Group Of Single-gene Disorders Research Articles

Gene-environment interactions in primary atopic disorders.

Environmental factors modify disease presentation and severity in allergic disorders. Primary atopic disorders (PADs) are a heterogenous group of single gene disorders that lead to significant atopic and allergic disease manifestations. However, a number of these monogenic diseases have variable penetrance suggesting that gene-gene and/or gene-environment interactions could modulate the clinical phenotype. Environmental factors such as diet, the microbiome at the epithelial-environment interface, the presence and/or extent of infection, and psychologic stress can alter disease phenotypic expression of allergic diseases, and PADs provide discrete contexts in which to understand these influences. We outline how gene-environment interactions likely contribute to a variable penetrance and expressivity in PADs. Dietary modifications of both macronutrients and/or micronutrients alter T-cell metabolism and may influence effector T-cell function. The mucosal microbiome may affect local inflammation and may remotely influence regulatory elements, while psychologic stress can affect mast cell and other allergic effector cell function. Understanding gene-environment interactions in PADs can hopefully provide a foundation for interrogating gene-environment interactions to common allergic disorders, and also present opportunities for personalized interventions based on the altered pathways and environmental influences in affected individuals.

Effectiveness of Awareness Programme on Knowledge of Thalassemia among Adolescent Students and their Motivation to Screen the Status as Thalassemic Carrier in a Selected School, Howrah, West Bengal

Thalassemia, the burden of inherited disorders of hemoglobin, the commonest group of single gene disorders in India is huge. A recent survey by Indian Council of Medical Research (ICMR) 10 reveals 9 of every 100 people in Kolkata are affected by thalassemia, a figure alarmingly high as compared to other major metros. According to ICMR, lack of awareness is the main reason for the high figure in Kolkata. Only education can reduce this barrier. So, this research was conducted to evaluate the effectiveness the awareness programme on knowledge and their motivation to screen the status regarding thalassemia among adolescent students. A pre-experimental study was conducted and the design used one group pre-test post-test. Non probability convenient sampling technique was used to select class IX & X students. Two hundred students were selected by total enumeration technique. A valid and reliable structured knowledge questionnaire and HPLC Test was used to collect data. The findings of the study revealed that majority of the subjects are within 14–15 years, 55% were male and rest 45% were female. 71% students were unknown to the term Thalassemia. Only 1% (2) had affected family member & relatives. There is a significant difference between mean pre-test and post-test knowledge score [t=47 “t” df(199)= 1.97; p<0.05]. The majority of the students (95%) agreed for thalassemia screening. Report of thalassemia screening showed 11% were thalassemia carrier. There was deficiency in knowledge regarding thalassemia among adolescent students. The awareness programme was effective in improving knowledge of adolescent students regarding thalssemia and to motivate them for screening.

Validating a rapid, real-time, PCR-based direct mutation detection assay for preimplantation genetic diagnosis.

Although co-amplification of polymorphic microsatellite markers is the current gold standard for preimplantation genetic diagnosis (PGD) of single-gene disorders (SGD), this approach can be hampered by the lack of availability of informative markers. We recently (2011) devised a novel in-house assay for PGD of aromatic L-amino acid decarboxylase deficiency, based on an amplification refractory mutation system and quantitative PCR (ARMS-qPCR). The objective of the present study was to verify ARMS-qPCR in a cohort of 20 PGD cycles with a diverse group of SGDs (15 couples at risk for 10 SGDs). Day-3 cleavage-stage embryos were subjected to biopsy and genotyping, followed by fresh embryo transfer (FET). The diagnostic rate was 82.9%; unaffected live births were achieved in 9 of 20 FET cycles (45%), with only one false negative (among 54 transferred embryos). Overall, the ARMS-qPCR had frequent allele-dropout (ADO), rendering it inappropriate as the sole diagnostic method (despite a favorable live-birth rate). Regardless, it has the potential to complement the current gold-standard methodology, especially when trophectoderm biopsy becomes a preferred option and genotyping needs to be timely enough to enable FET.

Thalassemias: can we reduce the national burden?

The burden of inherited disorders of hemoglobin, the commonest group of single gene disorders in India is huge. With a population of 1.21 billion and an average prevalence of β-thalassemia carriers being around 3.5-4%, there would be 35-45 million carriers and the estimated number of births of affected babies annually would be 10,000-12,000. The carrier rates vary from 1-17% in different ethnic groups. Apart from β-thalassemia, Hb E is common in the north eastern region and in West Bengal (4 to > 50%) and Hb S is prevalent in parts of central, western and eastern India (5-40%). Thus interaction of the β-thalassemias with these Hb variants is not uncommon and can lead to a severe disorder. One way to combat the burden is by prenatal diagnosis but the only approach to reduce the national burden is by a comprehensive community control programme. Awareness is very limited in different states (<20% among pregnant women) and the entire public health infrastructure from medical colleges to district hospitals and down to the community health centres must be mobilized for education and generating awareness on these disorders. Experience shows that screening for carriers in India will have to be done at multiple levels – schools, colleges, antenatal clinics as well as cascade screening where extended family members of an affected child are screened. However, antenatal screening with subsequent testing of the husbands of carrier women would be the most cost effective way to identify couples at-risk and give them the option of prenatal diagnosis. For this, obstetricians must recognize the implications of hypochronic and microcytic red cell indices (MCV <80 fl, MCH < 27 pg and a high RBC count) and ask for a β-thalassemia screen by estimation of HbA2 levels. Several laboratories in the country use automated HPLC for reliable HbA2 estimation and identification of heterozygotes is not a problem. Late registration at antenatal clinics (only 15-20% in the first trimester in public hospitals) is an impediment resulting in many couples at-risk being identified late and requiring second trimester fetal diagnosis. Social stigmatization is an issue to be dealt with during premarital screening of marriage partners of carrier individuals. Only education can reduce this barrier. Many State Governments in India are now undertaking population screening and counselling programmes and Gujarat and West Bengal have taken the lead. There are 10-12 centres offering prenatal diagnosis by CVS and DNA analysis and recently the Indian Council of Medical Research has established 6 more centres in different regions. However, many more centres would be required once there is an increasing demand. The spectrum of mutations and their distribution are now known which would facilitate prenatal diagnosis. Thus, there are many challenges – a large and diverse population, limited awareness, late registration in antenatal clinics and inequality of available services (urban v/s rural areas) with around 70% of the population residing in rural areas. There is a need for the Central and State Governments to join hands and involve NGO groups to form networks in different regions which when backed by political will could gradually reduce the national burden of hemoglobinopathies in this vast country.

Monogenic Models: What Have the Single Gene Disorders Taught Us?

Monogenic diabetes constitutes a heterogeneous group of single gene disorders. The molecular background and clinical picture of many of these diseases have been described. While each of these forms is much less prevalent than multifactorial type 1 and type 2 diabetes mellitus (T2DM), together they affect millions of patients worldwide. Genetic diagnosis, which has become widely available, is of great clinical importance for patients with single gene diabetes. It helps to fully understand the pathophysiology of the disease, tailor the optimal hypoglycemic treatment, and define the prognosis for the entire family. Monogenic diabetes forms can be divided into 2 large groups, resulting from impaired insulin secretion or from an abnormal response to insulin. There are several lessons we have been taught by single-gene diabetes. We learned that the gene responsible for the occurrence of diabetes can be identified if an appropriate search strategy is used. In addition, discoveries of genes responsible for monogenic disorders pointed to them as susceptibility candidates for T2DM. Moreover, establishing that some families of proteins or biological pathways, such as transcription factors or potassium channel subunits, are involved in monogenic diabetes sparked research on their involvement in multifactorial diabetes. Finally, the example of single gene diabetes, particularly HNF1A MODY and permanent neonatal diabetes associated with the KCNJ11 and ABCC8 genes, all efficiently controlled on sulfonylurea, inspires us to continue the efforts to tailor individual treatment for T2DM patients. In this review paper, we summarize the impact of single gene disease discoveries on diabetes research and clinical practice.

Hereditary spastic paraplegia: clinical genomics and pharmacogenetic perspectives

Hereditary spastic paraplegias (HSPs) are a group of single-gene disorders characterised by degeneration of the corticospinal tract axons, leading to bilateral, symmetrical, slowly-progressive spastic paraparesis, predominantly of the lower extremities. So far, ~ 30 different chromosomal HSP loci have been identified by genetic linkage analysis. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis. At present, treatment of the HSPs is primarily directed symptomatically toward reducing muscle spasticity. Yet, recent progresses in the identification of HSP mutations are providing formidable tools to pharmacogenetic approaches of drug discovery, validation and prediction of individual response.

ACOG Practice Bulletin #64: Hemoglobinpathies in Pregnancy

The hemoglobinopathies are a heterogeneous group of single-gene disorders that include the structural hemoglobin variants and the thalassemias. More than 270 million people worldwide are heterozygous carriers of hereditary disorders of hemoglobin, and at least 300,000 affected homozygotes or compound heterozygotes are born each year (1). The purpose of this document is to review the most common hemoglobinopathies and to provide recommendations for the screening and clinical management of hemoglobinopathies during pregnancy.

Genetic diseases: Diagnosis by restriction endonuclease analysis

We have summarized a number of different genetic disorders which can be diagnosed at the DNA level using restriction endonuclease fragment analysis. A whole spectrum of defects can be recognized: point mutations, deletions, additions, and crossing-over products or hybrid genes. These same restriction endonuclease techniques can enable different genes to be marked by polymorphism patterns. Thus, abnormal genes can be identified even if their exact DNA lesion is unknown or cannot be directly detected. The progress that has been made with the hemoglobinopathies and the experience from this group of single gene disorders should find application to other diseases as soon as specific probes become available.