Home About us Contact
|
Home About us Contact | ||
|
|
||
Affected Families (affected + family)
Terms modified by Affected Families Selected AbstractsORIGINAL ARTICLE Laboratory science: Spectrum of F8 gene mutations in haemophilia A patients from a region of Italy: identification of 23 new mutationsHAEMOPHILIA, Issue 5 2010F. RICCARDI Summary., Haemophilia A (HA) is an X-linked recessive bleeding disorder caused by a lack or decrease of coagulation factor VIII activity. The molecular diagnosis of HA is challenging and a variety of different mutations have been identified throughout the F8 gene. Our aim was to detect the causative mutation in 266 HA patients from Emilia-Romagna region (Italy) and in all suspected carriers. Molecular analysis of F8 in 201 HA patients (152 index cases) was performed with a combination of several indirect and direct molecular approaches, such as long distance polymerase chain reaction, multiplex ligation-dependent probe amplification, denaturing high performance liquid chromatography and direct sequencing. The analysis revealed 78 different mutations, 23 of which were novel, not having been reported in national or international databases. The detection rate was 100%, 86% and 89% in patients with severe, moderate and mild HA, respectively. The information provided by this registry will be helpful for monitoring the treatment of HA patients in Emilia-Romagna and also for reliable genetic counselling of affected families in the future. [source] The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory NetworkHAEMOPHILIA, Issue 5 2008S. KEENEY Summary., von Willebrand disease (VWD) is a common autosomally inherited bleeding disorder associated with mucosal or trauma-related bleeding in affected individuals. VWD results from a quantitative or qualitative deficiency of von Willebrand factor (VWF), a glycoprotein that is essential for primary haemostasis and that carries and protects coagulation factor VIII (FVIII) in the circulation. Through characterization of the phenotype and identification of mutations in the VWF gene in patients with VWD, understanding of the genetics and biochemistry of VWF and VWD has advanced considerably. The importance of specific regions of VWF for its interaction with other components of the vasculature has been revealed, and this has facilitated the formal classification of VWD into three subtypes based upon quantitative (types 1 and 3) and qualitative (type 2) deficiency of VWF. The underlying genetic lesions and associated molecular pathology have been identified in many cases of the qualitative type 2 VWD variants (2A, 2B, 2M, 2N) and in the severe quantitative deficiency, type 3 VWD. However in the partial quantitative deficiency, type 1 VWD, the picture is less clear: there is a variable relationship between plasma levels of VWF and bleeding, there is incomplete penetrance and variable expressivity within affected families, the causative molecular defect is unknown in a substantial number of cases, and even in those cases where the causative mutation is known, the associated molecular pathology is not necessarily understood. This guideline aims to provide a framework for best laboratory practice for the genetic diagnosis of VWD, based upon current knowledge and understanding. [source] The pathology of hypertrophic cardiomyopathyHISTOPATHOLOGY, Issue 5 2004S E Hughes Sudden cardiac death (SCD) is devastating at any age, but even more so when the individual affected is young and asymptomatic, and the death is entirely unexpected. SCD is a catastrophic complication of hypertrophic cardiomyopathy (HCM) and may be the first manifestation of this disease. HCM is an inherited intrinsic disease of the myocardium characterized by left ventricular hypertophy without chamber dilatation, in the absence of either a systemic or other cardiac disease, which may cause a similar magnitude of hypertrophy. HCM may be a clinically silent disease. Indeed, the pathologist may be the first to encounter a case of HCM at autopsy. HCM has wide-ranging implications for affected families, who will require cardiac screening and genetic counselling even if mutations are not known. Therefore, prompt and accurate diagnosis of HCM is vital. This review article will focus on the pathological diagnosis of HCM, recent advances in the genetics of this disease, and common pitfalls which may arise, leading to diagnostic uncertainty. [source] Mutations in severe combined immune deficiency (SCID) due to JAK3 deficiencyHUMAN MUTATION, Issue 4 2001Luigi D. Notarangelo Abstract During the last 10 years, an increasing number of genes have been identified whose abnormalities account for primary immunodeficiencies, with defects in development and/or function of the immune system. Among them is the JAK3 -gene, encoding for a tyrosine kinase that is functionally coupled to cytokine receptors which share the common gamma chain. Defects of this gene cause an autosomal recessive form of severe combined immunodeficiency with almost absent T-cells and functionally defective B-cells (T,B+ SCID). Herewith, we present molecular information on the first 27 unique mutations identified in the JAK3 gene, including clinical data on all of the 23 affected patients reported so far. A variety of mutations scattered throughout all seven functional domains of the protein, and with different functional effects, have been identified. Availability of a molecular screening test, based on amplification of genomic DNA, facilitates the diagnostic approach, and has permitted recognition that JAK3 deficiency may also be associated with atypical clinical and immunological features. Development of a structural model of the JAK3 kinase domain has allowed characterization of the functional effects of the various mutations. Most importantly, molecular analysis at the JAK3 locus results in improved genetic counseling, allows early prenatal diagnosis, and prompts appropriate treatment (currently based on hematopoietic stem cell transplantation) in affected families. Hum Mutat 18:255,263, 2001. © 2001 Wiley-Liss, Inc. [source] Von Hippel-Lindau diseaseMICROSCOPY RESEARCH AND TECHNIQUE, Issue 2 2003Toshiaki Sano Abstract Von Hippel-Lindau (VHL) disease is an uncommon, autosomal dominant hereditary multitumor syndrome caused by germline alterations of the VHL gene, which has been cloned recently and identified as a tumor suppressor gene. The major lesions in VHL disease include hemangioblastomas in the central nervous system and retina, clear cell renal cell carcinomas, pheochromocytomas, pancreatic tumors, epididymal cystadenomas, endolymphatic sac tumors, carcinoid tumors, and multiple cysts of the kidney, pancreas, and epididymis. Compared with sporadic ones, the tumors in VHL disease develop at an earlier age and often multifocally. Histologic features of VHL tumors are characterized by their high degree of vascularization and the presence of a clear cell component. Hypervascularization is induced by overexpression of vascular endothelial growth factor (VEGF), and because the principal function of VHL protein is the negative regulation of hypoxia-inducible mRNAs including VEGF mRNA, inactivation of VHL gene plays critical roles in angiogenesis of the VHL tumors. In addition, since VHL protein is also required for the down-regulation of transcription activity of certain genes for the cell growth and cell cycle, inactivation of VHL gene may contribute to tumorigenesis of the VHL tumors. A significant difference in the frequency of types of VHL gene mutation has been noted among the affected families, known as the genotype-phenotype correlations. Microsc. Res. Tech. 60:159,164, 2003. © 2003 Wiley-Liss, Inc. [source] Central core disease due to recessive mutations in RYR1 gene: Is it more common than described?MUSCLE AND NERVE, Issue 5 2007Patrícia M. Kossugue MS Abstract Central core disease (CCD) is an autosomal-dominant congenital myopathy, with muscle weakness and malignant hyperthermia (MH) susceptibility. We identified two of nine Brazilian CCD families carrying two mutations in the RYR1 gene. The heterozygous parents were clinically asymptomatic, and patients were mildly affected, differing from the few autosomal-recessive cases described previously. Recessive inheritance in CCD may therefore be more common than previously appreciated, which has important implications for genetic counseling and MH prevention in affected families. Muscle Nerve, 2007 [source] Harlequin Ichthyosis in Association with Hypothyroidism and Juvenile Rheumatoid ArthritisPEDIATRIC DERMATOLOGY, Issue 5 2003Yuin-Chew Chan M.D. Two Chinese children, a 2-year-old boy and an 11-year-old girl, presented with these classic features as well as alopecia and loss of eyebrows and eyelashes. The boy was small for his age and was found to have hypothyroidism at the age of 18 months; he is currently on thyroxine replacement therapy. At 6 years of age, the girl developed symmetrical polyarthritis associated with positive rheumatoid factor and radiologic evidence of erosive arthritis, suggestive of juvenile rheumatoid arthritis. She received prednisolone, nonsteroidal anti-inflammatory drugs (NSAIDs), and subsequently methotrexate for her arthritis, with clinical and radiologic improvement. Early therapy with oral retinoids in both children accelerated shedding of the hyperkeratotic plates as well as improved ectropion and eclabium. There was no major adverse reaction to oral retinoids. The development of juvenile rheumatoid arthritis in survivors with harlequin ichthyosis has not been previously described. The use of prednisolone and NSAIDs in the girl did not affect the skin condition, but the addition of methotrexate led to a decrease in erythema. The association with autoimmune disease is probably coincidental. The psychosocial impact of this severe lifelong disease on the two families was enormous. Early retinoid therapy may improve the disorder and help increase survival rates. A multidisciplinary approach, including psychosocial support of the affected families, is vital in the management of this lifelong disease. [source] Genetic counseling and "molecular" prenatal diagnosis of holoprosencephaly (HPE),AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Sandra Mercier Abstract Holoprosencephaly (HPE) is a structural anomaly of the developing brain in which the forebrain fails to divide into two separate hemispheres and ventricles. The poor prognosis in the most severe forms justifies the importance of genetic counseling in affected families. The genetic counseling requires a thorough clinical approach given the extreme variability of phenotype and etiology. The karyotype is an essential diagnostic tool. Since mutations in the four major genes (SHH, ZIC2, SIX3, and TGIF) have been identified in HPE patients, molecular study is performed routinely in nonsyndromic HPE. New molecular tools, such as array-CGH analysis, are now part of the diagnostic process. Prenatal diagnosis is based primarily on fetal imaging, but "molecular" prenatal diagnosis can be performed if a mutation has been previously identified in a proband. Interpretations of molecular diagnosis must be given with caution, given the lack of strict genotype,phenotype correlation, and should be offered in addition to fetal imaging, using ultrasound followed by fetal MRI. We report on our experience of 15 molecular prenatal diagnoses from chorionic villi or amniotic fluid sampling. In eight instances, we were able to reassure the parents after taking into account the absence of the mutation in the fetus, previously identified before in a parent and/or a proband. Fetal RMI was normal later in pregnancy, and no child had medical problems after birth. The mutation was found in the seven other cases: four children were born, either without brain malformation and asymptomatic, or had a less severe form than the index case. © 2010 Wiley-Liss, Inc. [source] Evaluation of a fetus at risk for dihydropteridine reductase deficiency by direct mutation analysis using denaturing gradient gel electrophoresisPRENATAL DIAGNOSIS, Issue 10 2001H. Serap Kalkano Abstract Dihydropteridine reductase (DHPR) is an enzyme involved in the recycling of tetrahydrobiopterin (BH4), which is an obligate co-factor of the aromatic amino acid hydroxylases. DHPR deficiency is a rare, autosomal recessive disorder caused by mutations in the QDPR gene. DHPR-deficient patients are diagnosed by a lack of response to a low phenylalanine diet and by severe neurological symptoms. Final diagnosis is made by measurements of neurotransmitters and pterin metabolites in cerebrospinal fluid (CSF) and urine, in addition to DHPR enzyme activity, which can be assessed in whole red blood cells. Treatment of DHPR deficiency can be difficult and the outcome is not always satisfying, even if all treatment strategies are followed. Therefore prenatal diagnosis is of great importance in affected families. Prenatal diagnosis is possible by measuring DHPR activity in different cell types but this is time consuming. More than 25 different mutations have to date been identified in the QDPR gene and direct identification of a mutation in a fetus would be easy and rapid. We have developed a method based on denaturing gradient gel electrophoresis (DGGE) for the analysis of the QDPR gene. The method is useful for rapid and simultaneous scanning of all exons and flanking intronic sequences of the QDPR gene. We describe the first prenatal diagnosis conducted using this method. Copyright © 2001 John Wiley & Sons, Ltd. [source] Genetics and delusional disorderBEHAVIORAL SCIENCES & THE LAW, Issue 3 2006Alastair G. Cardno M.B., M.R.C.Psych., Ph.D. This article gives an overview of genetic research approaches and their application to delusional disorder. Most studies have been based on small samples and have had other methodological limitations, so it is not clear whether there is a genetic contribution to the aetiology of delusional disorder. It is unlikely that delusional disorder is strongly related genetically to affective disorder or schizophrenia, but more subtle relationships cannot be ruled out. The rarity of multiply affected families prohibits linkage studies and, to date, molecular genetic investigations have been mainly limited to small association studies of dopamine receptor polymorphisms. A range of considerably larger, epidemiologically rigorous studies is required, but the uncommonness and other features of the disorder put strong limitations on the prospects for ascertaining adequate samples. Copyright © 2006 John Wiley & Sons, Ltd. [source] Collection, use, and protection of population-based birth defects surveillance data in the united states,BIRTH DEFECTS RESEARCH, Issue 12 2007Cara T. Mai Abstract Birth defects surveillance systems collect population-based birth defects data from multiple sources to track trends in prevalence, identify risk factors, refer affected families to services, and evaluate prevention efforts. Strong state and federal public health and legal mandates are in place to govern the collection and use of these data. Despite the prima facie appeal of "opt-in" and similar strategies to those who view data collection as a threat to privacy, the use of these strategies in lieu of population-based surveillance can severely limit the ability of public health agencies to accurately access the health status of a group within a defined geographical area. With the need for population-based data central to their mission, birth defects programs around the country take their data stewardship role seriously, recognizing both moral and legal obligations to protect the data by employing numerous safeguards. Birth defects surveillance systems are shaped by the needs of the community they are designed to serve, with the goal of preventing birth defects or alleviating the burdens associated with them. Birth Defects Research (Part A) 79:811,814, 2007. © 2007 Wiley-Liss, Inc. [source] A novel missense mutation in the COL7A1 gene causes epidermolysis bullosa pruriginosaCLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 8 2009B.-J. Shi Summary Epidermolysis bullosa (EB) pruriginosa, characterized by severe itching and the presence of nodular prurigo-like or lichenoid lesions, is a rare clinical type of dystrophic EB. Mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils, have been implicated in the pathogenesis of the disorder. In the present study, we screened a Chinese family with EB pruriginosa for COL7A1 mutations by PCR amplification of genomic sequences and direct nucleotide sequencing. The mutation consists of a G,T substitution at nucleotide 6724 in exon 85, which leads to the substitution of glycine by tryptophan at codon 2242. This report adds new variants to the known COL7A1 mutations underlying EB pruriginosa, and provides the basis for genetic counselling and prenatal diagnosis for affected families. [source] A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor geneCLINICAL ENDOCRINOLOGY, Issue 4 2001D. Söderlund BACKGROUND and OBJECTIVE Mutations in the GnRH receptor (GnRH-R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH-R gene in three families with isolated hypogonadotrophic hypogonadism. PATIENTS Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included. MEASUREMENTS DNA sequencing was performed after polymerase chain reaction amplification of each of the three exons of the gene. RESULTS A novel homozygous missense mutation, at nucleotide 268, turning glutamic acid into lysine, located at the second transmembrane domain of the GnRH-R gene was found in two patients pertaining to one of the families studied. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the other two affected families no mutations were found in the GnRH-R gene. CONCLUSIONS This constitutes the first description of an spontaneous mutation located at the second transmembrane domain (Glu90Lys) of the GnRH-R, indicating that the integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates that mutations are distributed throughout the GnRH-R gene and that as in the only other homozygous mutation previously described, affected patients present a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume that the mutation derived from a common ancestor, by a founder gene effect. [source] Perils and pitfalls of permutation tests for distinguishing the effects of neighbouring polymorphismsGENETIC EPIDEMIOLOGY, Issue 7 2006Joanna M. Biernacka Abstract In a small region several marker loci may be associated with a trait, either because they directly influence the trait or because they are in linkage disequilibrium (LD) with a causal variant. Having established a potentially causal effect at a primary variant, we may ask if any other variants in the region appear to further contribute to the trait, indicating that the additional variant is either causal or is in LD with another causal locus. Methods of approaching this problem using case-parent trio data include the stepwise conditional logistic regression approach described by Cordell and Clayton ([2002] Am. J. Hum. Genet. 70:124,141), and a constrained-permutation method recently proposed by Spijker et al. ([2005] Ann. Hum. Genet. 69:90,101). Through simulation we demonstrate that the procedure described by Spijker et al. [2005], as well as unconditional logistic regression with "affected family-based controls" (AFBACs), can lead to inflated type 1 errors in situations when haplotypes are not inferable for all trios, whereas the conditional logistic regression approach gives correct significance levels. We propose an alternative to the permutation method of Spijker et al. [2005], which does not rely on haplotyping, and results in correct type 1 errors and potentially high power when assumptions of random mating, Hardy-Weinberg Equilibrium, and multiplicative effects of disease alleles are satisfied. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Familial cutaneous collagenoma: New affected family with prepubertal onsetTHE JOURNAL OF DERMATOLOGY, Issue 7 2007Mehmet Salih GUREL ABSTRACT Two siblings presented with clinical and histopathological findings of familial cutaneous collagenoma which is a rare connective tissue nevus, inherited in an autosomal-dominant pattern. A 13-year-old girl had oval-round, soft, painless papules, 5,10 mm in size and a total of 9,10 on her abdomen and flanks. Skin biopsy demonstrated dense, coarse collagen fibers in the dermis and a decrease in elastic fibers. Doppler echocardiography indicated an atrioseptal defect of the secundum type. Her 9-year-old brother was also examined; four lesions were discovered on his back but he was otherwise normal. Our cases comprise the sixth affected family to be reported in the medical published work and all lesions had appeared prepubertally. [source] EFFECTS OF A CHILD'S DISABILITY ON AFFECTED FEMALE'S LABOUR SUPPLY IN AUSTRALIAAUSTRALIAN ECONOMIC PAPERS, Issue 3 2010ZENG-HUA LU Australia has experienced a growing rate of child disability, with the rate of 3.7 per cent in 1998 increasing to 4.3 per cent in 2003 for children aged under four years and from 9.5 per cent to 10 per cent for children aged five to 14 years in the same period. However, surprisingly no study has examined the economic effects of child disability in the Australian context. This paper attempts to quantify the link between a child's disability and the work behaviour of the female in the affected family. Our findings provide empirical justifications for the current policy linking the severity level of child disability to the assessment of eligibility for Carer Payment (Child). We also found that child disability has different impacts on the labour market activities of married women and non-married women. It appears that child disability imposes a greater hardship on non-married women than on married women in terms of work choice decision. Once non-married women manage to enter the labour force, they may have to stay on to work as usual even if they have a disabled child, because they may not have other family members to turn to for help as married women do. [source] A novel homozygous mutation in the second transmembrane domain of the gonadotrophin releasing hormone receptor geneCLINICAL ENDOCRINOLOGY, Issue 4 2001D. Söderlund BACKGROUND and OBJECTIVE Mutations in the GnRH receptor (GnRH-R) gene cause hypogonadotrophic hypogonadism. Here, we present the molecular studies of the GnRH-R gene in three families with isolated hypogonadotrophic hypogonadism. PATIENTS Three unrelated families, with at least two members diagnosed with isolated hypogonadotrophic hypogonadism were included. MEASUREMENTS DNA sequencing was performed after polymerase chain reaction amplification of each of the three exons of the gene. RESULTS A novel homozygous missense mutation, at nucleotide 268, turning glutamic acid into lysine, located at the second transmembrane domain of the GnRH-R gene was found in two patients pertaining to one of the families studied. Both parents and an unaffected brother were heterozygous carriers of one mutant allele, an unaffected sister was homozygote wild type. In the other two affected families no mutations were found in the GnRH-R gene. CONCLUSIONS This constitutes the first description of an spontaneous mutation located at the second transmembrane domain (Glu90Lys) of the GnRH-R, indicating that the integrity of glutamic acid at this position is crucial for receptor function. Also this report, complementing others, demonstrates that mutations are distributed throughout the GnRH-R gene and that as in the only other homozygous mutation previously described, affected patients present a complete form of hypogonadotrophic hypogonadism. Due to the fact that apparently consanguinity was present in our affected family, we presume that the mutation derived from a common ancestor, by a founder gene effect. [source] | |||||||||||||