FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W1978392488> ?p ?o ?g. }

• W1978392488 endingPage "369" @default.
• W1978392488 startingPage "367" @default.
• W1978392488 abstract "Hemophilia A is an X‐linked bleeding disorder caused by a wide range of mutations in the factor VIII (F8) gene [1HAMSTeRS haemophilia A Mutation database.http://europium.csc.mrc.ac.uk/; accessed 18 December 2008.Google Scholar]. About one‐third of cases are due to a de novo mutation. The majority are thought to occur in a single germ cell but some, occurring during early embryogenesis, produce a germline and/or somatic mosaic. In hemophilia, somatic mosaicism has been generally observed in women and seems to represent a fairly common event [2Leuer M. Oldenburg J. Lavergne J.M. Ludwig M. Fregin A. Eigel A. Ljung R. Goodeve A. Peake I. Olek K. Somatic mosaicism in hemophilia A: a fairly common event.Am J Hum Genet. 2001; 69: 75-87Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. We report here a case of exceptional mosaicism in the asymptomatic maternal grandfather of a hemophilia A patient. The proband has severe hemophila A with factor (F)VIIIc levels <1% and no previous family history of the disorder. Gene mutation studies were performed in order to identify the deleterious mutation and offer genetic counselling to the mother and the family. The mutation p.Arg336X in exon 8 was identified in the proband by direct sequencing and subsequently searched for in the mother and maternal grandmother. It was found only in the mother, suggesting a de novo germline mutation in one of the grandparents or a de novo somatic mutation early during embryogenesis in the mother. The maternal aunt, who had not been tested, was at first reassured as being probably not a carrier. Several years later, when undergoing medically assisted procreation because of the infertility of her partner, a genetic test was performed. Unexpectedly, the mutation p.Arg336X was identified, leading to a modification of her status as being a carrier of severe hemophilia A. The presence of the mutation in the two sisters thus first suggested the grandmother was a carrier with a somatic mosaicism. The absence of the mutation in her peripheral blood as well as in her buccal and uroepithelial cells, which have different embryological origins, then raised the question of the mechanism of occurrence of this mutation. Linkage analysis, using intragenic and extragenic markers linked to the F8 gene, actually showed that the deleterious allele originated from the asymptomatic maternal grandfather, whose FVIIIc was normal FVIIIc = 96% (Fig. 1). Somatic mosaicism in the grandfather was then hypothesized. However, it is well known that somatic mosaicism may be difficult to detect with conventional methods such as direct sequencing. Mutation‐enrichment procedures, not used during routine test analyses, are often required [2Leuer M. Oldenburg J. Lavergne J.M. Ludwig M. Fregin A. Eigel A. Ljung R. Goodeve A. Peake I. Olek K. Somatic mosaicism in hemophilia A: a fairly common event.Am J Hum Genet. 2001; 69: 75-87Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar]. Nowadays, due to technology progress, methods presenting higher sensitivity are available. One of them, denaturing‐high‐liquid‐pressure‐chromatography (DHPLC) was used in this family. High liquid pressure chromatography is well known for its efficiency to detect heteroduplexes that are DNA molecules containing mismatched base pairs and created during amplification reaction (PCR) when a mutation is present in heterozygosity. Under partial denaturation, heteroduplexes are eluted from the column by an acetonitrile gradient flow before homoduplexes [3Xiao W. Oefner P.J. Denaturing high‐performance liquid chromatography: a review.Hum Mutat. 2001; 17: 439-74Crossref PubMed Scopus (0) Google Scholar]. Analysis of the grandfather’s leucocytes, buccal and uroepithelial cells showed the presence of the mutated allele with a proportion estimated between 15% and 20% (Fig. 1). Karyotype analysis showed a normal 46, XY karyotype, ruling out Klinefelter syndrome. The presence of the mutation in all tested grandpaternal tissues and in his two daughters suggested that the mutation had arisen very early during embryonic development. The distinction between isolated or sporadic cases is of major importance in genetic counselling. A case may appear to be isolated because family size is small; DNA testing may help for carrier diagnosis but negative results will not rule out the possibility of an occult mosaic. In a recent study only a small number (11%) of maternal grandmothers of isolated cases had the mutation in their white blood cells, while 85% of mothers were carriers, which favours the hypothesis that isolated cases may have originated as a de novo germline mutation in one of the grandparents or a de novo somatic mutation early during embryogenesis in the proband’s mother [2Leuer M. Oldenburg J. Lavergne J.M. Ludwig M. Fregin A. Eigel A. Ljung R. Goodeve A. Peake I. Olek K. Somatic mosaicism in hemophilia A: a fairly common event.Am J Hum Genet. 2001; 69: 75-87Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 4Kasper C.K. Lin J.C. Prevalence of sporadic and familial haemophilia.Haemophilia. 2007; 13: 90-2Crossref PubMed Scopus (0) Google Scholar]. Somatic mosaicism has been found in around 10% of mothers of isolated cases [2Leuer M. Oldenburg J. Lavergne J.M. Ludwig M. Fregin A. Eigel A. Ljung R. Goodeve A. Peake I. Olek K. Somatic mosaicism in hemophilia A: a fairly common event.Am J Hum Genet. 2001; 69: 75-87Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar] and in 13% of patients’ mothers and grandmothers in a study which used mutation enrichment procedures [5Peyvandi F. Jayandharan G. Chandy M. Srivastava A. Nakaya S.M. Johnson M.J. Thompson A.R. Goodeve A. Garagiola I. Lavoretano S. Menegatti M. Palla R. Spreafico M. Tagliabue L. Asselta R. Duga S. Mannucci P.M. Genetic diagnosis of haemophilia and other inherited bleeding disorders.Haemophilia. 2006; 12: 82-89Crossref PubMed Scopus (0) Google Scholar]. These results indicate that mosaicism is a fairly common event in hemophilia, but is still underestimated due to the limited sensitivities of the methods for detection of mosaicism and probably also because the distinction between carrier and 50% mosaicism is difficult. It is of note that most of the time mosaicism has been reported in families with point mutations while only once in an isolated case with intron 22 inversion [2Leuer M. Oldenburg J. Lavergne J.M. Ludwig M. Fregin A. Eigel A. Ljung R. Goodeve A. Peake I. Olek K. Somatic mosaicism in hemophilia A: a fairly common event.Am J Hum Genet. 2001; 69: 75-87Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, 5Peyvandi F. Jayandharan G. Chandy M. Srivastava A. Nakaya S.M. Johnson M.J. Thompson A.R. Goodeve A. Garagiola I. Lavoretano S. Menegatti M. Palla R. Spreafico M. Tagliabue L. Asselta R. Duga S. Mannucci P.M. Genetic diagnosis of haemophilia and other inherited bleeding disorders.Haemophilia. 2006; 12: 82-89Crossref PubMed Scopus (0) Google Scholar, 6Oldenburg J. Ros S. El‐Maarri O. Leuer M. Olek K. Müller C.R. Schwaab R. De novo factor VIII gene intron 22 inversion in a female carrier presents as a somatic mosaicism.Blood. 2000; 96: 2905-2906Crossref PubMed Google Scholar]. Somatic mosaicism in families with apparent de novo mutations is, however, rarely explored in women, and grandfathers are usually not considered. In this present case we have been questioned because the proband’s mother and aunt were carriers while the grandmother was not. In the literature only three cases of mosaicism in men have been reported, all of them in grandfathers in families with point mutations [7Casey G.J. Rodgers S.E. Hall J.R. Rudzki Z. Lloyd J.V. Grandpaternal mosaicism in a family with isolated haemophilia A.Br J Haematol. 1999; 107: 560-2Crossref PubMed Scopus (0) Google Scholar, 8Lebo R.V. Koerper M.A. Kim J.H. Chueh J. Golbus M.S. Prenatal diagnosis of hemophilia involving grandpaternal mosaicism.Am J Med Genet. 1993; 47: 401-4Crossref PubMed Scopus (5) Google Scholar, 9Cutler J.A. Mitchell M.J. Smith M.P. Savidge G.F. Germline mosaicism resulting in the transmission of severe hemophilia B from a grandfather with a mild deficiency.Am J Med Genet A. 2004; 129: 13-5Crossref Google Scholar]. Our case underlines that somatic mosaicism in men is probably underestimated because of the difficulties of obtaining blood sample from grandfathers, and points to the need for testing men in such apparent isolated cases. In these situations and even if the mutation is characterized, linkage analysis remains aprecious help in identifying the origin of the deleterious allele. Assessment of mosaicism in mothers of apparent isolated cases is now part of genetic counselling. It also seems important now to take into account the risk of mosaicism in grandfathers as well as grandmothers with a view to the genetic counselling of all their daughters. The authors state that they have no conflict of interest." @default.
• W1978392488 created "2016-06-24" @default.
• W1978392488 creator A5027103743 @default.
• W1978392488 creator A5039171006 @default.
• W1978392488 creator A5065966056 @default.
• W1978392488 creator A5072937166 @default.
• W1978392488 creator A5080571425 @default.
• W1978392488 date "2009-02-01" @default.
• W1978392488 modified "2023-10-14" @default.
• W1978392488 title "Mosaicism in men in hemophilia: is it exceptional? Impact on genetic counselling" @default.
• W1978392488 cites W1964660930 @default.
• W1978392488 cites W2031327112 @default.
• W1978392488 cites W2037919104 @default.
• W1978392488 cites W2038222010 @default.
• W1978392488 cites W2054007006 @default.
• W1978392488 cites W2054762959 @default.
• W1978392488 cites W2085745830 @default.
• W1978392488 cites W4240450516 @default.
• W1978392488 cites W85322748 @default.
• W1978392488 doi "https://doi.org/10.1111/j.1538-7836.2008.03246.x" @default.
• W1978392488 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2695984" @default.
• W1978392488 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/19054320" @default.
• W1978392488 hasPublicationYear "2009" @default.
• W1978392488 type Work @default.
• W1978392488 sameAs 1978392488 @default.
• W1978392488 citedByCount "12" @default.
• W1978392488 countsByYear W19783924882015 @default.
• W1978392488 countsByYear W19783924882016 @default.
• W1978392488 countsByYear W19783924882017 @default.
• W1978392488 countsByYear W19783924882018 @default.
• W1978392488 countsByYear W19783924882019 @default.
• W1978392488 countsByYear W19783924882020 @default.
• W1978392488 countsByYear W19783924882021 @default.
• W1978392488 countsByYear W19783924882023 @default.
• W1978392488 crossrefType "journal-article" @default.
• W1978392488 hasAuthorship W1978392488A5027103743 @default.
• W1978392488 hasAuthorship W1978392488A5039171006 @default.
• W1978392488 hasAuthorship W1978392488A5065966056 @default.
• W1978392488 hasAuthorship W1978392488A5072937166 @default.
• W1978392488 hasAuthorship W1978392488A5080571425 @default.
• W1978392488 hasBestOaLocation W19783924881 @default.
• W1978392488 hasConcept C15744967 @default.
• W1978392488 hasConcept C54355233 @default.
• W1978392488 hasConcept C71924100 @default.
• W1978392488 hasConcept C80227256 @default.
• W1978392488 hasConcept C86803240 @default.
• W1978392488 hasConceptScore W1978392488C15744967 @default.
• W1978392488 hasConceptScore W1978392488C54355233 @default.
• W1978392488 hasConceptScore W1978392488C71924100 @default.
• W1978392488 hasConceptScore W1978392488C80227256 @default.
• W1978392488 hasConceptScore W1978392488C86803240 @default.
• W1978392488 hasIssue "2" @default.
• W1978392488 hasLocation W19783924881 @default.
• W1978392488 hasLocation W19783924882 @default.
• W1978392488 hasLocation W19783924883 @default.
• W1978392488 hasLocation W19783924884 @default.
• W1978392488 hasLocation W19783924885 @default.
• W1978392488 hasLocation W19783924886 @default.
• W1978392488 hasLocation W19783924887 @default.
• W1978392488 hasLocation W19783924888 @default.
• W1978392488 hasOpenAccess W1978392488 @default.
• W1978392488 hasPrimaryLocation W19783924881 @default.
• W1978392488 hasRelatedWork W1506200166 @default.
• W1978392488 hasRelatedWork W1995515455 @default.
• W1978392488 hasRelatedWork W2048182022 @default.
• W1978392488 hasRelatedWork W2080531066 @default.
• W1978392488 hasRelatedWork W2604872355 @default.
• W1978392488 hasRelatedWork W2748952813 @default.
• W1978392488 hasRelatedWork W2899084033 @default.
• W1978392488 hasRelatedWork W3031052312 @default.
• W1978392488 hasRelatedWork W3032375762 @default.
• W1978392488 hasRelatedWork W3108674512 @default.
• W1978392488 hasVolume "7" @default.
• W1978392488 isParatext "false" @default.
• W1978392488 isRetracted "false" @default.
• W1978392488 magId "1978392488" @default.
• W1978392488 workType "article" @default.