Home About us Contact
|
Home About us Contact | ||
|
|
||
Consanguineous Family (consanguineous + family)
Selected AbstractsMutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function,,HUMAN MUTATION, Issue 4 2008Saima Riazuddin Abstract Recessive mutations of MYO7A, encoding unconventional myosin VIIA, can cause either a deaf-blindness syndrome (type 1 Usher syndrome; USH1B) or nonsyndromic deafness (DFNB2). In our study, deafness segregating as a recessive trait in 24 consanguineous families showed linkage to markers for the DFNB2/USH1B locus on chromosome 11q13.5. A total of 23 of these families segregate USH1 due to 17 homozygous mutant MYO7A alleles, of which 14 are novel. One family segregated nonsyndromic hearing loss DFNB2 due to a novel three-nucleotide deletion in an exon of MYO7A (p.E1716del) encoding a region of the tail domain. We hypothesized that DFNB2 alleles of MYO7A have residual myosin VIIA. To address this question we investigated the effects of several mutant alleles by making green fluorescent protein (GFP) tagged cDNA expression constructs containing engineered mutations of mouse Myo7a at codons equivalent to pathogenic USH1B and DFNB2 alleles of human MYO7A. We show that in transfected mouse hair cells an USH1B mutant GFP-myosin VIIa does not localize properly to inner ear hair cell stereocilia. However, a GFP-myosin VIIa protein engineered to have an equivalent DFNB2 mutation to p.E1716del localizes correctly in transfected mouse hair cells. This finding is consistent with the hypothesis that p.E1716del causes a less severe phenotype (DFNB2) than the USH1B -associated alleles because the resulting protein retains some degree of normal function. Hum Mutat 29(4), 502,511, 2008. Published 2008 Wiley-Liss, Inc. [source] Molecular epidemiology of hypospadias: Review of genetic and environmental risk factorsBIRTH DEFECTS RESEARCH, Issue 10 2003Jeanne M. Manson Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 125 live male births. It is characterized by altered development of the urethra, foreskin, and ventral surface of the penis. In this review, the embryology, epidemiology, risk factors, genetic predisposition, and likely candidate genes for hypospadias are described. Recent reports have identified increases in the birth prevalence of mild and severe forms of hypospadias in the United States from the 1960s to the present. Studies in consanguineous families and small case series have identified allelic variants in genes controlling androgen action and metabolism that cause hypospadias, but the relevance of these findings to the general population is unknown. Concern has also focused on whether exposure to endocrine disrupting chemicals (EDC) with antiandrogenic activity is the cause of this increase. Hypospadias is believed to have a multifactorial etiology in which allelic variants in genes controlling androgen action and metabolism predispose individuals to develop this condition. When genetic susceptibility is combined with exposure to antiandrogenic agents, a threshold is surpassed, resulting in the manifestation of this birth defect. A clear role for exposure to antiandrogenic environmental chemicals has yet to be established in the etiology of hypospadias, although results from laboratory animal models indicate that a number of environmental chemicals could be implicated. Molecular epidemiology studies that simultaneously examine the roles of allelic variants in genes controlling androgen action and metabolism, and environmental exposures are needed to elucidate the risk factors for these anomalies and the causes of the increased rate of hypospadias. Birth Defects Research (Part A), 2003. © 2003 Wiley-Liss, Inc. [source] Novel mutations in the EXT1 gene in two consanguineous families affected with multiple hereditary exostoses (familial osteochondromatosis)CLINICAL GENETICS, Issue 2 2004M Faiyaz-Ul-Haque Multiple hereditary exostoses (HME) is an autosomal dominant developmental disorder exhibiting multiple osteocartilaginous bone tumors that generally arise near the ends of growing long bones. Here, we report two large consanguineous families from Pakistan, who display the typical features of HME. Affected individuals also show a previously unreported feature , bilateral overriding of single toes. Analysis using microsatellite markers for each of the known EXT loci, EXT1, EXT2, and EXT3 showed linkage to EXT1. In the first family, mutation analysis of the EXT1 gene revealed that affected individuals were heterozygous for an in-frame G-to-C transversion at the conserved splice donor site in intron 1. This mutation is predicted to disrupt splicing of the first intron and produce a frameshift that leads to a premature termination codon. In the second family, an insertion of an A in exon 8 is predicted to produce a frameshift at codon 555 followed by a premature termination, a further 10 codons downstream. In both families, an increased number of affected male subjects were observed. In affected females in family 2, phenotypic variability and incomplete penetrance were noted. [source] Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis,,HUMAN MUTATION, Issue 1 2005Stefan J. White Abstract We have designed Multiplex Amplifiable Probe Hybridization (MAPH) probes for 28 exons of the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD. The set was used to screen DNA from limb-girdle muscular dystrophy (LGMD) patients for the presence of pathogenic deletion or duplication mutations. An unexpected heterozygous deletion of SGCG exon 7 was detected in a patient from a consanguineous family in which a known c.525delT mutation segregates. The exon 7 deletion was inherited from the father, who was part of the consanguineous c.525delT branch of the family but who did not carry the c.525delT mutation. A similar, homozygous deletion had been identified in two unrelated LGMD patients from southern Italy. The deletion breakpoints were mapped, isolated, and sequenced, and were identical in all cases. Haplotype analysis showed the same alleles segregating with the mutation in all three patients, suggesting a common ancestor. Exonic deletions in sarcoglycanopathies appear to be rare events. However, we recommend screening for exonic deletions/duplications in patients where a mutation has not been identified in both alleles, as well as in seemingly homozygous cases where segregation of the mutations can not be confirmed in the parents. © 2005 Wiley-Liss, Inc. [source] A consanguineous Turkish family with early-onset Parkinson's disease and an exon 4 parkin deletionMOVEMENT DISORDERS, Issue 7 2004Okan Dogu MD Abstract The importance of parkin in early-onset Parkinson's disease in Japan, Europe, and the United States is well established. The contribution of this gene to the risk of Parkinson's disease in other populations is less well known. To explore the importance of parkin in those of Turkish ancestry, we studied familial cases from that country, and identified a consanguineous family with early-onset Parkinson's disease due to a homozygous mutation in parkin. © 2004 Movement Disorder Society [source] 2163: Identification of novel disease gene for primary congenital glaucoma (PCG) through homozygosity mapping and next-generation sequencing strategies in a large consanguineous pedigreeACTA OPHTHALMOLOGICA, Issue 2010H VERDIN Purpose Primary congenital glaucoma (PCG) is caused by developmental anomalies of the trabecular meshwork and the anterior chamber angle resulting in an increased ocular pressure (IOP) and optic nerve damage. In general PCG displays an autosomal recessive inheritance pattern and is genetically heterogeneous. To date, three PCG loci are known, namely GLC3A, GLC3B and GLC3C, and two causal genes have been identified, CYP1B1 located in the GLC3A locus and LTPB2 located at 1.3 MB proximal to the GLC3C locus. The purpose of the current study is to identify the causal disease gene in a large consanguineous family with PCG, originating from Jordany. CYP1B1 mutations and linkage to the LTBP2, GLCB3 and GLCC3 locus were previously excluded. Methods In a first step, DNA from members from the consanguineous family will be genotyped by 250K GeneChip Mapping Affymetrix arrays. Homozygosity mapping will be applied to identify potential disease loci, using a homemade Perl script. Next, microsatellite analysis will be performed in order to confirm findings and to narrow down candidate regions. Subsequently, candidate regions of interest will be captured (Agilent) and sequenced on the Illumina Genome Analyser IIx (GAIIx). Gene and variant prioritization will be done using in-house developed software, followed by segregation analysis and screening in control individuals. At last, a cohort of 30 molecularly unsolved PCG patients will be screened for mutations in the newly identified disease. Conclusion The identification of a new disease gene for PCG may lead to better insights into the molecular pathogenesis of glaucoma, and might uncover novel therapeutic strategies. [source] Homozygous LMNA mutation R527C in atypical Hutchinson,Gilford progeria syndrome: evidence for autosomal recessive inheritanceACTA PAEDIATRICA, Issue 8 2009Lili Liang Abstract Aim:, To describe two Chinese siblings of atypical Hutchinson,Gilford progeria syndrome (HGPS), with genetic diagnosis and special clinical manifestation. Methods:, We screened the LMNA gene in four members of a consanguineous family, in which two children were suffering from atypical HGPS. Besides general HGPS features, such as growth retardation and characteristic appearance, special clinical phenotypes including disorders of digestive system and severe skeletal damages were observed. Results:, Homozygous mutation 1579C>T, which predicts R527C, was identified in the exon 9 of LMNA among the affected siblings. Heterozygous carrier status 1579C>T was detected in both of the asymptomatic parents. Conclusion:, Homozygous mutation R527C in LMNA yields atypical HGPS, and it suggests an autosomal recessive inheritance in this family. [source] Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblingsACTA PAEDIATRICA, Issue 6 2009Srdjan Pasic Abstract We report different immunological phenotypes in three siblings from consanguineous family with recombinase-activating gene 1 (RAG1) gene mutations. Null mutations of RAG genes result in severe combined immunodeficiency (SCID) with absent T and B cells. Hypomorphic mutations with retained activity of RAG genes may lead to a ,leaky' SCID with some features of Omenn syndrome (OS) or typical OS. In our three patients, homozygous, hypomorphic RAG1 gene mutation (g.368,369delAA) was detected. Two patients presented with T,B,SCID phenotype while the youngest patient developed T+B+NK+SCID phenotype with expansion of autologous T-cell receptor (TCR) ,,-positive T cells, increased immunoglobulin levels and retained ability for antibody production. Similar to originally reported patients with this newly recognized immune phenotype, our patient developed disseminated cytomegalovirus (CMV) infection and autoimmune cytopenia. Conclusion: In infants with disseminated cytomegalovirus infection and autoimmune cytopenia, even if basic immunologic investigation appears normal, RAG1 immunodeficiency should be considered. [source] | |||||||||||||