bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of the I507 deletion by site‐directed mutagenesis
Authors: Orozco Lorena , Friedman Kenneth , Chávez Margarita , Lezana José Luis , Villarreal María Teresa , Carnevale Alessandra
Published: June 2005

We describe a compound heterozygous Δ‐F508/Δ‐I507 cystic fibrosis patient. Molecular analysis by polymerase chain reaction (PCR)‐mediated site‐directed mutagenesis showed the 219 bp fragment observed in Δ‐F508 homozygotes. The father showed a Δ‐F508 heterozygous pattern while the mother and sister showed a normal pattern. There were four possibilities to explain these results: a) the patient was a Δ‐F508/Δ‐I507 compound heterozygote, because the Δ‐I507 allele fails to amplify when analyzed with Δ‐F508 primers due to a double mismatch between the primers and template; b) uniparental isodisomy; c) nonmaternity; and d) sample processing mix‐up.

We then tested for the Δ‐I507 mutation using specific primers with a single base mismatch, and we found that the patient was in fact a compound heterozygote who inherited the Δ‐F508 mutation from the father and the Δ‐I507 from the mother. We underscore the need to detect this rare deletion in patients showing a Δ‐F508 homozygous pattern when one parent, particularly the father, is a noncarrier. © 1994 Wiley‐Liss, Inc.
Distinct phenotype in maternal uniparental disomy of chromosome 14
Authors: Healey Sue , Powell Fiona , Battersby Miriam , Chenevix‐Trench Georgia , McGill James
Published: June 2005

We report on the occurrence of maternal uniparental disomy for chromosome 14 (mUPD14) in a 4‐year‐old girl with a de novo Robertsonian translocation, 45,XX,t (13q,14q). The child has arrested hydrocephalus, short stature, minor anomalies, small hands with hyperextensible joints, and mild to moderate developmental delay. Comparison of her phenotype with those of three previously described individuals show some common distinct traits which suggest a mUPD14 syndrome. © 1994 Wiley‐Liss, Inc.
DNA analysis of an uncommon missense mutation in a Gaucher disease patient of Jewish‐Polish‐Russian descent
Authors: Choy Francis Y. M. , Wei Chao , Applegarth Derek A. , McGillivray Barbara C.
Published: June 2005

Gaucher disease is the most frequent lysosomal lipid storage disease. It results from deficient glucocerebrosidase activity and is transmitted as an autosomal recessive trait. Three clinical forms of Gaucher disease have been described: type 1, non‐neuronopathic; type 2, acute neuronopathic; and type 3, subacute neuronopathic. We have sequenced the full length cDNA of the gluco cerebrosidase gene and identified an uncommon mutation in nucleotide position 1604 (genomic DNA nucleotide position 6683) from a Gaucher disease patient of Jewish‐Polish‐Russian descent with type 1 Gaucher disease. It is a G→A transition in exon 11 that results in 496Arg→496 His of glucocerebrosidase. This missense mutation is present in the heterozygous form and creates a new cleavage site for the endonuclease HphI. We have developed a simple method to detect the presence of this mutation by using HphI restriction fragment length polymorphism analysis of glucocerebrosidase genomic DNA or cDNA. The mutation in the other Gaucher allele of this patient is an A→G transition at cDNA nucleotide position 1226 which creates an XhoI cleavage site after PCR mismatch amplification. The presence of this mutation was also confirmed by sequence analysis. Based on previous reports that mutation 1226 is present only in type 1 Gaucher disease and the observation that there is no neurological involvement in this patient, we conclude that our patient with the 1226/1604 genotype is diagnosed as having type 1 Gaucher disease. Since it was also postulated that mutation 1226 in the homozygous form will usually result in a good prognosis, we speculate that the orthopedic complications and the unusual presence of glomerulosclerosis in this patient may be attributable to the mutation at nucleotide 1604. This speculation will require a description of more patients with this mutation for confirmation. © 1994 Wiley‐Liss, Inc.
Bone dysplasia in a child born to parents with osteogenesis imperfecta and pseudoachondroplasia
Authors: Kitoh Hiroshi , Oki Takashi , Arao Kazuhiko , Nogami Hiroshi
Published: June 2005

We report on a boy born to a mother with pseudoachondroplasia and a father with osteogenesis imperfecta (Sillence type III). At birth, the boy was found to have osteogenesis imperfecta type III. Although clinical findings of pseudoachondroplasia were not manifested at the age of 8 months, roentgenographic findings showed characteristics of pseudoachondroplasia in addition to those of osteogenesis imperfecta. He died of respiratory distress at age 15 months. © 1994 Wiley‐Liss, Inc.
New syndrome: Autosomal dominant microcephaly and radio‐ulnar synostosis
Authors: Giuffrè Liborio , Corsello Giovanni , Giuffrè Mario , Piccione Maria , Albanese Achille
Published: June 2005

To date, the combination of microcephaly and radio‐ulnar synostosis has not been recognized as a distinct clinical and genetic entity. We report on 4 familial cases with this previously undescribed combination of defects, showing autosomal dominant inheritance (Fig. 1). © 1994 Wiley‐Liss, Inc.
Molecular‐neurobehavioral associations in females with the fragile X full mutation
Authors: Abrams Michael T. , Reiss Allan L. , Freund Lisa S. , Baumgardner Thomas L. , Chase Gary A. , Denckla Martha B.
Published: June 2005

In this study, young females with the fragile X [fra(X)] full mutation (fM) were assessed using quantitative measures of mutation amplification size (Amp) as well as the ratio of active normal X chromosome to total normal X chromosome (activation ratio‐AR). Neurobehavioral assessments of females with the fM were performed and included specific and general measures of cognitive and behavioral/developmental functioning. To investigate molecular‐behavioral associations, Amp and AR were used as independent variables, while cognitive and behavioral scores were used as dependent variables. Significant correlations were observed between both molecular variables (Amp and AR) and measures of cognitive functioning, with AR showing the most consistent and robust correlations. As AR increased, overall IQ and specific subtest and area scores from the cognitive tests increased. Conversely, as Amp increased, the overall IQ and specific subtest and area cognitive scores decreased. No significant associations were observed between AR or Amp and measures of behavior or development. The molecular‐cognitive associations were generally consistent with the cognitive profile previously described in studies comparing females with fra(X) to age‐matched controls. Amp and AR were not associated with one another, nor were they associated with the same cluster of cognitive measures. Though this report does not conclusively show that AR and Amp can be used to clinically assess the risk of a female with the fM for cognitive disability, the evidence presented does suggest that these molecular variables, especially AR, reflect important underlying genetic factors contributing to the fra(X) phenotype. © 1994 Wiley‐Liss, Inc.
Obstetrical and gynecological complications in fragile X carriers: A multicenter study
Authors: Schwartz C. E. , Dean J. , Howard‐Peebles P. N. , Bugge M. , Mikkelsen M. , Tommerup N. , Hull C. , Hagerman R. , Holden J. J. A. , Stevenson R. E.
Published: June 2005

We have conducted a multicenter obstetrical and gynecological survey of women in fragile X families. Included in the study were 131 gene carriers (39 with a full mutation and 92 with a premutation) and 109 noncarriers. Analysis indicated that higher numbers of fragile X gene carriers reported having irregular menses and other gynecological complications. As a group they also experienced cessation of menses prior to age 40 years at a significantly higher rate. The data appear to indicate that the FMR1 gene may play a role in the development and proliferation of oogonia. © 1994 Wiley‐Liss, Inc.
Haplotype analysis at the FRAXA locus in the Japanese population
Authors: Richards Robert I. , Kondo Ikuko , Holman Kathy , Yamauchi Masatake , Seki Naohiko , Kishi Kunikazu , Staples Alan , Sutherland Grant R. , Hori Tada‐Aki
Published: June 2005

Fragile X syndrome, one of the most common human genetic diseases, is characterized by a unique genetic mechanism which involves dynamic mutation in a heritable unstable DNA sequence, a p(CCG)n repeat, in the FRAXA locus. It has recently been suggested that a few founder chromosomes are responsible for most fragile X mutations in the Caucasian population. In order to investigate the origin of the fragile X mutations in the Japanese population, we analyzed haplotypes of the FRAXA locus in 40 unrelated fragile X chromosomes and 142 normal X chromosomes in Japanese males, by using two polymorphic AC repeats, FRAXAC1 and FRAXAC2, which flank the fragile site. This analysis provided evidence for founder fragile X chromosomes in the Japanese population, similar to that in Caucasians, although different haplotypes are involved. The distribution of normal allele size of the p(CCG)n repeat among the X chromosomes in the Japanese population is very similar to that reported for Caucasians, except that the most frequent copy number (n = 28) is one copy less than that in Caucasians and that there is an additional peak at 35 copies. There is significant correlation between FRAXAC alleles and the p(CCG)n repeat copy number in non‐fragile X chromosomes, however, alleles with more than 31 copies of the p(CCG)n repeat do not segregate with either of the fragile X common FRAXAC haplotypes. © 1994 Wiley‐Liss, Inc.
Relationship of expansion of CGG repeats and X‐inactivation with expression of fra(X) (q27.3) in heterozygotes
Authors: Mingroni‐Netto Regina C. , Fernandes J. G. , Vianna‐Morgante Angela M.
Published: June 2005

Expression of the fragile site Xq27.3 was investigated in 82 heterozygotes (58 normal and 24 mentally impaired) diagnosed by DNA analysis. EcoRI and EagI DNA digests were probed with StB12.3. This allowed the detection of the expansion of the CGG repeat of the FMR1 gene and the methylation pattern of the adjacent CpG island. Heterozygotes with Δ ≤400 bp (52/82) were all mentally normal and manifested fra(X) in less than 3% of the cells or did not express it. Unmethylated mutant alleles were always observed. About two thirds of females with Δ >500 bp (21/30) showed fra (X) frequencies above 3% (3 normal and 18 mentally impaired). Lower frequencies of fra (X) or negative results were observed in the remaining 9 females (3 normal and 6 affected). The large mutant alleles were always methylated. Therefore, while Δ ⩽400 bp is always associated with negative or low expression of fra (X), larger expansions are not present exclusively in heterozygotes with high frequencies of fra (X).

In 25 of 30 heterozygotes with Δ >500 bp, active and inactive normal alleles were observed. Three fra (X)‐negative or low manifesting heterozygotes showed completely skewed X‐inactivation, with the normal allele either active or inactive. Two females with high frequencies of fra (X) always had the normal allele inactivated. Densitometry studies showed no difference in the inactivation of the normal allele between heterozygotes who manifested fra (X) or not. Thus fra (X) expression does not seem to be influenced by X‐inactivation. © 1994 Wiley‐Liss, Inc.
XLMR genes: Update 1994
Authors: Neri Giovanni , Chiurazzi Pietro , Arena J. Fernando , Lubs Herbert A.
Published: June 2005

We provide a comprehensive list of all known forms of X‐linked mental retardation. It comprises 127 entries, subdivided into 5 categories (syndromes, dominant disorders, metabolic disorders, neuromuscular disorders, and nonspecific mental retardation). Map location of 69 putative loci demonstrates several overlaps, which will only be resolved by more refined mapping or cloning of the respective genes.

The ultimate goal of identifying all the genes on the X chromosome whose mutations cause mental retardation will require a concerted effort between clinical and molecular investigators. © 1994 Wiley‐Liss, Inc.
Pericentromeric genes for non‐specific X‐linked mental retardation (MRX)
Authors: Gedeon Agi , Kerr Bronwyn , Mulley John , Turner Gillian
Published: June 2005

Extensive linkage analyses in three families with non‐specific X‐linked mental retardation (MRX) have localized the gene in each family to the pericentromeric region of the chromosome. The MRX17 gene is localized with a peak lod of 2.41 (θ = 0.0) with the trinucleotide repeat polymorphism at the androgen receptor (AR) gene locus. This gene lies in the interval between the markers DXS255 and DXS990, as defined by recombinants. The MRX18 gene maps to the interval between the markers DXS538 and DXS1126, with a peak lod score of 2.01 (θ = 0.0) at the PFC gene locus. In the third family (Family E) with insufficient informative meioses for assignment of an MRX acronym, the maximum lod score is 1.8 at a recombination fraction of zero for several marker loci between DXS207 and DXS426. Exclusions from the regions of marker loci spanning Xq support the localization of the MRX gene in Family E to the pericentromeric region.

Localizations of these and other MRX genes have determined that MRX2 and MRX19 map to distal Xp, MRX3, and MRX6 map to distal Xq, whilst the majority cluster in the pericentromeric region. In addition, we confirm that there are at least two distinct MRX genes near the centromere as delineated by the non‐overlapping regional localizations of MRX17 and MRX18. Determination of these non‐overlapping localizations is currently the only means of classifying non‐syndromal forms of mental retardation and determining the minimum number of MRX loci. © 1994 Wiley‐Liss, Inc.
Mental retardation and Ullrich‐Turner syndrome in cases with 45,X/46,X,+ mar: Additional support for the loss of the X‐inactivation center hypothesis
Authors: Cole Heath , Huang Bing , Salbert Bonnie Anne , Brown Judith , Howard‐Peebles Patricia N. , Black Susan H. , Dorfmann Andrew , Febles Oscar R. , Stevens Cathy A. , Jackson‐Cook Colleen
Published: June 2005

Four cases having mosaicism for a small marker or ring [45,X/46,X,+mar or 45,X/46,X,+r] chromosome were ascertained following cytogenetic studies requested because of minor anomalies (cases 1, 3, and 4 ) and/or short stature (cases 2 and 4). While all 4 cases had traits typical of Ullrich‐Turner syndrome (UTS), cases 1, 3, and 4 had manifestations not usually present in UTS, including unusual facial appearance, mental retardation/developmental delay (MR/DD) (cases 3 and 4), and syndactylies (case 1). The facial appearances of cases 1 and 3 were similar yet distinct from that of case 4.

Using fluorescence in situ hybridization (FISH), each of the markers in these 4 cases was identified as having been derived from an X chromosome. The level of mosaicism for the mar/r(X) cell line in these cases varied from 70% (case 1) to 16% (case 4) but was not apparently correlated with the presence of MR/DD. Replication studies demonstrated a probable early replication pattern for the mar/r(X) in cases 1,3, and 4, while the marker in case 2 was apparently late replicating.

To date, 41 individuals having mosaicism for a small mar/r(X) chromosome have been described. Interestingly, most of the 14 individuals having a presumedly active mar/r(X) demonstrated clinical findings atypical of UTS, including abnormal facial changes (11) and MR/DD (13). MR was noted most frequently in those cases having at least 50% mosaicism for the marker or ring. In contrast, atypical UTS facial appearance or MR/DD was not noted in 14 of the 16 cases with UTS who carried a probable late replicating marker or ring.

In conclusion, although the phenotype of 45,X/46,X,mar/r(X) individuals appears to be influenced by the genetic content and degree of mosaicism for the mar/r(X), the most significant factor associated with MR/DD appears to be the activity status of the mar/r(X) chromosome. Thus, our 4 cases provide further support for the hypothesis that a lack of inactivation of a small mar/r(X) chromosome may be a factor leading to the MR and other phenotypic abnormalities seen in this subset of individuals having atypical UTS. © 1994 Wiley‐Liss, Inc.
Molecular cytogenetic determination of a deletion/duplication of 1q that results in a trisomy 18 syndrome‐like phenotype
Authors: Mewar Reema , Harrison Wilbur , Weaver David D. , Palmer Catherine , Davee Margaret A. , Overhauser Joan
Published: June 2005

We report on an infant who presented at birth with some characteristics of trisomy 18 syndrome, including low birth weight, facial abnormalities, overlapping fingers, and congenital heart defects. On chromosome analysis, no additional chromosome 18 was observed and both chromosome 18 homologues appeared normal. However, a small piece of chromosomal material of unknown origin was detected at the tip of the long arm of chromosome 1. Fluorescence in situ hybridization (FISH) using whole chromosome 18 painting probes disclosed no additional hybridization at the telomere of 1q, suggesting that the material was derived from another chromosome. Further chromosome painting experiments suggested that the telomeric addition was of chromosome 1 origin. To identify subchromosomal regions involved in the rearrangement, additional FISH analyses were performed using single copy and repetitive DNA probes mapping to different portions of chromosome 1. The analyses showed that probes mapping to 1q34‐43 were duplicated in the derivative chromosome 1. In addition, a DNA probe mapping to 1q44 was found to be deleted from the derivative chromosome 1. Our composite analysis suggests that a deletion and a duplication of chromosome 1q can result in some of the clinical findings usually associated with trisomy 18 syndrome. These results demonstrate the usefulness of FISH analysis when karyotype analysis is not consistent with the clinical description. © 1994 Wiley‐Liss, Inc.
von Voss‐Cherstvoy syndrome: A variable perinatally lethal syndrome of multiple congenital anomalies
Authors: Lubinsky Mark S. , Kahler Stephen G. , Speer Isabell E. , Hoyme H. Eugene , Kirillova Irena A. , Lurie I. W.
Published: June 2005

We report 4 cases and review 7 from the literature with a pattern suggesting a variable early lethal multiple congenital anomaly syndrome. This was first reported by von Voss et al. [1979: “Klinische Genetik in der Pädiatrie,” pp 70–74 ] and Cherstvoy et al. [1980: Lancet ii:485], and can affect upper limbs, face, brain, heart, lungs, urogenital and gastrointestinal systems, vertebrae and ribs, and can include thrombocytopenia. The initial cases had occipital encephaloceles and phocomelia, but milder cerebellar anomalies and radial ray defects may be seen instead. Both sexes are affected and parental age is not increased. This may be heterogeneous, but two consanguineous families, one with recurrences, suggest autosomal recessive inheritance in at least some instances, although the recurrences had milder brain findings than the other cases. The original designation of DK‐pho‐comelia syndrome is inaccurate, since arm findings may be limited to radial anomalies; we suggest instead the von Voss–Cherstvoy syndrome. This may be heterogeneous, but at present, phenotypic overlap prevents differentiation of subgroups. The disorder appears to be part of a group of syndromes with radial and hematologic abnormalities. © 1994 Wiley‐Liss, Inc.
Head circumference of children with Williams‐Beuren syndrome
Authors: Pankau Rainer , Partsch Carl‐J. , Neblung Anke , Gosch Angela , Wessel Armin
Published: June 2005

Head circumference is considered an important parameter of brain growth and development. Syndrome‐specific standards for head circumference in Williams‐Beuren syndrome (WBS) are not available to date, although mental retardation is a leading manifestation in the syndrome. Therefore, we investigated head growth in 63 girls (251 measurements) and 88 boys (298 measurements) with WBS between birth and adulthood. Most measurements in both sexes were from the first 4 years of life (n = 162 in girls and n = 189 in boys). Mean (±SD) head circumference at birth was 33.39 ± 1.38 cm and 34.02 ± 1.44 cm for term girls and boys, respectively.

Although head growth in WBS girls and boys was at a slower velocity, the pattern of head circumference was similar to that in the normal population. After the age of 3 months, head circumference started to fall below the normal mean in girls (0.5–2 cm). In boys, mean head circumference was below the normal mean already at 1 month of age (2 cm). The deficit increased to 3 cm from 6 months to 4 years. Adult OFC was 52.85 ± 1.75 cm (n = 16) compared to 55.70 ± 1.83 cm (n = 46; P < 0.00001) in WBS women and 55.51 ± 1.68 cm (n = 30) compared to 57.87 ± 1.29 cm (n = 31; P < 0.00001) in WBS men. During development, microcephaly is only seen in about one third of WBS patients. © 1994 Wiley‐Liss, Inc.
Mixoploidy in humans: Two surviving cases of diploid‐tetraploid mixoploidy and comparison with diploid‐triploid mixoploidy
Authors: Edwards Matthew J. , Park Jonathan P. , Wurster‐Hill Doris H. , Graham John M.
Published: June 2005

We report on 2 cases of diploid/tetraploid (2n/4n) mixoploidy in surviving females, 11 and 21 years old. Both individuals manifested severe mental retardation, reduced peripheral limb muscle bulk, asymmetric growth deficiency, seizure disorder, and skin pigmentary dysplasia. Previous lymphocyte karyotypes had been normal on 2 occasions, but when skin fibroblast karyotypes were done, 33% of the cells were tetraploid on the younger woman, and over 60% were tetraploid in the older woman (on 2 separate occasions). In both individuals, the distal limbs and digits were long and thin, with reduced small muscle bulk. The similarity in distal limb findings prompted reexamination of the younger woman's chromosomal constitution in skin fibroblasts. We concluded that the clinical findings in these cases are unique and similar, and we caution clinicians about uniformly dismissing tetraploidy as artifactual in amniocytes from normal patients, especially since this phenotype would be very difficult to detect, even with directed prenatal ultrasonography. We compare the 2n/4n phenotype with that in diploid/triploid (2n/3n) mixoploidy and note subtle differences which might be detected postnatally. These findings should be useful in guiding clinicians on when to request skin fibroblast karyotypes in mentally‐deficient individuals with asymmetric growth deficiency and pigmentary skin variation. © 1994 Wiley‐Liss, Inc.
FISH mapping of a human chromosome 16 constitutional pericentric inversion inv(16)(p13q22) found in a large kindred
Authors: Stallings Raymond L. , Bianchi Diana W.
Published: June 2005

Fluorescence in situ hybridization analysis (FISH) was used to map the constitutional chromosome 16 pericentric inversion breakpoints inv(16)(p13q22) detected in one individual (II‐2) from a large kindred [Bianchi et al., 1992: Am J Med Genet 43:791–795]. The breakpoints found in individual II‐2 mapped to distinctly different locations than the chromosome 16 pericentric inversion breakpoints commonly acquired in acute nonlymphocytic leukemia. The constitutional pericentric inversion breakpoints also do not map to regions where low abundance repetitive DNA sequences found in bands 16p13 and q22 are located. The results indicate that low abundance, chromosome 16‐specific repetitive DNA sequences in bands p13 and q22 are probably not causally related to the inversion that is found in many members of a large kindred [Bianchi et al., 1992]. © 1994 Wiley‐Liss, Inc.
Lessons on objectivity in clinical studies
Authors: Harvey Elizabeth A. , Hayes Ailish M. , Holmes Lewis B.
Published: June 2005

Clinical assessments made with measuring devices are generally considered “objective” and “accurate” and are, therefore, more discriminating than subjective assessments. We show that the choice of measuring devices or non‐standardized landmarks to be used with the measuring devices affect the “accuracy” of the “objective” findings. © 1994 Wiley‐Liss, Inc.
OEIS complex with craniofacial anomalies—defect of blastogenesis?
Authors: Haldar Ashutosh , Sharma Anita K. , Phadke Shubha R. , Jain Anita , Agarwal S. S.
Published: June 2005

We report on a 31‐week fetus with hydrocephalus, hypertelorism, microtia, short neck, vertebral and rib defects, scoliosis, omphalocele, exstrophy of bladder, absent external genitalia and pubic rami, imperforate anus, diaphragmatic hernia, defective lobulation of lungs, single kidney, bicornuate uterus, and flexion deformities of the limbs. Similar extensive anomalies in the rostral and caudal regions were described by Russell et al. [Pediatrics, 67:176–182, 1981] and Stewart et al. [Am J Med Genet, 45:426–429, 1993]. The patients described by them had a combination of the oculo‐au‐riculo‐vertebral sequence (OAV) and caudal deficiency sequence, whereas the patient reported here can best be described as a combination of OAV and OEIS (omphalocele, exstrophy of bladder, imperforate anus, spinal defects) complexes. The widespread malformations seen in our patient may be the result of an error during blastogenesis. © 1994 Wiley‐Liss, Inc.
Monozygotic twins of different apparent sex
Authors: Yokota Yukifumi , Akane Atsushi , Fujino Nobuyuki , Sato Yoshiaki , Matsunobu Akira , Matsuura Nobuo , Maeda Tohru , Tadokoro Mamoru , Nakahori Yutaka , Nakagome Yasuo
Published: June 2005

We report on twins of unlike sex who shared a 45, X/46, X, +mar karyotype. The mar chromosome was found to be Yq− by DNA analysis. Marker studies, including 8 VNTR loci, yielded a probability of monozygosity of 0.99999996. © 1994 Wiley‐Liss, Inc.
Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1
Authors: Edwards M. J. , Challinor C. J. , Colley P. W. , Roberts J. , Partington M. W. , Hollway G. E. , Kozman H. M. , Mulley J. C.
Published: June 2005

Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBNl, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uninformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible. © 1994 Wiley‐Liss, Inc.
Bartsoeas–Papas syndrome with internal anomalies: Evidence for a more generalized epithelial defect or new syndrome?
Authors: Hennekam Raoul C. M. , Huber Jonne , Variend Dick
Published: June 2005

We report on two Dutch sibs with external anomalies compatible with Bartsocas–Papas syndrome, who also had internal anomalies: bilateral renal agenesis in one, and esophageal atresia, hypoplastic diaphragma, unilateral renal agenesis, agenesis of the shaft of the penis, and anal atresia in the other patient. Several possible patterns for the pathogenesis of this combination of anomalies are discussed. We propose a generalized epithelial defect, affecting both epidermis and other lining epithelia, as the most probable cause in the present patients. © 1994 Wiley‐Liss, Inc.
Phenotype/Karyotype correlations of Y chromosome aneuploidy with emphasis on structural aberrations in postnatally diagnosed cases
Authors: Hsu Lillian Y. F.
Published: June 2005

Over 600 cases with a Y aneuploidy (other than non‐mosaic 47,XYY) were reviewed for phenotype/karyotype correlations. Except for 93 prenatally diagnosed cases of mosaicism 45,X/46,XY (79 cases), 45,X/47,XYY (8 cases), and 45,X/46,XY/47,XYY (6 cases), all other cases were ascertained postnatally. Special emphasis was placed on structural abnormalities. This review includes 11 cases of 46,XYp‐; 90 cases of 46,XYq‐ (52 cases non‐mosaic; 38 cases 45,X mosaic); 34 cases of 46,X,r(Y) (9 cases non‐mosaic and 25 cases 45,X mosaic); 8 cases of 46,X,i(Yp) (4 non‐mosaic and 4 mosaic with 45,X); 12 cases of 46,X,i(Yq) (7 non‐mosaic and 5 mosaic); 44 cases of 46,X,idic(Yq); 80 cases of 46,X, idic(Yp) (74 cases had breakpoints at Yq11 and 6 cases had breakpoints at Yq12); 130 cases of Y/autosome translocations (50 cases with a Y/A reciprocal translocation, 20 cases of Y/A translocation in 45,X males, 60 cases of Y/Dp or Y/Gp translocations); 52 cases of Y/X translocations [47 cases with der(X); 4 cases with der(Y), and 1 case with 45,X with a der(X)], 7 cases of Y/Y translocations; 151 postnatally diagnosed cases of 45,X/46,XY; 14 postnatally diagnosed cases of 45,X/47,XYY; 18 cases of 45,X/46,XY/47,XYY; and 93 aforementioned prenatally diagnosed cases with a 45,X cell line.

It is clear that in the absence of a 45,X cell line, the presence of an entire Yp or a region of it including SRY would lead to a male phenotype in an individual with a Y aneuploidy, whereas the lack of Yp invariably leads to a female phenotype with typical or atypical Ullrich‐Turner syndrome (UTS). Once there is a 45,X cell line, regardless of whether there is Yp, Yq, or both Yp and Yq, or even a free Y chromosome in other cell line, there is an increased chance for that individual to be a phenotypic female with UTS manifestations or to have ambiguous external genitalia.

This review once again shows a major difference in reported phenotypes between postnatally and prenatally diagnosed cases of 45,X/46,XY, 45,X/47,XYY, and 45,X/46,XY/47,XYY mosaicism. It appears that ascertainment bias can explain the fact that all known patients with postnatal diagnosis are phenotypically abnormal, while over 90% of prenatally diagnosed cases are reported to have a normal male phenotype.

Further elucidation of major Y genes and their clinical significance can be expected in the rapidly expanding gene mapping projects. More, consequently better, phenotype/karyotype correlations can be anticipated at both the cytogenetic and the molecular level. © 1994 Wiley‐Liss, Inc.
Psychosocial functioning in the Ehlers‐Danlos syndrome
Authors: Lumley Mark A. , Jordan Margaret , Rubenstein Ralph , Tsipouras Petros , Evans Mark I.
Published: June 2005

Ehlers‐Danlos Syndrome (EDS) is a group of related genetic disorders of connective tissue presenting with joint hypermobility, skin extensibility, and tissue fragility. Although the pathophysiology of EDS is increasingly understood, the psychosocial effects of having EDS have not been examined. We psychologically tested and interviewed 41 adults and 7 children with EDS. Anxiety, depression, anger, and interpersonal concerns were significantly elevated, varying from one‐quarter to one‐third of patients; over 70% had a history of some mental health care use. Psychological difficulties appear to result from chronic pain and disability, ostracism or avoidance of relationships and social activities, sexual difficulties and reproductive concerns, and frustration with the medical system. Specific types of EDS (e.g., EDS Type I) are associated with greater pain and psychological distress. Psychological intervention, prescribed with the recognition that psychiatric features are secondary to EDS, is recommended for some patients. © 1994 Wiley‐Liss, Inc.
New case of the Carey‐Fineman‐Ziter syndrome
Authors: Baraitser M. , Reardon W.
Published: June 2005

We present a further case, the fourth known to us, of the Carey‐Fineman‐Ziter syndrome. The emergence of a consistent and recognisable phenotype, characterised by hypotonia, weakness, ophthalmoplegia, and a Möbius‐like clinical picture, is emphasised. © 1994 Wiley‐Liss, Inc.
Oblique facial clefts: Report on 4 Brazilian patients. Evidence for clinical variability and genetic heterogeneity
Authors: Richieri‐Costa A. , Gorlin Robert J.
Published: June 2005

Oblique facial clefts are rare and include types 2–6 of Tessier's classification. Here we report on 4 patients with oblique facial clefts and a strikingly similar facial appearance. The pattern of facial involvement, the presence of consanguinity in 3 of them, as well as the entire clinical picture, suggest a unique dysmorphogenetie process which could represent, in some instances, an oculomaxillofacial dysostosis. © 1994 Wiley‐Liss, Inc.
Non‐immune hydrops fetalis associated with impaired fetal movement: A case report and review
Authors: Robin Nathaniel H. , Curtis Mark T. , Mulla Wadia , Reynolds Carol A. , Anday Endla , Rorke Lucy B. , Zackai Elaine H.
Published: June 2005

Non‐immune hydrops fetalis (NIHF) is due to many different causes. Fetal hypomobility has been alluded to as a possible cause. We present a preterm fetus with NIHF secondary to fetal hypomobility. Fetal movements were undetected after the 20th week of gestation. The infant was born 8 weeks later and was edematous, had pleural effusions, and no spontaneous movements. He died on day four of life. Diffuse massive central nervous system (CNS) destruction found on post‐mortem examination was thought to be the origin of the hypomobility. As all other causes of NIHF were eliminated, we propose that the NIHF in this infant was due to the hypomobility. This case then gives support to the assertion that fetal hypomobility is another cause of NIHF. The cause of the CNS catastrophy remains unelucidated. © 1994 Wiley‐Liss, Inc.
Molecular analysis of a complex chromosomal rearrangement and a review of familial cases
Authors: Batista Denise A. S. , Pai G. Shashidhar , Stetten Gail
Published: June 2005

A complex chromosome rearrangement (CCR) involving chromosomes 7, 8, and 13 was detected in a phenotypically normal woman ascertained through her mentally retarded son with abnormal phenotype. He had a karyotype with 47 chromosomes including an extra der(13). In initial banding studies the CCR in the mother was interpreted as a three‐way translocation. Fluorescence in situ hybridization with whole chromosome libraries and a telomerespecific probe was used to better characterize the rearrangement. Combined data allowed us to reinterpret the CCR as a translocation and an insertion. A review of 35 familial CCRs involving at least three chromosomes led to the following observations: 1) familial CCRs tend to have fewer chromosomes involved and fewer breakpoints than do de novo CCRs; 2) familial transmission is mainly observed through female carriers although the origin of de novo cases is paternal; 3) an apparent excess of balanced female carriers among the off‐spring of index carriers was noted; and 4) meiotic segregation resulting in malformed liveborn infants is most frequently due to adjacent‐1 segregation, followed by 4:2 segregation; no adjacent‐2 segregation was observed. © 1994 Wiley‐Liss, Inc.
Chorionic villi sampling: Laboratory experience with 4,000 consecutive cases
Authors: Wang Boris T. , Peng Willow , Cheng Kao‐Tien , Chiu Shui‐Feng , Ho William , Khan Yusuf , Wittman Maria , Williams John
Published: June 2005

Experience with 4,000 consecutive CVS cases shows that 1) the combination of both the direct and culture methods greatly reduces false diagnoses and maternal cell contamination; 2) the time interval between the sampling procedure and processing of villus specimens influences the quality of direct preparations; 3) maternal cell contamination (MCC) can be minimized with dissection of CVS specimens. We have compiled a large volume of confined placen‐tal mosaicism (CPM) cases to serve as a resource in interpreting mosaic cytogenetic findings. It was noted that, in up to 92% of the mosaic cases, the abnormal cell line was confined to the placenta. The frequency of true chromosomal mosaicism was 0.2%, and is not different from that for amniocentesis. © 1994 Wiley‐Liss, Inc.
Deletion of (11)(q24.2) in a mother and daughter with similar phenotypes
Authors: Neavel Celia B. , Soukup Shirley
Published: June 2005

A del(11) (q24.2) was ascertained in a 2‐year‐old child and subsequently in her 20‐year‐old mother. Both mother and daughter had developmental delay, short stature, and “coarse” facial appearance. We compare our patients' manifestations to those associated with the distal 11q2 deletion phenotype (“Jacobsen” syndrome), and to the one other reported case of del(11)(q24.2). Our patients did not resemble this latter case, but had some findings in common with Jacobsen syndrome. We present our findings in order to contribute to the information on 11q2 deletions. © 1994 Wiley‐Liss, Inc.
Social‐emotional and behavioral adjustment in children with Williams‐Beuren syndrome
Authors: Gosch Angela , Pankau Rainer
Published: June 2005

In children with Williams‐Beuren syndrome (WBS), disturbed behaviors (neurotic, antisocial, and hyperactive) [Arnold et al., 1985: Dev Med Child Neurol 27:49–59; Udwin et al., 1987: J Child Psychol Psychiat 28:297–309] have been described.

To study the behavior disturbances and social‐emotional adjustment in children with WBS, a group of N = 19 patients was compared with a control group, matched for age, gender, and nonverbal reasoning abilities. Parents were asked to assess the children's behavior in terms of a list of 20 items of the Child Behavior Checklist (CBCL) [Achenbach and Edelbrock, 1983: Manual for the Child Behavior Checklist] and the Vineland Social Maturity Scale (VSMS) [Lüer et al., 1972: Kurzform der Vineland Social Maturity Scale].

As compared with the control group, children with WBS differ significantly in their social behavior towards strangers. They exhibit no reserve or distancing behavior and would, for instance, follow a stranger without hesitation. They are described as showing a hypersensitivity to sounds that is more pronounced than in the control group. Finally, they are found to be significantly less well‐adjusted socially than the control individuals. © 1994 Wiley‐Liss, Inc.
Molecular analysis of 53 fragile X families with the probe StB12.3
Authors: Puissant H. , Malinge M. C. , Larget‐Piet A. , Martin D. , Chauveau P. , Odent S. , Plessis G. , Parent Ph. , Lemarec B. , Larget‐Piet L.
Published: June 2005

Fifty‐three pedigrees with the fragile X syndrome have been studied for amplification of the CGG repeat sequence adjacent to the CpG island in the FMR1 gene. Probe StB12.3 allowed direct detection of affected males, carrier females, normal transmitting males, as well as prenatal diagnosis. Comparison of our molecular data with our previous linkage data from 38 families indicates the effectiveness of direct DNA analysis. A total of 325 individuals were studied and no new mutation was found. All daughters of males with a premutation had a premutation. When the mother had a full mutation no children had a premutation. In premutated mothers, the size of the premutation seems to be a determining factor for the transition to the full mutation. All affected males had a full mutation or mosaicism and only 42% of the females with a full mutation were mentally impaired. Analysis of large families over 3 generations illustrated clearly the Sherman paradox. Furthermore, the analysis of these families is in reasonable agreement with the multiallelic model of Morton and Macpherson [Proc Natl Acad Sci USA 89:4215–4217, 1992]. Mosaic cases in the offspring of the mothers with a full mutation suggest a maternal germinal mosaicism. Then an abnormal methylation and a somatic heterogeneity established in very early steps of embryogenesis could explain these Cases. © 1994 Wiley‐Liss, Inc.
Failure to find linkage between a functional polymorphism in the dopamine D4 receptor gene and schizophrenia
Authors: Shaikh S. , Gill M. , Owen M. , Asherson P. , McGuffin P. , Nanko S. , Murray R. M. , Collier D. A.
Published: June 2005

We report the results of a linkage study in 24 families multiply affected with schizophrenia using a polymorphic DNA sequence encoding the third cytoplasmic loop of the dopamine D4 receptor. Two‐point LOD score analyses with a range of single gene models ranging from near dominant to near recessive revealed no evidence for linkage. In addition, we examined the data by non‐parametric sib‐pair analysis and found no excess sharing of alleles between affected sib‐pairs. We therefore conclude that mutations within the dopamine D4 receptor gene do not have a major aetiological role in schizophrenia in our collection of pedigrees. © 1994 Wiley‐Liss, Inc.
Psychiatric genetics: Research challenges and pathways forward
Authors: Rutter M.
Published: June 2005

Lessons from past psychiatric genetic research, together with key issues in psychiatry requiring genetic investigation, are reviewed in order to consider the implications for the ways forward. It is argued that traditional quantitative genetics needs to use a combination of twin, adoptee, and family strategies, to examine continuities and discontinuities in psychopathology between childhood and adult life, to compare dimensions and categories, to employ adequate conceptualization and measurement of disorders, to use statistical techniques based on latent constructs, to use biological trait indicators where possible, to examine risk factors as well as diseases, to include good measures of postulated environmental risk variables, to study the interplay between genes and environment, and to study the key assumptions underlying genetic strategies. Molecular cytogenetics needs to consider both the general and specific psychopathological risks associated with chromosome abnormalities and to examine the mechanism involved, to examine the role of submicroscopic chromosomal deletions and of mitochondrial disorders, and to investigate the mechanisms involved in trinucleotide repeat amplifications that take place during intergenerational transmission. Molecular genetics needs to make greater use of smaller pedigrees in view of the concerns over phenotypic definition and genetic heterogeneity in very large extended dense pedigrees, to use sib‐pair designs in view of the likelihood that most psychiatric disorder will prove to be multifactorial, to combine association strategies with linkage analyses, to pay careful attention to the definition of phenotypes in probands, to remain in close touch with other branches of biological psychiatry, and to make effective use of collaboration between centers. To date, transgenic models have had a rather limited application in psychiatry but, despite their difficulties, they are likely to provide an underpinning for gene therapy in disorders where that seems feasible. © 1994 Wiley‐Liss, Inc.
A variety of genetic mechanisms are associated with the Prader–Willi syndrome
Authors: Woodage Trevor , Deng Ze‐Min , Prasad Madhuri , Smart Robert , Lindeman Robert , Christian Susan L. , Ledbetter David H. , Robson Lisa , Smith Arabella , Trent Ronald J.
Published: June 2005

An extensive set of chromosome 15 DNA polymorphisms and densitometric analysis with four markers mapping to the Prader–Willi chromosome region (PWCR) of chromosome 15 have been used to characterize a cohort of 30 subjects with classical Prader–Willi syndrome (PWS). Molecular analysis enabled the classification of the PWS subjects into four groups: (A) 18 subjects (60%) had deletions of paternal 15q11–13 involving a common set of DNA markers. Two subjects had differently sized deletions, one larger and one smaller than the other cases. (B) Eight (27%) had maternal uniparental disomy for chromosome 15. (C) One (3%) had a marker chromosome carrying an extra copy of the PWCR. The marker chromosome was demonstrated to be of paternal origin and the two intact chromosomes were maternally derived. This case represents an apparent exception to the generally held view that PWS is associated with an absence of paternally inherited gene(s) located in the PWCR. (D) The remaining three cases (10%) had none of the above abnormalities. This last subgroup of patients has not previously been well characterized but could represent limited deletions not detectable with the markers used or abnormalities in the imprinting process. These cases represent potentially valuable resources to elucidate more precisely the fundamental disorders responsible for PWS. © 1994 Wiley‐Liss, Inc.
Association analysis of the dopamine D2receptor gene in Tourette's syndrome using the haplotype relative risk method
Authors: Nöthen Markus M. , Hebebrand Johannes , Knapp Michael , Hebebrand Kathrin , Camps Astrid , von Gontard Alexander , Wettke‐Schäfer Roswitha , Lisch Sonja , Cichon Sven , Poustka Fritz , Schmidt Martin , Lehmkuhl Gerd , Remschmidt Helmut , Propping Peter
Published: June 2005

Comings et al. [1991: JAMA 266: 1793–1800] have recently reported a highly significant association between Tourette's syndrome (TS) and a restriction fragment length polymorphism (RFLP) of the dopamine D2receptor gene (DRD2) locus. The A1 allele of the DRD2TaqI RFLP was present in 45% of the Tourette patients compared with 25% of controls. We tried to replicate this finding by using the haplotype relative risk (HRR) method for association analysis. This method overcomes a major problem of conventional case‐control studies, where undetected ethnic differences between patients and controls may result in a false‐positive finding, by using parental alleles not inherited to the proband as control alleles. Sixtyone nuclear families encompassing an affected child and parents were typed for the DRD2TaqI polymorphism. No significant differences in DRD2 A1 allele frequency were observed between TS probands, subpopulations of probands classified according to tic severity, or parental control alleles. Our data do not support the hypothesis that the DRD2 locus may act as a modifying gene in the expression of the disorder in TS probands. © 1994 Wiley‐Liss, Inc.
Association of apolipoprotein E allele ϵ4 with late‐onset sporadic Alzheimer's disease
Authors: Lucotte G. , Visvikis S. , Leininger‐Möler B. , David F. , Berriche S. , Revéilleau S. , Couderc R. , Babron M. C. , Aguillon D. , Siest G.
Published: June 2005

Apolipoprotein E, type ϵ4 allele (ApoE ϵ4), is associated with late‐onset sporadic Alzheimer's disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls forϵ4 allele frequencies). These data support the involvement of ApoEϵ4 allele as a very important risk factor for the clinical expression of AD. © 1994 Wiley‐Liss, Inc.
Mediastinal teratoma and precocious puberty in a boy with mosaic Klinefelter syndrome
Authors: Derenoncourt Ajanta N. , Castro‐Magana M. , Jones Kenneth Lee
Published: June 2005

We describe a boy who developed precocious puberty resulting from chorionic gonadotropin produced by a mediastinal germ cell tumor. Following tumor removal he began spontaneous precocious sexual development which was treated and then arrested spontaneously. Investigation of this arrested puberty established that he had Klinefelter syndrome (KS) mosaicism. He represents the first instance of KS mosaicism reported with a mediastinal germ cell tumor, a neoplasm commonly reported in males with a 47,XXY karyotype. We recommend that all males with KS and early sexual development or with “normal” testicular growth be screened with measurement of germ cell tumor markers including β‐subunit of human chorionic gonadotropin and α‐fetoprotein. © 1995 Wiley‐Liss, Inc.