheritance is increased in females with Alport syndrome and early onset renal failure, hearing loss, lenticonus, and, possibly, central retinopathy. [ABSTRACT FROM AUTHOR]

Background: Female subjects with X-linked Alport syndrome have a single COL4A5 mutation, germ cell mosaicism in affected tissues and typically develop renal failure later or less often than male subjects. Women with two mutations are exceedingly rare, and usually have consanguineous parents or uniparental disomy. We describe here a 20-year-old woman who inherited two different COL4A5 variants, one from her father (c.2677G>C) and one from her mother (c.384 +1 G>A). Case-diagnosis/treatment: The index case had normal renal function, proteinuria and no clinically detectable hearing loss, or ocular abnormalities. Her father and paternal uncle developed end-stage renal disease at 37 and 28 years respectively, together with hearing loss, but not lenticonus or central retinopathy. Her mother had mildly impaired renal function, proteinuria, hearing loss, but no ocular abnormalities. Her maternal grandfather and 22-year-old brother, both with this mutation, developed renal failure by 28 years with hearing loss, or had proteinuria and hearing loss respectively. Conclusion: The index case has clinical features consistent with germ cell mosaicism of two COL45A mutations associated with adult-onset renal failure, but no ocular abnormalities. Her risk of renal failure is high, but the rate of progression to end-stage disease depends on the underlying mutations, and disease modification with renin-angiotensin blockade. [ABSTRACT FROM AUTHOR]

Objective: To describe the clinical and molecular genetic findings in 2 carriers of Duchenne muscular dystrophy (DMD) who exhibited marked hemiatrophy. Duchenne muscular dystrophy is an X-linked disorder in which affected male patients harbor mutations in the dystrophin gene. Female patients with heterozygous mutations may be manifesting carriers. Design: Case study. Setting: Neurology clinic. Patients: Two manifesting carriers of DMD. Interventions: Clinical and radiologic examinations along with histologic and molecular investigations. Results: Both patients had marked right-sided hemiatrophy on examination with radiologic evidence of muscle atrophy and fatty replacement on the affected side. In each case, histologic analysis revealed a reduction in dystrophin staining on the right side. Genetic analysis of the dystrophin gene revealed a tandem exonic duplication in patient 1 and a multiexonic deletion in patient 2 with no further point mutations identified on the other chromosome. Conclusions: Marked hemiatrophy can occur in DMD manifesting carriers. This is likely to result from a combination of skewed X-inactivation and somatic mosaicism. [ABSTRACT FROM AUTHOR]

The article offers updates on the clinical genetics for Alport syndrome in 2014. It explores the disease characteristics, mutational spectrum, and prevalence of the genetic reference sequence. It explains the analytical validation of the genes or DNA and chromosome segments to determine the etiology and causative variants from expressed protein and DNA sequence to confirm diagnosis.

The article offers test method for Alport's syndrome. It has been stated that mutation analysis is used for clinical diagnosis and in relation to genetic counselling of the disease. The article discusses mutational spectrum, analytical validation, prevalence of the disease in particular ethnic group and clinical predictive value of Alport's syndrome.