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Incomplete Penetrance (incomplete + penetrance)
Selected AbstractsIncomplete penetrance of the NOD2 E383K substitution among members of a pediatric granulomatous arthritis pedigreeARTHRITIS & RHEUMATISM, Issue 6 2009Frank T. Saulsbury Pediatric granulomatous arthritis (PGA) has been associated with 12 different substitutions in the NOD2 gene thus far. We report a case of PGA in a 6-year-old girl with the NOD2 E383K gene substitution. Genotype analysis of the patient's family members revealed that her affected paternal aunt, as well as her asymptomatic father and 3 younger siblings, were heterozygous for the E383K substitution. The patient's mother did not have a NOD2 mutation. This is the first report of a pedigree in which 4 asymptomatic members carry the E383K substitution in NOD2, as well as the first observation of an asymptomatic carrier state for any of the NOD2 "Blau mutations." [source] Incomplete penetrance and variable expressivity: is there a microRNA connection?BIOESSAYS, Issue 9 2009Jasmine K. Ahluwalia Abstract Incomplete penetrance and variable expressivity are non-Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine-tuning gene expression at translational level, we propose miRNA-mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3, UTR, co-expression of target gene,miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles. [source] Familial trends of inheritance in gastro esophageal reflux disease, Barrett's esophagus and Barrett's adenocarcinoma: 20 familiesDISEASES OF THE ESOPHAGUS, Issue 1 2007R. S. Sappati Biyyani SUMMARY., We reported four families with familial Barrett's esophagus (FBE) in 1993. This follow-up study includes an additional 16 families with FBE, gastroesophageal reflux disease (GERD) and BE-related adenocarcinoma (BEAC) highlighting the familial trends of inheritance. A retrospective survey of endoscopic and histopathological reports on 95 confirmed cases of BE from 1975 to 2005 was performed and a detailed family history was obtained. Five representative pedigrees from a total of 20 are discussed here. These 20 families represent one of the largest cohorts studied over three decades from a single institution. Familial BE is more common than previously thought and the prevalence of GERD, BE and BEAC in these families is distinctly higher than with sporadic cases. The conditions appear to be inherited in an autosomal dominant fashion with incomplete penetrance. Hence diligence in taking family history with BE patients is critical since the endoscopic screening of relatives is warranted in FBE. Earlier diagnosis and surveillance of FBE should hopefully improve outcomes. [source] Genetic aspects of the Paget's disease of bone: concerns on the introduction of DNA-based tests in the clinical practice.EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2010Advantages, disadvantages of its application Eur J Clin Invest 2010; 40 (7): 655,667 Abstract Background, A large amount of genetic studies have clearly demonstrated the existence of a genetic susceptibility to Paget's disease of bone (PDB). Although the disease is genetically heterogeneous, the SQSTM1/p62 gene, encoding a protein with a pathophysiological role in both osteoclast differentiation and activity, has been found worldwide to harbour germline mutations in most of the PDB patients from geographically distant populations originating from different areas of Europe, both in sporadic and familial cases. Materials and Methods, Thus, SQSTM1/p62 gene mutations may confer an increased lifetime risk of developing PDB. Results, Several different genotype-phenotype analyses have shown a high penetrance for such mutations. These results suggest the opportunity to perform genetic testing in affected individuals and then, after the identification of a SQSTM1/p62 gene germline mutation, in their relatives as a real and concrete strategy to increase the diagnostic sensitivity in most of the asymptomatic mutant carriers. However, it is of note to underlie that an incomplete penetrance for SQSTM1/p62 gene mutations has also been reported. Conclusions, In light of all these contradictory evidences, a review on whether, when and why apply the DNA test to those subjects, its interpretation and clinical application is necessary. In fact, a growing number of preventive care options are now available to affected patients and families and the process of systematically assessing risk is becoming increasingly important for both patients and physicians. [source] Availability of autoantigenic epitopes controls phenotype, severity, and penetrance in TCR Tg autoimmune gastritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 12 2008Ditza Levin Abstract We examined TCR:MHC/peptide interactions and in vivo epitope availability to explore the Th1- or Th2-like phenotype of autoimmune disease in two TCR Tg mouse models of autoimmune gastritis (AIG). The TCR of strains A23 and A51 recognize distinct IAd -restricted peptides from the gastric parietal cell H/K-ATPase. Both peptides form extremely stable MHC/peptide (MHC/p) complexes. All A23 animals develop a Th1-like aggressive, inflammatory AIG early in life, while A51 mice develop indolent Th2-like AIG at 6,8,wk with incomplete penetrance. A51 T cells were more sensitive than A23 to low doses of soluble antigen and to MHC/p complexes. Staining with IAd/peptide tetramers was only detectable on previously activated T cells from A51. Thus, despite inducing a milder AIG, the A51 TCR displays a higher avidity for its cognate IAd/peptide. Nonetheless, in vivo proliferation of adoptively transferred A51 CFSE-labeled T cells in the gastric lymph node was relatively poor compared with A23 T cells. Also, DC from WT gastric lymph node, presenting processed antigen available in vivo, stimulated proliferation of A23 T cells better than A51. Thus, the autoimmune potential of these TCR in their respective Tg lines is strongly influenced by the availability of the peptide epitope, rather than by differential avidity for their respective MHC/p complexes. [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] Identification of five chromosomal regions involved in predisposition to melanoma by genome-wide scan in the MeLiM swine modelINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Claudine Geffrotin Abstract In human familial melanoma, 3 risk susceptibility genes are already known, CDKN2A, CDK4 and MC1R. However, various observations suggest that other melanoma susceptibility genes have not yet been identified. To search for new susceptibility loci, we used the MeLiM swine as an animal model of hereditary melanoma to perform a genome scan for linkage to melanoma. Founders of the affected MeLiM stock were crossed with each other and with healthy Duroc pigs, generating MeLiM, F1 and backcross families. As we had previously excluded the MeLiM CDKN2A gene, we paid special attention to CDK4 and MC1R, as well as to other candidates such as BRAF and the SLA complex, mapping them on the swine radiation hybrid map and/or isolating close microsatellite markers to introduce them into the genome scan. The results revealed, first, that swine melanoma was inherited as an autosomal dominant trait with incomplete penetrance, preferably in black animals. Second, 4 chromosomal regions potentially involved in melanoma susceptibility were identified on Sus Scrofa chromosomes (SSC) 1, 2, 7 and 8, respectively, in intervals 44,103, 1.9,18, 59,73 and 47,62 cM. A fifth region close to MC1R was revealed on SSC 6 by analyzing an individual marker located at position 7.5 cM. Lastly, CDK4 and BRAF were unlikely to be melanoma susceptibility genes in the MeLiM swine model. The 3 regions on SSC 1, 6 and 7, respectively, have counterparts on human chromosomes (HSA) 9p, 16q and 6p, harboring melanoma candidate loci. The 2 others, on SSC 2 and 8, have counterparts on HSA 11 and 4, which might therefore be of interest for human studies. © 2004 Wiley-Liss, Inc. [source] Linkage Disequilibrium Mapping of Disease Susceptibility Genes in Human PopulationsINTERNATIONAL STATISTICAL REVIEW, Issue 1 2000David Clayton Summary The paper reviews recent work on statistical methods for using linkage disequilibrium to locate disease susceptibility genes, given a set of marker genes at known positions in the genome. The paper starts by considering a simple deterministic model for linkage disequilibrium and discusses recent attempts to elaborate it to include the effects of stochastic influences, of "drift", by the use of either Writht-Fisher models or by approaches based on the coalescence of the genealogy of the sample of disease chromosomes. Most of this first part of the paper concerns a series of diallelic markers and, in this case, the models so far proposed are hierarchical probability models for multivariate binary data. Likelihoods are intractable and most approaches to linkage disequilibrium mapping amount to marginal models for pairwise associations between individual markers and the disease susceptibility locus. Approaches to evalutation of a full likelihood require Monte Carlo methods in order to integrate over the large number of unknowns. The fact that the initial state of the stochastic process which has led to present-day allele frequencies is unknown is noted and its implications for the hierarchical probability model is discussed. Difficulties and opportunities arising as a result of more polymorphic markers and extended marker haplotypes are indicated. Connections between the hierarchical modelling approach and methods based upon identity by descent and haplotype sharing by seemingly unrelated case are explored. Finally problems resulting from unknown modes of inheritance, incomplete penetrance, and "phenocopies" are briefly reviewed. Résumé Ce papier est une revue des travaux récents, protant sur les méthodes statistiques qui utilisent I'étude, des liaisons désé, quilib rées, pour identifer les génes, de susceptibilité des maladies,ápartir d'une série, de marqueurs de géncs á des positions définies du génome,. Le papier commence par considérer, un modéle, détéministe, simple pour liaisons déséquilibr,ées, puis nous discutons les améliorations, ré centes proposées, de ce modéle, dans but de tenir compte des effects des influences stochastiques soit en utilisant les modéles, de wright-fisher, soit par des approches basées, sur la coalescence de la géné alogic de I'échantillon, des chromosomes malades. La plupart de cette premiére, partie porte sur une série, de marqueurs dialléliques et, dans ce cas, les modéles, proposés, sont des modéles, hiérerchiques, probabilistes pour dinnées, binaires multivariées. Les viaisemblances n'ont pas de forme analytique et la plupart des approches pour la cartographie des liaisons déséquilibrées, sont équivalentes aux modéles, marginaux pour dinnées, appariées, entre des marqueurs individuels et le géne, de susceptibilité de la maladie.Pour évaluer, la vriausemblance compléte, des méthodes de Monte carlo sont nécessaires, afin d'intégrer, le large nombre d; inconnues. Le fait que l'état, initial du process stochastique qui a conduit éla fré, quence, allélique, actuel soit inconnu est á noter et ses implications pour le modéle, hiérarchique, probabiliste sont discutées.Les difficultés, et implications issues de marqueurs polumorphiques et de marquers haplotypes sont dévéloppées.Les liens entire l'approche de modélisation, hiérerchique, et les méthodes, d'analyse d'identite pardescendance et les haplotypes partagés, par des cas apparement non apparentés, sont explorés. Enfin les problémes, relatifs à des modes de transmission inconnus,à des pénétrances, incomplé, tes, et aux "phénocopies" sont briévenment evoqués. [source] Determination of the inheritance pattern of hyperthelia in cattle by maximum likelihood analysis 1JOURNAL OF ANIMAL BREEDING AND GENETICS, Issue 6 2000M. Brka Summary A previously published data-set with observations on supernumerary teats (hyperthelia) in dual-purpose Simmental was reanalysed by maximum-likelihood. The data comprised 537 unrelated animals and 614 members of 27 paternal half-sib families with known phenotype of each sire. The frequency of hyperthelia was 58% in unrelated animals, 51% in families with unaffected sire, and 73% in families with affected sires. Six different cases of single-gene inheritance were considered. The highest log-likelihood was obtained for additive inheritance and for a recessive pattern with 100% penetrance for recessive homozygotes and 32% for both other genotypes. Estimates for the gene frequency of the favourable allele were 0.34 and 0.29, respectively. Simple dominance or recessiveness with full or incomplete penetrance could be excluded. The possibility of finding paternal half-sib families with a heterozygous sire as a resource for a mapping experiment seem to be good in German Simmental. Zusammenfassung Untersuchung des Erbganges für Hyperthelie beim Rind mittels Maximum-Likelihood-Analyse Schon früher veröffentliche Daten mit Beobachtungen zum Auftreten überzähliger Zitzen (Hyperthelie) bei Fleckviehtieren wurden einer Maximum-Likelihood-Analyse unterzogen. Das Material bestand aus 537 unverwandten Tieren und 614 Tieren, die aus 27 verschiedenen väterlichen Halbgeschwistergruppen stammten, wobei der Phänotyp des Vaters jeweils bekannt war. Die relative Häufigkeit überzähliger Zitzen betrug 58% bei unverwandten Tieren, 51% bei Nachkommen von nicht betroffenen Vätern und 73% bei Nachkommen von Vätern, die selbst überzählige Zitzen aufwiesen. Sechs verschiedene Möglichkeiten monogener Vererbung wurden untersucht. Die höchsten Werte für die log-likelihood ergaben sich für einen additiven Erbgang sowie für eine Variante mit 100% Penetranz für die rezessiv Homozygoten und jeweils 32% Penetranz für die beiden anderen Genotypen. Für das erwünschte Allel wurde in beiden Varianten eine ähnliche Frequenz von 34% bzw. 29% geschätzt. Einfache dominante oder rezessive Erbgänge, auch mit unvollständiger Penetranz, konnten ausgeschlossen werden. Die Aussicht, für Kartierungsexperimente geeignete väterlichen Halbgeschwisterfamilien zu finden, scheint für die Rasse Fleckvieh günstig zu sein. [source] ISOLATION AND CHARACTERIZATION OF A CELL WALL-DEFECTIVE MUTANT OF CHLAMYDOMONAS MONOICA (CHLOROPHYTA),JOURNAL OF PHYCOLOGY, Issue 6 2003Cesar Fuentes Cell wall,defective strains of Chlamydomonas have played an important role in the development of transformation protocols for introducing exogenous DNA (foreign genes or cloned Chlamydomonas genes) into C. reinhardtii. To promote the development of similar protocols for transformation of the distantly related homothallic species, C. monoica, we used UV mutagenesis to obtain a mutant strain with a defective cell wall. The mutant, cw-1, was first identified on the basis of irregular colony shape and was subsequently shown to have reduced plating efficiency and increased sensitivity to lysis by a non-ionic detergent as compared with wild-type cells. Tetrad analysis of crosses involving the cw-1 mutant confirmed 2:2 segregation of the cw:cw+ phenotypes, indicating that the wall defect resulted from mutation of a single nuclear gene. The phenotype showed incomplete penetrance and variable expressivity. Although some cells had apparently normal cell walls as viewed by TEM, many cells of the cw-1 strain had broken cell walls and others were protoplasts completely devoid of a cell wall. Several cw-1 isolates obtained from crosses involving the original mutant strain showed a marked enhancement of the mutant phenotype and may prove especially useful for future work involving somatic cell fusions or development of transformation protocols. [source] Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia,MOVEMENT DISORDERS, Issue 9 2010Alessandro Brussino MD Abstract SCA12 is an autosomal dominant cerebellar ataxia characterized by onset in the fourth decade of life with action tremor of arms and head, mild ataxia, dysmetria, and hyperreflexia. The disease is caused by an expansion of ,51 CAGs in the 5, region of the brain- specific phosphatase 2 regulatory subunit B-beta isoform (PPP2R2B) gene. SCA12 is very rare, except for a single ethnic group in India. We screened 159 Italian ataxic patients for SCA12 and identified two families that segregated an expanded allele of 57 to 58 CAGs, sharing a common haplotype. The age at onset, phenotype, and variability of symptoms were compatible with known cases. In one family, the disease was apparently sporadic due to possible incomplete penetrance and/or late age at onset. Our data indicate that SCA12 is also present in Italian patients, and its genetic testing should be applied to both sporadic and familial ataxias. © 2010 Movement Disorder Society [source] Phenotypic characterization of DYT13 primary torsion dystonia,MOVEMENT DISORDERS, Issue 2 2004Anna Rita Bentivoglio MD Abstract We describe the phenotype of DYT13 primary torsion dystonia (PTD) in a family first examined in 1994. A complete neurological evaluation was performed on all available family members: 8 individuals were definitely affected by dystonia. The family was re-evaluated in March 2000: at that time, 3 more individuals had developed symptoms of dystonia. Inheritance of PTD was autosomal dominant, with affected individuals spanning three consecutive generations and male-to-male transmission. Age at onset ranged from 5 to 43 years. Onset occurred either in the craniocervical region or in upper limbs. Progression was mild, and the disease course was benign in most affected individuals; generalization occurred only in 2 cases. We did not find anticipation of age at onset or of disease severity through generations. Most subjects presented with jerky, myoclonic-like dystonic movements of the neck or shoulders. DYT13-PTD is an autosomal dominant disease, with incomplete penetrance (58%). Clinical presentation and age at onset were more variable than in DYT1-PTD, and the neck was involved in most of those affected. Moreover, the individuals with generalised dystonia were not severely disabled and were able to lead independent lives. To date, this is the only family with DYT13-PTD. © 2003 Movement Disorder Society [source] Cowden's syndrome (multiple hamartoma and neoplasia syndrome): diagnostic dilemmas in three casesORAL DISEASES, Issue 4 2000SI Chaudhry Cowden's syndrome is a multisystem disease inherited as an autosomal dominant trait with incomplete penetrance and variable expression. The disease has typical oral manifestations which often precede more systemic involvement, and the dental professional is therefore well placed to institute a regime of regular checks to ensure early treatment of any neoplasms which may occur. However, since not all of the classical signs are present in all patients, diagnosis may be difficult. The case report of a patient with most of the features of Cowden's syndrome is presented and features compared with two other possible cases. [source] Current recommendations for the molecular evaluation of newly diagnosed holoprosencephaly patients,,AMERICAN JOURNAL OF MEDICAL GENETICS, Issue 1 2010Daniel E. Pineda-Alvarez§ Abstract Holoprosencephaly (HPE) is the most common structural malformation of the developing forebrain in humans and is typically characterized by different degrees of hemispheric separation that are often accompanied by similarly variable degrees of craniofacial and midline anomalies. HPE is a classic example of a complex genetic trait with "pseudo"-autosomal dominant transmission showing incomplete penetrance and variable expressivity. Clinical suspicion of HPE is typically based upon compatible craniofacial findings, the presence of developmental delay or seizures, or specific endocrinological abnormalities, and is then followed up by confirmation with brain imaging. Once a clinical diagnosis is made, a thorough genetic evaluation is necessary. This usually includes analysis of chromosomes by high-resolution karyotyping, clinical assessment to rule-out well recognized syndromes that are associated with HPE (e.g., Pallister-Hall syndrome, Smith-Lemli-Opitz syndrome and others), and molecular studies of the most common HPE associated genes (e.g., SHH, ZIC2 and SIX3). In this review, we provide current step-by-step recommendations that are medically indicated for the genetic evaluation of patients with newly diagnosed HPE. Moreover, we provide a brief review of several available methods used in molecular diagnostics of HPE and describe the advantages and limitations of both currently available and future tests as they relate to high throughput screening, cost, and the results that they may provide. Published 2010 Wiley-Liss, Inc. [source] Incomplete penetrance and variable expressivity: is there a microRNA connection?BIOESSAYS, Issue 9 2009Jasmine K. Ahluwalia Abstract Incomplete penetrance and variable expressivity are non-Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (miRNA) in fine-tuning gene expression at translational level, we propose miRNA-mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3, UTR, co-expression of target gene,miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles. [source] A family with hereditary hyperferritinaemia cataract syndrome: evidence of incomplete penetrance and clinical heterogeneityBRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2008Luz Gonzalez-Huerta No abstract is available for this article. [source] 2461: Increasing complexity of ocular genetic diseases : the case of BEST diseaseACTA OPHTHALMOLOGICA, Issue 2010M ABITBOL Purpose Monogenic diseases until recently appeared simple from a molecular genetics point of view but correlations between genotypes and phenotypes still remain difficult to establish in many diseases and for many genes. For autosomal dominant diseases such as Best Vitelliform Macular Dystrophy, supposed to be a juvenile disease, it appears that mutations of BEST1 gene can cause multiple phenotypes including early onset and late onset phenotypes as well as unexpected phenotypes such as RP. We report several novel mutations and their associated phenotypes and describe phenotypes linked to previously reoported mutations for which the phenotype had not been describe at all previously. The role of SOX9, MITF and OTX2 in the incomplete penetrance and the variable expressivity of BVMDs is duscussed as well the potential roles of SNPs occuring in coding exons Methods We used genomic PCR with appropriate primers flanking all the exons of the BEST1 gene in order to amplify them. This Genomic PCR was followed by automated sequencing and careful analysis of the sequences obtained. Results We report the case of an unusual family where the Mother II2 of the proband III1, his maternal aunt II3, his brother III3 and his first cousin IIIIV, the son of his maternal aunt, carry a missense mutatation causing apparently only electrophysiological abnormalities. The Father II1 of the proband III1 turned out to carry a stop codon instead of the fifth normal BEST1 codon. The father did not display any electrophysiological nor any clinical abnormality and has a perfect monocular and binocular vision. In contrast the proband III1 carries both mutations with a severe phenotype. Conclusion This report exemplifies the necessity to study all family members in the case of BVMDs. [source] Congenital central hypoventilation syndrome: genotype,phenotype correlation in parents of affected children carrying a PHOX2B expansion mutationCLINICAL GENETICS, Issue 3 2010S Parodi Parodi S, Vollono C, Baglietto MP, Balestri M, Di Duca M, Landri PA, Ceccherini I, Ottonello G, Cilio MR. Congenital central hypoventilation syndrome: genotype,phenotype correlation in parents of affected children carrying a PHOX2B expansion mutation. Congenital Central Hypoventilation Syndrome (CCHS) is a rare genetic disorder. Although most CCHS associated PHOX2B mutations occur de novo, about 10% of the cases are inherited from apparently asymptomatic parents, thus confirming variable expressivity and incomplete penetrance of PHOX2B mutations. Three asymptomatic parents of children affected with CCHS, and found to carry the same PHOX2B expansion mutations as their siblings, were studied by overnight polysomnography and somatic mosaicism analysis. In one case, significant sleep breathing control anomalies were detected, while the other two resulted in normal. In tissue-specific allele studies, mosaicism with a comparatively low mutant allele proportion was showed in the two unaffected adult carriers. Accurate polysomnography and assessment of the degree of somatic mosaicism should be conducted in asymptomatic carriers of PHOX2B mutations, as they may unmask subclinical but significant anomalies [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] | |||||||||||||