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ABSTRACT: To analyze the aneuploidy risk and treatment outcome of prenatally diagnosed isolated clubfoot, to determine the false-positive rate (FPR) of ultrasound diagnosis and to calculate the risk of diagnostic revision to complex clubfoot.
By chart review, 65 patients were retrospectively ascertained to have unilateral or bilateral clubfeet diagnosed prenatally. We calculated the rates of false positives, aneuploidy and diagnostic revision to complex clubfoot, and used an ad hoc scoring system to determine orthopedic outcome. Published rates of aneuploidy were pooled and evaluated.
Prenatally diagnosed isolated clubfoot FPR (defined as 1 - positive predictive value) was 10.5% (95% CI, 5.8-18%) (calculated per foot). After a minimum of 1-year postnatal follow-up, 13% (95% CI, 6-26%) of patients had revised diagnoses of complex clubfoot. No patients had aneuploidy identified by cytogenetic analysis or clinical assessment. Of the 34 patients with 2-year postnatal follow-up, 76.5% were treated with serial casting with or without Botox. All children with isolated clubfoot were walking and had an average outcome score of 'very good' to 'excellent'.
When counseling women regarding prenatally diagnosed isolated clubfoot, it is important to tell them that approximately 10% of individuals will have a normal foot or positional foot deformity requiring minimal treatment. Conversely, 10-13% of prenatally diagnosed cases of isolated clubfoot will have complex clubfoot postnatally, based on the finding of additional structural or neurodevelopmental abnormalities. Although this study did not identify an increased risk of fetal aneuploidy associated with isolated clubfoot, a review of the literature indicates a risk of 1.7-3.6% with predominance of sex chromosome aneuploidy.
Ultrasound in Obstetrics and Gynecology 06/2010; 35(6):708-14. · 3.01 Impact Factor
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A M Lehman,
P Eydoux,
D Doherty,
I A Glass,
D Chitayat,
B Y H Chung, S Langlois,
S L Yong,
R B Lowry,
F Hildebrandt,
P Trnka
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ABSTRACT: Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown.
American Journal of Medical Genetics Part A 06/2010; 152A(6):1411-9. · 2.39 Impact Factor
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A.M. Lehman,
P. Eydoux,
D. Doherty,
I.A. Glass,
D. Chitayat,
B.Y.H. Chung, S. Langlois,
S.L. Yong,
R.B. Lowry,
F. Hildebrandt,
P. Trnka
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ABSTRACT: Ciliary disorders share typical features, such as polydactyly, renal and biliary cystic dysplasia, and retinitis pigmentosa, which often overlap across diagnostic entities. We report on two siblings of consanguineous parents and two unrelated children, both of unrelated parents, with co-occurrence of Joubert syndrome and Jeune asphyxiating thoracic dystrophy, an association that adds to the observation of common final patterns of malformations in ciliary disorders. Using homozygosity mapping in the siblings, we were able to exclude all known genes/loci for both syndromes except for INVS, AHI1, and three genes from the previously described Jeune locus at 15q13. No pathogenic variants were found in these genes by direct sequencing. In the third child reported, sequencing of RPGRIP1L, ARL13B, AHI1, TMEM67, OFD1, CC2D2A, and deletion analysis of NPHP1 showed no mutations. Although this study failed to identify a mutation in the patients tested, the co-occurrence of Joubert and Jeune syndromes is likely to represent a distinct entity caused by mutations in a yet to be discovered gene. The mechanisms by which certain organ systems are affected more than others in the spectrum of ciliary diseases remain largely unknown. © 2010 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 05/2010; 152A(6):1411 - 1419. · 2.39 Impact Factor
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ABSTRACT: Sensorineural hearing loss (SNHL) is the most common inherited sensory disorder, reported in 1-3 of every 1,000 births. It has been estimated that 50% of all cases of prelingual SNHL are genetically determined. There is tremendous genetic heterogeneity, with multiple dominant and recessive loci. Mutations of the gap junction beta-2 gene (GJB2) emerge as a leading cause of autosomal recessive non-syndromic SNHL. Over 90 sequence alterations have been reported, the pathogenicity of some of them being unknown or unclear. The status of the V37I allele of connexin 26 (GJB2 amino acid product) with regards to its association with SNHL has been controversial. This study examines the pathogenicity of V37I by comparing the frequency of this allele in 40 patients with SNHL of Chinese and Caucasian descent with the frequency of the allele in 100 anonymized, ethnically matched controls. The V37I allele was identified in 43.75 and 11.5% of the patient and control alleles of Chinese ethnicity, respectively, but was not found in either Caucasian cohort. We also compiled the audiograms of 15 individuals with SNHL homozygous for the V37I allele, and showed that these individuals present with a mild to moderate SNHL. These results indicate that (1) the V37I allele is common in individuals of Chinese descent but rarely present in individuals of Caucasian decent; and (2) the V37I allele is pathogenic, but produces milder hearing loss compared to nonsense mutations of connexin 26 such as the 35delG mutation.
American Journal of Medical Genetics Part A 12/2006; 140(22):2394-400. · 2.39 Impact Factor
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ABSTRACT: Reading to children and storytelling has documented developmental benefits. Traditional Nursery Rhymes (Mother Goose tales in North America) encapsulate 'snapshots' of the people described and chronicle their customs, superstitions, and amusements. Art has long been employed to document the impact of human imperfections and diseases. We investigated whether illustrations accompanying nursery rhymes, suggest that any characters illustrated may have had or been based on recognized morphological abnormalities, and if this literature documents a role for grandmothers as storytellers. Archival materials were reviewed at the Victoria and Albert museum and Mary Evans picture library, and via the web. As early as 1695, Perrault included a frontispiece of a mature woman as storyteller in his book of fairytales. Similar scenes by various artists (Boilly, Cruikshank, Guy, Highmore, Maclise, Richter, and Smith) are found consistently from 1744 to 1908. Many illustrators (Aldin, Caldecott, Cruikshank, Doré, Dulac, Gale, Greenaway, Rackham, Tarrant, and Wood) portray infants, children, and adults who are dwarfed, giant, or whimsically grotesque. Many images certainly suggest genetic syndromes, and in some characters consistency of specific features is evident between artists. Our research confirms the wealth of children's nursery rhyme illustrations suggesting pathology; that an authoritative compilation of the morphologies depicted is lacking; and that historically, grandmothers have a central role as storytellers.
American Journal of Medical Genetics Part A 02/2006; 140(2):180-3. · 2.39 Impact Factor
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C Tyson,
C Harvard,
R Locker,
J M Friedman, S Langlois,
M E S Lewis,
M Van Allen,
M Somerville,
L Arbour,
L Clarke,
B McGilivray,
S L Yong,
J Siegel-Bartel,
E Rajcan-Separovic
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ABSTRACT: Intellectual disability (ID) affects about 3% of the population (IQ < 70), and in about 40% of moderate (IQ 35-49) to severe ID (IQ < 34), and 70% of cases of mild ID (IQ 50-70), the etiology of the disease remains unknown. It has long been suspected that chromosomal gains and losses undetectable by routine cytogenetic analysis (i.e., less than 5-10 Mb in size) are implicated in ID of unknown etiology. Array CGH has recently been used to perform a genome-wide screen for submicroscopic gains and losses in individuals with a normal karyotype but with features suggestive of a chromosome abnormality. In two recent studies, the technique has demonstrated a approximately 15% detection rate for de novo copy number changes of individual clones or groups of clones. Here, we describe a study of 22 individuals with mild to moderate ID and nonsyndromic pattern of dysmorphic features suspicious of an underlying chromosome abnormality, using the 3 Mb and 1 Mb commercial arrays (Spectral Genomics). Deletions and duplications of 16 clones, previously described to show copy number variability in normal individuals [Iafrate et al., 2004; Lapierre et al., 2004; Schoumans et al., 2004; Vermeesch et al., 2005] were seen in 21/22 subjects and were considered polymorphisms. In addition, three subjects showed submicroscopic deletions and duplications not previously reported as normal variants. Two of these submicroscopic changes were of de novo origin (microdeletions at 7q36.3 and a microduplication at 11q12.3-13.1) and one was of unknown origin as parental testing of origin could not be performed (microduplication of Xp22.3). The clinical description of the three subjects with submicroscopic chromosomal changes at 7q36.3, 11q12.3-13.1, Xp22.3 is provided.
American Journal of Medical Genetics Part A 12/2005; 139(3):173-85. · 2.39 Impact Factor
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ABSTRACT: Two cases of trisomy 4 mosaicism are reported including one with molecularly confirmed uniparental disomy (UPD) of chromosome 4. Cytogenetic analysis of a chorionic villus sample (CVS) in Case 1 showed complete trisomy 4 in trophoblast and diploidy in chorionic stroma. Amniotic fluid analysis demonstrated a 46,XX complement. After intrauterine fetal death at 30 weeks, molecular analysis confirmed the presence of trisomy 4 of maternal meiotic origin, while fetal tissues showed maternal UPD for chromosome 4. Cultured CVS in Case 2 revealed trisomy 4 in 2/30 cells analyzed. This pregnancy resulted in a healthy livebirth with biparental inheritance of chromosome 4. Molecularly confirmed UPD4 has not been previously reported, and therefore, although the adverse outcome in Case 1 is likely due to the trisomy 4 in the placenta, an imprinting effect associated with UPD4 cannot be excluded.
Prenatal Diagnosis 02/2001; 21(1):36-9. · 2.11 Impact Factor
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ABSTRACT: Skewed X-chromosome inactivation (XCI) is frequently found in the diploid fetal tissues of individuals with mosaic trisomy that originated from a 'trisomic zygote rescue' event. This may result from a high number of trisomic cells in the embryonic cell pool at the time of XCI, which are subsequently eliminated by selection. We hypothesize that extremely skewed XCI in these mosaic cases will be associated with a poor fetal outcome due to failure to completely eliminate the trisomy from all fetal tissues. To test this hypothesis, XCI status was evaluated in 17 cases of prenatally detected trisomy 16 mosaicism. Ten of the 15 informative cases showed extreme XCI skewing ( > or = 90% inactivation of one allele) in blood or other diploid fetal tissues compared to six of the 111 controls (p < 0.001). Among these 10 'skewed' cases, 6 showed an abnormal outcome, defined as developmental abnormalities and/or intrauterine or neonatal death. In contrast, of the 5 cases without extreme skewing, none showed abnormal outcome, although outcome information was incomplete in 1 case. An additional 6 cases analyzed, involving trisomy mosaicism for other chromosomes, showed similar results. Further studies are warranted to determine if XCI status adds useful information to the prediction of pregnancy outcome in prenatally detected mosaic trisomy.
Clinical Genetics 12/2000; 58(6):436-46. · 3.13 Impact Factor
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ABSTRACT: Triploidy is a common finding both in early spontaneous abortions and in the fetal period. Previous studies suggested that the majority of triploidy was the result of diandry, specifically dispermy. Molecular determination of parental origin in fetal triploids has shown that digyny accounts for the majority of triploids in the fetal period. The aim of this study was to determine the meiotic level at which the error leading to digynic triploidy occurs and to extend the molecular analysis of parental origin of triploidy into the embryonic period. Maternal age of digynic triploids was compared with that of the diandric cases. Using polymorphic pericentromeric markers, we have shown that the majority of digynic triploidy is the result of errors in the second meiotic division. Digyny accounted for the majority of triploids, even in the nonfetal cases. Diandry predominated in a subset of the non-fetal cases in which embryos were not present and in which the placental findings of partial hydatidiform mole (PHM) were encountered. Maternal age differed between the digynic and diandric groups only for the non-fetal cases; this was attributed to differences in ascertainment.
Clinical Genetics 10/2000; 58(3):192-200. · 3.13 Impact Factor
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ABSTRACT: In the practice of clinical genetics chromosomal aneuploidy in both mosaic and nonmosaic forms has long been recognized as a cause of abnormal prenatal and postnatal development. Traditionally, cytogenetic analysis of cultured lymphocytes has been used as a standard test for detection of constitutional aneuploidies. As lymphocytes represent only one lineage, chromosomal mosaicism expressed in other tissues often remains undetected. The purpose of this study was to assess the utilization of molecular cytogenetic analysis for detection of chromosomal aneuploidy in placental tissues. Using placentas from 100 pregnancies with viable nonmalformed livebirths, both trophoblast and chorionic stroma were analyzed using comparative genomic hybridization (CGH). In all cases with an indication of chromosomal imbalance by CGH, fluorescence in situ hybridization (FISH) analysis was performed to confirm the presence of aneuploidy. To differentiate between constitutional aneuploidy and confined placental mosaicism (CPM), amniotic membrane was analyzed by CGH and FISH techniques. Our results demonstrated five placentas with CPM for chromosomes 2, 4, 12, 13, and 18, respectively, and two constitutional nonmosaic aneuploidies (47,XXX and 47,XXY). Molecular cytogenetic studies of human placental tissues enables easy analysis of both embryonic (amnion) and extraembryonic (chorion) cell lineages. Detection at birth of chromosomal defects affecting intrauterine placental and fetal development is important because these chromosomal defects may continue to have an influence on postnatal development.
American Journal of Medical Genetics 07/2000; 92(4):281-4.
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ABSTRACT: The clinical presentation of prenatal and postnatal growth deficiency, triangular face, relative macrocephaly, and body asymmetry is frequently diagnosed as Russell-Silver syndrome (RSS). Maternal uniparental disomy (UPD) of chromosome 7 was reported previously in a small subset of individuals with RSS phenotype or primordial growth retardation. The primary purpose of this study was to identify RSS patients with UPD7 and determine whether or not they present phenotypic findings that distinguish them from RSS patients without UPD7. UPD7 testing was performed in 40 patients with unexplained growth retardation, including 21 patients with a diagnosis of RSS. In addition, a subset of patients was screened with markers spanning chromosome 7 to detect potential microdeletions or segmental uniparental disomy. Two of the RSS cases were identified to have maternal UPD7; no cases with deletion or partial UPD were detected. Together with previously published studies, UPD7 was identified in 11/120 (9%) of individuals with classical RSS phenotype. Our patients with UPD7 and those previously published had a classical RSS phenotype and were not clinically distinguishable from other children diagnosed with RSS.
American Journal of Medical Genetics 12/1999; 87(3):230-6.
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ABSTRACT: The clinical presentation of prenatal and postnatal growth deficiency, triangular face, relative macrocephaly, and body asymmetry is frequently diagnosed as Russell-Silver syndrome (RSS). Maternal uniparental disomy (UPD) of chromosome 7 was reported previously in a small subset of individuals with RSS phenotype or primordial growth retardation. The primary purpose of this study was to identify RSS patients with UPD7 and determine whether or not they present phenotypic findings that distinguish them from RSS patients without UPD7. UPD7 testing was performed in 40 patients with unexplained growth retardation, including 21 patients with a diagnosis of RSS. In addition, a subset of patients was screened with markers spanning chromosome 7 to detect potential microdeletions or segmental uniparental disomy. Two of the RSS cases were identified to have maternal UPD7; no cases with deletion or partial UPD were detected. Together with previously published studies, UPD7 was identified in 11/120 (9%) of individuals with classical RSS phenotype. Our patients with UPD7 and those previously published had a classical RSS phenotype and were not clinically distinguishable from other children diagnosed with RSS. Am. J. Med. Genet. 87:230–236, 1999. © 1999 Wiley-Liss, Inc.
American Journal of Medical Genetics 11/1999; 87(3):230 - 236.
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American Journal of Medical Genetics 11/1999; 86(4):401.
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ABSTRACT: The syndrome of infantile spasms, hypsarrhythmia, and mental retardation (West syndrome) is a classical form of epilepsy, occurring in early infancy, which is etiologically heterogeneous. In rare families, West syndrome is an X-linked recessive condition, mapped to Xp11.4-Xpter (MIM 308350). We have identified a multi-generation family from Western Canada with this rare syndrome of infantile spasms, seen exclusively in male offspring from asymptomatic mothers, thereby confirming segregation as an X-linked recessive trait. Using highly polymorphic microsatellite CA-repeat probes evenly distributed over the entire X chromosome, linkage to markers DXS7110, DXS989, DXS1202, and DXS7106 was confirmed, with a maximum LOD score of 3.97 at a theta of 0.0. The identification of key recombinants refined the disease-containing interval between markers DXS1226 and the adrenal hypoplasia locus (AHC). This now maps the X-linked infantile spasms gene locus to chromosome Xp21.3-Xp22.1 and refines the interval containing the candidate gene to 7.0 cM. Furthermore, this interval overlaps several loci previously linked with either syndromic or non-syndromic X-linked mental retardation (XLMR), including one recognized locus implicated in neuroaxonal processing (radixin, RDXP2). Collectively, these studies lend strong support for the presence of one or more genes intrinsic to brain development and function, occurring within the critical interval defined between Xp21.3-Xp22.1.
Clinical Genetics 04/1999; 55(3):173-81. · 3.13 Impact Factor
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ABSTRACT: The goal of thalassemia screening is the identification, prior to the conception or birth of an affected child, of couples where both partners are thalassemia carriers. When both partners are identified as carriers for alpha- or beta-thalassemia, the risk of having a fetus who is homozygous or compound heterozygous for the abnormal gene is 25%. A study was performed to identify whether routine screening for thalassemia is indicated for the Chinese population in British Columbia (BC). In a population of 783 subjects, studied either prospectively or retrospectively, 5.0% were alpha-thalassemia carriers and 1.7% were beta-thalassemia carriers. In addition, a review of all BC cases of prenatal diagnosis for thalassemia over a 6-year period indicated that 26% of couples were identified as alpha-thalassemia carriers because of a second or third trimester diagnosis of fetal hydrops, and 17% of couples referred for beta-thalassemia already had an affected child. The experience with prenatal diagnosis shows that a significant proportion of at-risk couples are not identified prior to or early in a pregnancy. The prevalence of carriers for thalassemia would warrant a program of education and routine screening for this condition in the BC Asian population.
Clinical Genetics 02/1999; 55(1):20-5. · 3.13 Impact Factor
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P Fang,
E Lev-Lehman,
T F Tsai,
T Matsuura,
C S Benton,
J S Sutcliffe,
S L Christian,
T Kubota,
D J Halley,
H Meijers-Heijboer, S Langlois,
J M Graham,
J Beuten,
P J Willems,
D H Ledbetter,
A L Beaudet
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ABSTRACT: Angelman syndrome (AS) is characterized by mental retardation, absence of speech, seizures and motor dysfunction. AS is caused by maternal deletions for chromosome 15q11-q13, paternal uniparental disomy (UPD), imprinting defects or loss-of-function mutations in the UBE3A locus which encodes E6-AP ubiquitin-protein ligase. The UBE3A gene is imprinted with paternal silencing in human brain and similar silencing of the Ube3a locus in Purkinje cells and hippocampal neurons in the mouse. We have sequenced the major coding exons for UBE3A in 56 index patients with a clinical diagnosis of AS and a normal DNA methylation pattern. The analysis identified disease-causing mutations in 17 of 56 patients (30%) including 13 truncating mutations, two missense mutations, one single amino acid deletion and one stop codon mutation predicting an elongated protein. Mutations were identified in six of eight families (75%) with more than one affected case, and in 11 of 47 isolated cases (23%); no mutation was found in one family with two siblings, one with a typical and one with an atypical phenotype. Mutations were de novo in nine of the 11 isolated cases. An amino acid polymorphism of threonine substituted for alanine at codon 178 was identified, and a 3 bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting with a normal phenotype when a mutation was on the paternal chromosome and an AS phenotype when a mutation was on the maternal chromosome. Laboratory diagnosis and genetic counseling for AS are complex, and mutation analysis is valuable in clinically typical AS patients with a normal methylation analysis.
Human Molecular Genetics 02/1999; 8(1):129-35. · 7.64 Impact Factor
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ABSTRACT: Prenatal diagnosis by chorionic villus sampling (CVS) documents placental chromosomal mosaicism in approximately 2% of viable pregnancies at 9–12 weeks of gestation and can involve various chromosomes and placental cell lineages. Confined placental mosaicism (CPM) is the result of postzygotic mitotic errors occurring in either diploid or trisomic zygotes. With trisomic zygote rescue, depending on the parental origin of the chromosome which is lost, uniparental disomy (UPD) or biparental disomy (BPD) may arise [Kalousek et al., Am J Hum Genet 52: 8–16, 1993].In this paper, we present 14 pregnancies which were diagnosed by CVS as mosaic trisomy 7. All follow-up amniocenteses showed a normal diploid karyotype. Using both classical cytogenetics and interphase analysis, studies of term placentae showed variable levels of trisomy 7. DNA analysis was performed in nine cases to determine whether the diploid fetus had BPD 7 or UPD 7. Fetal UPD 7 was present only in one case; in eight other cases biparental inheritance was demonstrated. DNA analysis to establish the origin of trisomy 7 in the placenta was fully informative in six cases. One trisomy resulted from a meiotic error and was associated with fetal UPD 7, while the rest were somatic in origin.It is difficult to compare the effect of CPM for trisomy 7 to other trisomies confined to the placenta, as for most chromosomes there are few available cases. It appears that intrauterine fetal growth is not greatly affected by the presence of a trisomy 7 cell line in the placenta. This finding is in contrast to the serious effect of high levels of trisomy 16 within the placenta on fetal intrauterine growth in a series of well-documented cases of CPM 16 [Kalousek et al. 1993]. © 1996 Wiley-Liss, Inc.
American Journal of Medical Genetics 12/1998; 65(4):348 - 352.
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W P Robinson,
B D Kuchinka,
F Bernasconi,
M B Petersen,
A Schulze,
K Brondum-Nielsen,
S L Christian,
D H Ledbetter,
A A Schinzel,
B Horsthemke,
S Schuffenhauer,
R C Michaelis, S Langlois,
T J Hassold
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ABSTRACT: Non-disjoined chromosomes 15 from 115 cases of uniparental disomy (ascertained through Prader-Willi syndrome) and 13 cases of trisomy of maternal origin were densely typed for microsatellite loci spanning chromosome 15q. Of these 128 cases a total of 97 meiosis I (MI) errors, 19 meiosis II (MII) errors and 12 mitotic errors were identified. The genetic length of a map created from the MI errors was 101 cM, as compared with a maternal length of 137 cM based on CEPH controls. No significant differences were detected in the distribution of recombination events along the chromosome arm and a reduction was seen for most of the chromosome 15 intervals examined. It was estimated that 21% of tetrads leading to MI non-disjunction were achiasmate, which may account for most or all of the reduction in recombination noted. The mean age of mothers of cases involving MI errors which showed no transitions from heterodisomy to isodisomy was significantly lower (32.7) than cases showing one or more observable transitions (36.3) (P < 0.003, t -test). However, even among chiasmate pairs the highest mean maternal age was seen for multiple exchange tetrads. Chromosome-specific differences in maternal age effects may be related to the normal distribution of exchanges (and their individual susceptibilities) for each chromosome. However, they may also reflect the presence of multiple factors which act to ensure normal segregation, each affected by maternal age in a different way and varying in importance for each chromosome.
Human Molecular Genetics 06/1998; 7(6):1011-9. · 7.64 Impact Factor
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ABSTRACT: Hyperkalemic periodic paralysis (HPP) is caused by mutations of the adult skeletal muscle sodium channel (SCN4A) gene on chromosome 17. Malignant hyperthermia (MH) is a genetically heterogeneous autosomal-dominant disorder occurring in association with various neuromuscular diseases or without other apparent abnormalities. In some families, MH is associated with mutations of a calcium release channel (RYR1) gene on chromosome 19. In other families, linkage of this disorder to the SCN4A gene on chromosome 17 has been suggested. We report on linkage analysis in a family in which both HPP and MH are inherited as autosomal-dominant traits. Two polymorphisms within the SCN4A locus, an RFLP and a (C-A)n repeat, were typed on multiple family members. The findings were consistent with linkage of the polymorphic markers within the SCN4A gene to both HPP (Zmax = 6.79 at theta = 0.0) and MH (Zmax = 1.76 at theta = 0) in this family. Our data provide further evidence that MH is linked to the SCN4A locus in some families.
American Journal of Medical Genetics 02/1998; 76(1):21-7.
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ABSTRACT: The inactivation of one X chromosome in females is normally random with regard to which X is inactivated. However, exclusive or almost-exclusive inactivation of one X may be observed in association with some X-autosomal rearrangements, mutations of the XIST gene, certain X-linked diseases, and MZ twinning. In the present study, a methylation difference near a polymorphism in the X-linked androgen-receptor gene was used to investigate the possibility that nonrandom X inactivation is increases in fetuses and newborns that are associated with confined placental mosaicism (CPM) involving an autosomal trisomy. Extreme skewing was observed in 7 (58%) of 12 cases with a meiotic origin of the trisomy, but in none of 10 cases examined with a somatic origin of the trisomy, and in only 1 (4%) of 27 control adult females. In addition, an extremely skewed X-inactivation pattern was observed in 3 of 10 informative cases of female uniparental disomy (UPD) of chromosome 15. This may reflect the fact that a proportion of UPD cases arise by "rescue" of a chromosomally abnormal conceptus and are therefore associated with CPM. A skewed pattern of X inactivation in CPM cases is hypothesized to result from a reduction in the size of the early-embryonic cell pool, because of either poor early growth or subsequent selection against the trisomic cells. Since approximately 2% of pregnancies detected by chorionic villus sampling are associated with CPM, this is likely a significant contributor to both skewed X inactivation observed in the newborn population and the expression of recessive X-linked diseases in females.
The American Journal of Human Genetics 01/1998; 61(6):1353-61. · 10.60 Impact Factor
