bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection of sex chromosomal aneuploidies X‐X, Y‐Y, and X‐Y in human sperm using two‐chromosome fluorescence in situ hybridization
Authors: Wyrobek Andrew J. , Robbins Wendie A. , Mehraein Yasmin , Pinkel Dan , Weier H.‐U.
Published: June 2005

Sex chromosome aneuploidy is the most common numerical chromosomal abnormality in humans at birth and a substantial portion of these abnormalities involve paternal chromosomes. An efficient method is presented for using air‐dried smears of human semen to detect the number of X and Y chromosomes in sperm chromatin using two‐chromosome fluorescence in situ hybridization. Air‐dried semen smears were pre‐treated with dithiothreitol and 3,4‐diio‐dosalicylate salt to decondense the sperm chromatin and then were hybridized with repetitive sequence DNA probes that had been generated by PCR and differentially labeled. Hybridizations with X and Y specific probes showed the expected ratio of 50%X:50%Y bearing sperm. Sperm carrying extra fluorescence domains representing disomy for the X or Y chromosomes occurred at frequencies of ∼4 per 10,000 sperm each. Cells carrying both X and Y fluorescence domains occurred at a frequency of ∼6/10,000. Thus, the overall frequency of sperm that carried an extra sex chromosome was 1.4/1,000. The frequencies of sperm carrying sex chromosome aneuploidies determined by hybridization did not differ statistically from those reported from the same laboratory using the human‐sperm/hamster‐egg cytogenetic technique. Multi‐chromosome fluorescence in situ hybridization to sperm is a promising method for assessing sex‐ratio alterations in human semen and for determining the fraction of sperm carrying sex or other chromosome aneuploidies which may be transmissible to offspring. © 1994 Wiley‐Liss, Inc.
Recurrence of diaphragmatic agenesis associated with multiple midline defects: Evidence for an autosomal gene regulating the midline
Authors: Bird Lynne M. , Newbury Robert O. , Ruiz‐Velasco Rodolfo , Jones Marilyn C.
Published: June 2005

We report the familial occurrence of diaphragmatic agenesis in association with other midline anomalies in a brother and sister. Opitz and Gilbert [Am J Med Genet 1982, 12:443–455] introduced the concept of the midline as a developmental field, and there have been reports of pedigrees compatible with the hypothesis of an X‐linked gene regulating the development of the mid‐line. This family suggests that an autosomal gene also contributes to the morphogenesis of midline structures. © 1994 Wiley‐Liss, Inc.
Possible protection against asthma in heterozygotes for familial Mediterranean fever
Authors: Brenner‐Ullman Adi , Melzer‐Ofir Hana , Daniels Maya , Shohat Mordechai
Published: June 2005

To identify a specific heterozygote advantage in familial Mediterranean fever (FMF), responsible for the high carrier rate of 1/6 in North African Jews, we studied the morbidity and mortality of 148 parents of affected patients and of 148 ethnically matched control persons. Our data demonstrate an apparently reduced prevalence of asthma in the heterozygotes compared with the control persons (3 vs. 6). There were no significant differences between the 2 groups in fertility rate, number of pregnancies and deliveries, or the prevalence of common diseases. Our data are in agreement with previous studies which demonstrated decreased asthma prevalence in FMF patients. If further confirmed, these findings suggest that identification of the FMF gene on 16p may provide an insight into asthma. © 1994 Wiley‐Liss, Inc.
Lethal Pallister‐Killian syndrome: Phenotypic similarity with Fryns syndrome
Authors: Rodríguez José Ignacio , Garcia Isabel , Alvarez Javier , Delicado Alicia , Palacios José
Published: June 2005

The Pallister‐Killian syndrome is a sporadic multiple congenital anomaly syndrome characterized by “coarse” face, profound mental retardation, and epilepsy. Chromosomes of peripheral lymphocytes are usually normal, but tissue cultures show varying degrees of mosaicism for iso‐chromosome 12p.

In babies who die neonatally of severe malformations, including diaphragmatic hernia, and who also have a “coarse” face, acral hypoplasia, and other internal anomalies, Fryns syndrome is more likely to be suspected than Pallister‐Killian syndrome, especially if karyotyping is unavailable or if peripheral lymphocytes have a normal chromosome constitution.

An initial diagnosis of Fryns syndrome had to be modified in 3 successive newborn infants since chromosome analysis or in situ hybridization with a chromosome 12 probe on kidney tissue demonstrated the mosaic aneuploidy characteristic of Pallister‐Killian syndrome. These 3 patients confirm that a similar pattern of malformations can be present in both conditions at birth. It consists of “coarse” face, acral hypoplasia, diaphragmatic hernia, and other defects. Newborn infants who present this pheno‐type, but lack a conclusively normal chromosome test, may not have Fryns syndrome. A diagnosis of Fryns syndrome should be made carefully to avoid the risk of inappropriate genetic counseling. © 1994 Wiley‐Liss, Inc.
Chorionic villus sampling and transverse limb deficiencies: Maternal age is not a confounder
Authors: Mastroiacovo Pierpaolo , Botto Lorenzo D.
Published: June 2005

Advanced maternal age is a frequent indication for performing chorionic villus sampling (CVS) and it might be a confounder of the association between transverse limb deficiencies (TLD) and early CVS. We have first analyzed the maternal age‐specific rates of TLD in the population monitored by the Italian Multicentric Birth Registry; then we updated a case control study controlling for maternal age. The rate of all limb deficiencies (LD) was 5.9 per 10,000 births. No trend for an excess risk for TLD or other LD with advancing maternal age was found. The relative risk for women 35 years of age and older vs. those under 35 was 0.92 (95% CI, 0.72–1.19) for any LD and 0.99 (95% CI, 0.71–1.39) for TLD. In the case control study, 11 mothers of case patients with a TLD had been exposed to CVS out of a total of 206 (5.3%), compared to 54 mothers of control patients with defects other than TLD out of a total of 12,140 (0.4%). The risk estimate for TLD associated with CVS was high in the overall analysis (OR, 12.63) and did not decrease after stratification, both in the overall sample (Mantel‐Haenszel OR, 14.01) and in each gestational age stratum.

Thus, advanced maternal age does not explain the association between CVS and TLD found in this study and it is unlikely to explain that observed in the several other positive studies. We recommend that any study addressing the relationship between CVS and LD should include a careful evaluation of the type of LD and the timing of CVS, and present the results for specific gestational age periods. © 1994 Wiley‐Liss, Inc.
Deformations in infants of diabetic and control pregnancies
Authors: Van Allen Margot I. , Brown Zane A. , Plovie Barbara , Hanson Mary Lou , Knopp Robert H.
Published: June 2005

Severe and mild deformations in newborn infants of insulin dependent diabetic mothers (IDDMs) and control mothers were evaluated with respect to the types of anomalies and previously hypothesized constraint factors. Factors evaluated were gestational length, birth weight, corrected birth weight for gestation (weight ratio), maternal height and parity, and severe deformations. Newborn infants from 81 control and 133 insulin dependent diabetic pregnancies were recruited periconceptually as part of a larger study of diabetes in early pregnancy. Examinations were done at 48 to 72 hours of life by one examiner blinded to maternal status using a checklist of major and minor deformations and malformations.

Mild deformations were found to be common and were present in 84% of newborn infants. Severe deformations occurred in three (1.4%) IDMs, with two of three newborn infants having major malformations involving the CNS and/or musculoskeletal system which affected fetal movement. There was no significant difference between IDMs and control newborn infants with respect to the number with deformations; however, fetal macrosomia was not present in study participants. Using the entire cohort, a significantly greater number of deformations were present in newborn infants with a gestation >36 weeks (P < 0.001), birth weight >3,000 g (P < 0.001), and weight ratio ⩾1.2 (P = 0.05). There was no significant association with primiparous mothers or women with a height <165 cm and the presence of deformations. For gestational age and birth weight, mild deformations were apparent only after 33 weeks gestation (P ≪ 0.001) and/or birth weights of 2.0 kg or more (P ≪ 0.001). Infants with four or more deformations were more likely to have major malformations (P < 0.05).

In summary, in this study the constraint factors determined to be important in the development of mild deformations are gestational length, birth weight and birth weight corrected for gestational length (weight ratio), and severe deformations affecting the neurological and/or musculoskeletal systems. Severe deformations occur more frequently in association with major malformations which affect fetal movement. In IDDM pregnancies, an increase in deformations can be expected with major malformations or with macrosomia Should it occur. © 1994 Wiley‐Liss, Inc.
De novo translocation involving chromosomes 1 and 4 resulting in partial duplication of 4q and partial deletion of 1p
Authors: Legare Janet M. , Sekhon Gurbax S. , Laxova Renata
Published: June 2005

We describe an infant boy with a unique de novo translocation involving chromosomes 1 and 4, resulting in dup(4q) and del(1p). His karyotype was 46,XY,−l,+der(1)t(1;4) (p36.2;q31.2). He had minor anomalies, congenital heart defect, respiratory distress, seizures, and central nervous system abnormalities. He died at age 11 weeks. The patient had manifestations of dup(4q) del(1p), and he was more seriously affected than patients having only one of these. No other patient with an identical chromosomal finding has been reported. © 1994 Wiley‐Liss, Inc.
Child with oral, facial, digital, and skeletal anomalies and psychomotor delay: A new ofds form?
Authors: Gabrielli Orazio , Ficcadenti Anna , Fabrizzi Giancarlo , Perri Paolo , Mercuri Antonio , Coppa Giovanni V. , Giorgi Pierluigi
Published: June 2005

We report on a male infant with oral, facial, digital, and skeletal anomalies in association with severe psychomotor delay. This may represent a new oral‐facial‐digital syndrome. © 1994 Wiley‐Liss, Inc.
18q− and 18q+ mosaicism in a mentally retarded boy
Authors: Ausems Margreet G. E. M. , Bhola Shama L. , Post‐Blok Cornelie A. , Hennekam Raoul C. M. , de France Henny F.
Published: June 2005

A mentally retarded boy was found to have an unusual chromosomal mosaicism [46,XY, del(18) (q22)/46,XY,iso psu dic(18)(q23)]. The clinical manifestations are compatible with the 18q− syndrome. The chromosome alteration was denned by high resolution banding and fluorescence in situ hybridization (FISH). A mechanism to explain the origin of the two cell lines is presented and discussed. © 1994 Wiley‐Liss, Inc.
Ascertainment models incorporating effects of variable age of onset
Authors: Dawson Deborah V.
Published: June 2005

In pedigree analysis, nonrandom sampling, or ascertainment through affected persons, occurs commonly, making it necessary to adjust appropriately for the ascertainment procedure in order to secure the correct interpretation of results from genetic analysis. Ascertainment models for dichotomous phenotypes are considered for disorders characterized by variable age of onset, particularly considering those instances where the probability of ascertainment may be influenced by the age of onset of the disorder. For a variety of theoretical and practical reasons, sigmoidal functions appear to be well suited to the modeling of occurrence of a binary event, such as proband status. Relevant ascertainment models incorporating a modified exponential ascertainment function having such a sigmoidal form are described, together with associated modifications to the likelihood for the ascertained pedigree. Alternative parameterizations and methods for obtaining initial estimates are also discussed. © 1994 Wiley‐Liss, Inc.
Submicroscopic deletion of chromosome region 16p13.3 in a Japanese patient with Rubinstein‐Taybi syndrome
Authors: Masuno Mitsuo , Imaizumi Kiyoshi , Kurosawa Kenji , Makita Yoshio , Petrij Fred , Dauwerse Hans G. , Breuning Martijn H. , Kuroki Yoshikazu
Published: June 2005

In a series of 25 Japanese patients with Rubinstein‐Taybi syndrome, we screened, by high‐resolution GTG banding and fluorescence in situ hybridization of a cosmid probe (RT1, D16S237), for microdeletions associated with this syndrome. In one patient, a microdeletion was demonstrated by in situ hybridization, but none were detected by high‐resolution banding. © 1994 Wiley‐Liss, Inc.
Search for mutations in the β1 GABAA receptor subunit gene in patients with schizophrenia
Authors: Coon Hilary , Sobell Janet , Heston Leonard , Sommer Steve , Hoff Mark , Holik John , Umar Farah , Robertson Margaret , Reimherr Fred , Wender Paul , Vest Kevin , Myles‐Worsley Marina , Gershon Elliot S. , DeLisi Lynn E. , Shields Gail , Dale Paul W. , Polloi Anthony , Waldo Merilyne , Leonard Sherry , Sikela James , Freedman Robert , Byerley William
Published: June 2005

As alterations in GABAergic neurotransmission have been indirectly implicated in the pathogenetics of schizophrenia, GABAA receptor subunit genes are plausible candidate genes for the illness. We undertook a search for sequence variations in the coding region of β1 subunit gene by designing intron‐based primers to amplify its 9 exons. Using single strand conformation polymorphism (SSCP) analysis, we found an exon 9 variant present in 3 of 86 unrelated schizophrenic cases derived from families having at least 2 first degree relatives with schizophrenia. Direct sequencing of the SSCP variant revealed a C→G nucleotide transversion at codon 396 predicting a histidine to glutamine substitution in the β1 peptide. The predicted amino acid substitution occurs at a highly conserved site, 9 residues from a cAMP‐dependent serine phosphorylation consensus sequence. All known GABAA β1 subunit genes including human, bovine, and rat, code for histidine at position 396. Although the variant cosegregated with disease in a family with 2 affected sibs, it was only transmitted to 2 of 3 affected sibs in a multiplex family. The variant was not found in an additional sample comprising 155 unrelated schizophrenics and the sequence variant was present at a low frequency (∼1.1%) in control groups. Although these results indicate that the sequence variant is likely to be a natural polymorphism, it is possible that the variant may be a predisposing allele in rare instances. It is also possible that the variant may change the function or regulation of the GABAA receptor complex and it may be of pharmacogenetic relevance. © 1994 Wiley‐Liss, Inc.
Search for a schizophrenia susceptibility locus on human chromosome 22
Authors: Polymeropoulos Mihael H. , Coon Hilary , Byerley William , Gershon Elliot S. , Goldin Lynn , Crow Timothy J. , Rubenstein Jeffrey , Hoff Mark , Holik John , Smith Angela M. , Shields Gail , Bass Nicholas J. , Poulter Mark , Lofthouse Ray , Vita Antonio , Morganti Carla , Merril Carl R. , Delisi Lynn E.
Published: June 2005

We used 10 highly informative DNA polymorphic markers and genetic linkage analysis to examine whether a gene locus predisposing to schizophrenia is located on chromosome 22, in 105 families with schizophrenia and schizoaffective disorder. The LOD score method, including analysis for heterogeneity, provided no conclusive evidence of linkage under a dominant, recessive, or penetrance free model of inheritance. Affected sib‐pair analysis was inconclusive. Affected pedigree member analysis gave only suggestive evidence for linkage. Multipoint APM analysis, using 4 adjacent loci including D22S281 and IL2RB, a region of interest from the APM analysis, gave non‐significant results for the three different weighting functions. © 1994 Wiley‐Liss, Inc.
Velo‐cardio‐facial syndrome and psychotic disorders: Implications for psychiatric genetics
Authors: Chow Eva W. C. , Bassett Anne S. , Weksberg Rosanna
Published: June 2005

Psychiatric disorders have been reported in over 10% of patients with velo‐cardio‐facial syndrome (VCFS) in long‐term follow‐up. To further explore the behavioral and psychiatric findings associated with VCFS in adulthood, detailed clinical histories of two patients—one with VCFS who developed a psychotic illness, and one with schizophrenia who was found to have dysmorphological features associated with VCFS—are described in the current report. The observed overlap of physical and psychiatric symptoms in these two patients suggests that VCFS and psychotic disorders may share a pathogenetic mechanism. This could be consistent with a contiguous gene model for VCFS and psychosis, suggesting chromosome 22q11 as a possible candidate region for genetic studies of schizophrenia. © 1994 Wiley‐Liss, Inc.
Search for linkage to schizophrenia on the X and Y chromosomes
Authors: DeLisi Lynn E. , Devoto Marcella , Lofthouse Raymond , Poulter Mark , Smith Angela , Shields Gail , Bass Nick , Chen Gang , Vita Antonio , Morganti Carla , Ott Jurg , Crow Timothy J.
Published: June 2005

Markers for X chromosome loci were used in linkage studies of a large group of small families (n = 126) with at least two schizophrenic members in one sibship. Based on the hypothesis that a gene for schizophrenia could be X‐Y linked, with homologous loci on both X and Y, our analyses included all families regardless of the pattern of familial inheritance. Lod scores were computed with both standard X‐linked and a novel X‐Y model, and sibpair analyses were performed for all markers examining the sharing of maternal alleles. Small positive lod scores were obtained for loci pericentromeric, from Xp11.4 to Xq12. Lod scores were also computed separately in families selected for evidence of maternal inheritance and absence of male to male transmission of psychosis. The lod score for linkage to the locus DXS7 reached a maximum of 1.83 at 0.08% recombination, assuming dominant inheritance on the X chromosome in these families (n = 34). Further investigation of the X‐Y homologous gene hypothesis focussing on this region is warranted. © 1994 Wiley‐Liss, Inc.
Family patterns of developmental dyslexia: Clinical findings
Authors: Wolff Peter H. , Melngailis Ilze
Published: June 2005

Two separate groups of dyslexia families were ascertained through probands attending special schools for dyslexic students. An additional control group of families was ascertained through randomly selected students attending public schools. The 3 groups were interviewed by questionnaire about the family's demographic characteristics, and about the incidence of reading and spelling disorders in all first and second order relatives. One group of dyslexia families was also examined by standardized intelligence and academic achievement tests. Developmental dyslexia was found to aggregate in families; there were 4–5 times as many affected males as females among clinically identified students attending the special schools, but the sex ratio of affected relatives after probands had been excluded was approximately 1.4 males for every female. Sibs were at greater risk for reading difficulties when one parent was affected than when neither parent was affected. Sibs were also at greater risk for academic difficulties, and affected sibs were more severely impaired, when the father rather than the mother was the affected parent. In dyslexia families with 2 affected parents, the sibs were at greater risk, and the affected sibs were more severely impaired, than in families where only one parent was affected. Moreover, in families with 2 affected parents, both of the parents were more severely impaired in reading and spelling than parents of the same sex in families with one affected parent. Some indirect evidence is presented that assortative mating may codetermine patterns of affectedness in dyslexia families. © 1994 Wiley‐Liss, Inc.
Variation at the fragile X locus does not influence susceptibility to bipolar disorder
Authors: Craddock Nick , Daniels Jo , McGuffin Peter , Owen Mike
Published: June 2005

Over the last 20 years several pedigrees have been reported which are suggestive of linkage between susceptibility to bipolar disorder and markers on chromosome Xq28. Other workers have failed to replicate these reports and the methodology of the positive reports has been criticised. Recently there have been several reports of an association between fragile X (FRA(X)) and affective disorder within families and in unrelated individuals compared with controls. Such reports could be consistent with the Xq28 marker reports because FRA(X) maps to Xq27.3. We report a study at the FRA(X) CGG repeat locus in 79 unrelated Caucasian bipolar probands without fragile X syndrome and 77 unrelated controls. We found no evidence that variation at this locus confers susceptibility to bipolar disorder. © 1994 Wiley‐Liss, Inc.
Genetic epidemiologic study of hearing loss in an adult population
Authors: Sill Anne M. , Stick Melissa J. , Prenger Valerie L. , Phillips Susan L. , Boughman Joann A. , Arnos Kathleen S.
Published: June 2005

Previous population studies of hearing loss have been limited to children with moderate to profound impairment, and have reported that heritability accounts for at least 50% of congenital or early‐onset cases. The present study was designed to assess genetic factors associated with late‐onset hearing impairment in an adult population. A brief family history and audiologic questionnaire was sent to approximately 11,200 members of the consumer organization, Self Help for the Hard of Hearing, Inc., and 4,039 questionnaires were returned. All respondents reported having at least one previous audiologic exam. Reported data were verified against audiograms when available. Regardless of the reported causes, 49% of early‐onset cases (⩽20 years of age) had one or two parent(s) with some form of hearing loss compared with 62% in later‐onset cases. As expected, mean age at onset was substantially younger for cases with positive family histories than cases with negative family histories. Results from nuclear segregation analysis showed that fully recessive and dominant models failed to explain the early‐ or late‐onset hearing loss data.

In this nationwide survey, the large proportion of cases with positive family histories clearly indicates the importance of genetic factors in adult‐onset forms of hearing loss. Comparison with younger‐onset cases will permit further delineation of differences in inheritance patterns. This study should identify more homogeneous groups of adult‐onset families for further genetic study, and provide empiric information for use in genetic counselling. © 1994 Wiley‐Liss, Inc.
Self‐selection in predictive testing for Huntington's disease
Authors: Codori Ann‐Marie , Hanson Rebecca , Brandt Jason
Published: June 2005

Several studies have reported favorable psychological reactions to predictive testing for Huntington's disease (HD). However, few atrisk persons have been tested, and there is evidence that some at‐risk people avoid testing because they fear being unable to cope with the information. Favorable psychological reactions may result from self‐selection of persons who believe they are better‐equipped to handle “bad news.” We surveyed 32 at‐risk persons who had considered, but not chosen, testing and 66 persons who had been previously tested. Twelve persons decided not to be tested (No group); 20 persons postponed testing until some later date (Maybe group). Of the two untested groups, a significantly greater number of the No group had not been tested because they anticipated problems associated with their emotional reactions. The persons in the Tested group had less often anticipated problems with their emotional reactions; and among the minority who had anticipated some problems, most did not question their ability to cope. We conclude that the Tested persons are psychologically selected for favorable responses to genetic testing.

Surveys of health professionals suggest that a sizable minority would disclose genetic disease risk whether or not people want it. Thus, people who would not choose to be tested might be persuaded to do so, or have results thrust upon them. We should be wary about assuming that the generally favorable reactions to HD testing will continue when testing becomes more widespread, as is likely to happen with simplification of the technology and acceptance of these tests by the medical community. © 1994 Wiley‐Liss, Inc.
Further evidence of no linkage between schizophrenia and the dopamine D3 receptor gene locus
Authors: Nanko Shinichiro , Fukuda Rimmei , Hattori Mineko , Sasaki Tukasa , Dai Xiao Y. , Yamaguchi Kikuyo , Kazamatsuri Hajime
Published: June 2005

The dopamine hypothesis of schizophrenia proposed that dopaminergic pathways are involved in the etiology of the disease. In particular, interest among psychiatrists has focused on the D2 receptor because of its affinity to antipsychotic drugs. Recently a new dopamine receptor gene has been cloned, and named the dopamine D3 receptor. The D3 receptor is a potential site for antipsychotic drug action and may be involved in the pathophysiology of schizophrenia. We have carried out a linkage study between the susceptibility gene for schizophrenia and polymorphism of the dopamine D3 receptor gene in two Japanese pedigrees. The LOD scores were negative for, all genetic models and for all affective status at a recombination fraction θ = 0. Linkage of DRD3 has been excluded for the model 1 (dominant model) and the model13 (recessive model). The LOD score was ‐ 3.43 at θ = 0 for model 1 (dominant model) and broad definition of affected status. These results were consistent with previous studies. © 1994 Wiley‐Liss, Inc.
Elevated risks for amyotrophic lateral sclerosis and blood disorders in Ashkenazi schizophrenic pedigrees suggest new candidate genes in schizophrenia
Authors: Goodman Ann B.
Published: June 2005

Among relatives of Ashkenazi schizophrenic probands the rate of amyotrophic lateral sclerosis was 3/1,000, compared to expected population rates of approximately 2/100,000. Relative risk of bleeding disorders, including hematologic cancers, was increased more than three‐fold compared to controls. Co‐occurrence of motor neuron disease and blood dyscrasias, accompanied by psychosis, has long been recognized. A virally mediated autoimmune pathogenesis has been proposed. However, the familial co‐occurrence of these three disease entities raises the possibility that the disease constellation be considered as a manifestation of a common underlying genetic defect. Such expansion of the spectrum of affectation might enhance the power of both candidate gene and linkage studies. Based on these findings the loci suggested as candidate regions in schizophrenia include a potential hot spot on chromosome 21q21‐q22, involving the superoxide dismutase and amyloid precursor protein genes. Alternatively, genes on other chromosomes involved in the expression, transcription, or regulation of these genes, or associated with the illnesses of high frequency in these pedigrees are suggested. Candidates include the choroid plexus transport protein, transthyretin at 18q 11.2‐q12.1; the t(14;18)(q22;21) characterizing B‐cell lymphoma‐2, the most common form of hematologic cancer; and the 14q24 locus of early onset Alzheimer's disease, c‐Fos, transforming growth factor beta 3, and heat shock protein A2. Expression of hematologic cancers and the suggested candidate genes are known to involve retinoid pathways, and retinoid disregulation has been proposed as a cause of schizophrenia. © 1994 Wiley‐Liss, Inc.
Del(12)(p11.21p12.2) associated with an asphyxiating thoracic dystrophy or chondroectodermal dysplasia‐like syndrome
Authors: Nagai Toshiro , Nishimura Gen , Kato Rumiko , Hasegawa Tomonobu , Ohashi Hirofumi , Fukushima Yoshimitu
Published: June 2005

We describe a 5‐year‐old Japanese boy who has some radiographic findings characteristic of asphyxiating thoracic dystrophy (ATD)‐chondroectodermal dysplasia with a de novo chromosome abnormality. He also has mild mental retardation, short stature, hypoplastic hair and skin, oligodontia, small thoracic cage, hypoplastic pelvis and cone‐shaped epiphyses of hands. On cytogenetic studies he was found to have a de novo del(12)(p11.21p12.2). These results suggest that the locus of the gene associated with ATD‐chondroectodermal dysplasia may be situated at 12p11.21p12.2. © 1995 Wiley‐Liss, Inc.
Proportions of spontaneous mutations in males and females with ornithine transcarbamylase deficiency
Authors: Tuchman Mendel , Matsuda Ichiro , Munnich Arnold , Malcolm Sue , Strautnieks Sandra , Briede Trevor
Published: June 2005

We used specific mutation analysis to estimate the proportions of males and females with ornithine transcarbamylase (OTC) deficiency whose mutations occurred in the germ cells of one of the parents. The mutations were identified in the probands, and subsequently carrier testing was performed on their mothers and some of the grandmothers. Of 28 OTC deficient males, only 2 (7%) had sporadic mutations (95% CI, 0.6–18.5%), whereas of 15 OTC deficient females, 12 (80%) had sporadic mutations (95% CI, 63–99%) (P < 0.001). Based on these results we estimated the male/female mutation rate ratio (ν/μ) in the OTC gene to be approximately 52. Assuming a fitness for males with OTC deficiency of 0 and the proportion of new female mutants at 0.80, the estimated fitness of heterozygous females is 0.4. Because of the difference in mutation rates between male and female germ cells, we suggest that 9/10 or higher, rather than the conventional 2/3 proportion, be applied when estimating prior risk of carrier status in a mother of one affected male. The prior risk of a mother of an affected female is much lower, approximately 2/10. © 1995 Wiley‐Liss, Inc.
Interstitial deletion of the long arm of chromosome 4, del(4)(q28→q31.3)
Authors: Copelli Silvia , Rey Graciela Del , Heinrich Juan , Coco Roberto
Published: June 2005

Interstitial deletions of the long arm of chromosome 4 are rare. Different breakpoints are involved. Only one of the patients had a very similar deletion to that of the present case. Both had low birth weight at term; weight, length and head circumference less than the third centile; epicanthic folds; apparently low‐set abnormal ears; broad nasal bridge; micrognathia; hypoplastic nails; delayed psychomotor development; and mild mental retardation. © 1995 Wiley‐Liss, Inc.
A rapid method for PCR amplification of DNA directly from cells fixed in Carnoy's fixative
Authors: Li Shibo , Tuck‐Muller Cathy M. , Yan Qian , Wertelecki Wladimir , Chen Harold
Published: June 2005

We describe a method for rapid and efficient polymerase chain reaction (PCR) amplification of specific target DNA sequences directly from cells fixed in 3:1 methanol‐acetic acid (Carnoy's fixative) for routine cytogenetic analysis. The fixed cells used had been stored at −20°C from a few weeks up to 6 years. Primer sets used correspond to loci on an autosome (retinoblastoma, RB1), as well as the X (Duchenne muscular dystrophy, DMD) and Y (sex‐determining region of the Y, SRY) chromosomes. Sizes of amplified products were the expected 400, 251 and 609 bps, respectively. No differences in quality of amplification products were found between PCR templates obtained from fresh tissues or from cells fixed for varying lengths of time in Carnoy's fixative. This technique has the following advantages: (1) it allows retrospective studies of genetic disorders from archived specimens; (2) it requires only a limited number of cells; (3) it is rapid and simple; and (4) it avoids multistep procedures required in extraction of the DNA. © 1995 Wiley‐Liss, Inc.
Deletion involving D15S113 in a mother and son without Angelman syndrome: Refinement of the Angelman syndrome critical deletion region
Authors: Michaelis Ron C. , Skinner Steven A. , Lethco Bonné A. , Simensen Richard J. , Donlon Timothy A. , Tarleton Jack , Phelan Mary C.
Published: June 2005

Deletions of 15q11‐q13 typically result in Angelman syndrome when inherited from the mother and Prader‐Willi syndrome when inherited from the father. The critical deletion region for Angelman syndrome has recently been restricted by a report of an Angelman syndrome patient with a deletion spanning less than 200 kb around the D15S113 locus. We report here on a mother and son with a deletion of chromosome 15 that includes the D15S113 locus. The son has mild to moderate mental retardation and minor anomalies, while the mother has a borderline intellectual deficit and slightly downslanting palpebral fissures. Neither patient has the seizures, excessive laughter and hand clapping, ataxia or the facial anomalies which are characteristic of Angelman syndrome. The proximal boundary of the deletion in our patients lies between the D15S10 and the D15S113 loci. Our patients do not have Angelman syndrome, despite the deletion of the D15S113 marker. This suggests that the Angelman syndrome critical deletion region is now defined as the overlap between the deletion found in the previously reported Angelman syndrome patient and the region that is intact in our patients. © 1995 Wiley‐Liss, Inc.
Dubowitz syndrome: Long‐term follow‐up of an original patient
Authors: Hansen Karen E. , Kirkpatrick Susan J. , Laxova Renata
Published: June 2005

Dubowitz syndrome is an autosomal recessive disorder of growth retardation, characteristic face, mild mental retardation, and eczema originally described by Dubowitz [1965]. Little information is available on natural history and adulthood in this disorder. We report on a 30‐year‐old woman who was one of the first patients to be diagnosed with the condition [Grosse et al., 1971, Z Kinderheilkd 110:175–187]. Microcephaly, short stature, leg length discrepancy, hyperextensible joints, spina bifida occulta, and absence of anterior cruciate ligaments were present. Her facial appearance had been modified by several plastic surgery procedures. Eczema resolved with age, with occasional flareups. Asthma, headaches, and seizures were additional medical findings. Speech delays, an unusually soft, high‐pitched voice, submucous cleft palate, and velopharyngeal insufficiency were noted in childhood. Mild mental retardation was present. At age 30 years she is living independently in her own apartment and working full‐time in a nearby sheltered workshop. © 1995 Wiley‐Liss, Inc.
Interstitial deletions 4q21.1q25 and 4q25q27: Phenotypic variability and relation to Rieger anomaly
Authors: Kulharya Anita S. , Maberry Mark , Kukolich Mary K. , Day Donald W. , Schneider Nancy R. , Wilson Golder N. , Tonk Vijay
Published: June 2005

We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months of hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region. © 1995 Wiley‐Liss, Inc.
Paracentric inversions in humans: A review of 446 paracentric inversions with presentation of 120 new cases
Authors: Pettenati M. J. , Rao P. N. , Phelan M. C. , Grass F. , Rao K. W. , Cosper P. , Carroll A. J. , Elder F. , Smith J. L. , Higgins M. D. , Lanman J. T. , Higgins R. R. , Butler M. G. , Luthardt F. , Keitges E. , Jackson‐Cook C. , Brown J. , Schwartz S. , van Dyke D. L. , Palmer C. G.
Published: June 2005

We present a large review of 446 cases of paracentric inversions (PAI), including 120 new cases, to assess their incidence, distribution, inheritance, modes of ascertainment, interchromosomal effects, viable recombinant offspring, and clinical relevance. All 23 autosomes and sex chromosomes had inversions. However, none were identified in chromosome arms 18p, 19q, 20q, and Yp. PAI were most commonly reported in chromosomes 1, 3, 5, 6, 7, 11, and 14 and less frequently in chromosomes 4, 16, 17, 18, 19, 20, 21, 22, and Y. Inversions were most common in chromosome arms 6p, 7q, 11q, and 14q and observed least in chromosome arms 2p, 2q, 3q, 4q, and 6q. Frequently encountered breakpoints included 3(p13p25), 6(p12p23), 6(p12p25), 7(q11q22), and 11(q21q23).

Ascertainment was primarily incidental (54.5%), mental retardation and/or congenital anomalies (22.2%), spontaneous abortions (11.4%), associations with syndromes (3.0%), and infertility (2.0%) accounted for the remainder. Ascertainment was neither related to the length of the inverted segment nor to specific inversions except for PAI of Xq which often presented with manifestations of Ullrich‐Turner syndrome. Sixty‐six percent of PAI were inherited while 8.5% were de novo. Recombination was observed in 17 cases, 15 of which resulted in a monocentric chromosomal deletion or duplication. No common factors were identified that suggested a tendency towards recombination. The incidence of viable recombinants was estimated to be 3.8%.

This review documents that PAI are perhaps more commonly identified than suggested in previous reviews. Despite the possible bias of ascertainment in some cases, there may be associated risks with PAI that require further examination. Our data suggest that PAI carriers do not appear to be free of risks of abnormalities or abnormal progeny and caution is recommended when counseling. © 1995 Wiley‐Liss, Inc.
Heterogeneity in Roberts syndrome
Authors: Allingham‐Hawkins Diane J. , Tomkins Darrell J.
Published: June 2005

Roberts syndrome (RS) is a rare, autosomal recessive condition characterized primarily by growth retardation, developmental delay, and limb anomalies. Some RS patients (RS+), but not others (RS−), have an abnormality of their constitutive heterochromatin (the “RS effect”). RS+ patients also show a cellular hypersensitivity to DNA damaging agents such as mitomycin C (MMC). Lymphoblastoid cell lines from 2 unrelated RS+ patients were fused and hybrid cells examined for correction of the RS effect and MMC hypersensitivity. Neither cellular defect was corrected in the 2 hybrid cell lines examined, suggesting that these 2 patients represent a single complementation group. Fusions were also performed between one RS+ cell line and 2 different RS− cell lines. In both fusions, the hybrids demonstrated correction of both the heterochromatin abnormality and MMC hypersensitivity. These observations suggest that RS+ and RS− patients belong to different complementation groups and do not arise from the same single gene mutation. © 1995 Wiley‐Liss, Inc.
Discordant fibular aplasia in twins
Authors: Paes Bosco A.
Published: June 2005

A male infant, one of monozygotic twins, was born with absence of fibulae, ectrodactyly of the right hand and both feet, with accompanying deficiencies. This second case report of a discordant fibular aplasia developmental field defect occurring in monozygotic twins, although likely sporadic, is interesting because of the similar pattern of anomalies. © 1995 Wiley‐Liss, Inc.
Satellited 4q identified in amniotic fluid cells
Authors: Miller Ivan , Songster Giuliana , Fontana Silvana , Hsieh Chih‐Lin
Published: June 2005

Extra material was identified on the distal long arm of a chromosome 4 in an amniotic fluid specimen sampled at 16.6 weeks of gestational age. There was no visible loss of material from chromosome 4, and no evidence for a balanced rearrangement. The primary counseling issue in this case was advanced maternal age. Ultrasound findings were normal, and family history was unremarkable. The identical 4qs chromosome was observed in cells from a paternal peripheral blood specimen and appeared to be an unbalanced rearrangement. This extra material was NOR positive in lymphocytes from the father, but was negative in the fetal amniocytes. Father's relatives were studied to verify the familial origin of this anomaly. In situ hybridization with both exon and intron sequences of ribosomal DNA demonstrated that ribosomal DNA is present at the terminus of the 4qs chromosome in the fetus, father, and paternal grandmother. This satellited 4q might have been derived from a translocation event that resulted in very little or no loss from the 4q and no specific phenotype. This derivative chromosome 4 has been inherited through at least 3 generations of phenotypically normal individuals. © 1995 Wiley‐Liss, Inc.
Genetic linkage for Darier disease (keratosis follicularis)
Authors: Kennedy James L. , Berg Daniel , Bassett Anne S. , Roy Rochelle , King Nicole , Perkins Michelle
Published: June 2005

Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier disease locus to 12q23–24.1 in British families. We have carried out linkage analysis using the 12q markers D12S58, D12S84, D12S79, D12S86, PLA2, and D12S63 in 6 Canadian families. Pairwise linkage analysis generated positive lod scores at all 6 markers at various recombination fractions, and each family showed positive lod scores with more than one marker. The peak lod score in the multipoint analysis (Zmax) was 5.5 in the interval between markers D12S58 and D12S84. These positive lod scores in North American families of varied European ancestry confirm the location of the Darier disease gene, and suggest genetic homogeneity. The future identification and sequencing of the gene responsible for Darier disease should lead to improved understanding of the disease and of keratinocyte adhesion in general. © 1995 Wiley‐Liss, Inc.
Ulnar ray defect in an infant with a 6q21;7q31.2 translocation: Further evidence for the existence of a limb defect gene in 6q21
Authors: Gurrieri Fiorella , Cammarata Marina , Avarello Rosa Maria , Genuardi Maurizio , Pomponi Maria Grazia , Neri Giovanni , Giuffrè Liborio
Published: June 2005

Ectrodactyly is a developmental defect of the distal limbs characterized by marked clinical variability and genetic heterogeneity, also reflected in the observation of different chromosome abnormalities non randomly associated with longitudinal postaxial limb deficiencies. The one most frequently found in patients with split hand‐split foot (SHSF) involves chromosome band 7q22. Recently, structural anomalies of chromosome 6q21 have been reported in 2 unrelated patients with SHSF, suggesting that this region may also contain genes responsible for limb development [Braverman et al., 1993. Am J Hum Genet, suppl 53: 410; Viljoen and Smart, 1993. Clin Dysmorph 2: 274–277]. We report on a third patient who had a de novo, apparently balanced t(6;7)(q21;q31.2) translocation and bilateral ulnar aplasia with postaxial oligodactyly. In spite of the different phenotypic effects observed in these 3 patients, we consider our case as further evidence that genes in 6q21 may play a role in distal limb development. © 1995 Wiley‐Liss, Inc.
Arthrogryposis multiplex congenita in an Arab kindred: Update
Authors: Jaber Lutfi , Weitz Raphael , Bu Xiangdong , Fischel‐Ghodsian Nathan , Rotter Jerome I. , Shohat Mordechai
Published: June 2005

We have restudied the genetic and clinical characteristics of a large Arab kindred previously reported in 1970 by Lebenthal et al. [Pediatrics 46:891–899].

At total of 40 affected individuals was identified; all, except one, were products of 22 different consanguineous matings between the parents. The syndrome, which is present at birth, is expressed mainly by flexion contractures at the knees and elbows, with muscle hypotrophy/weakness around the involved joints. Five of the 6 individuals who were originally reported as having congenital and lethal heart defects were limited to one sibship. None of the new cases had heart defect or any associated malformation. Neurologic examination and electrophysiological studies demonstrated a neuropathic (non‐myopathic) type of arthrogryposis.

This is an autosomal recessive trait with wide variability in expression and possibly incomplete penetrance in the females. Because of the high consanguinity rate, it allows the use of homozygosity linkage studies to map the gene for this disorder. © 1995 Wiley‐Liss, Inc.
SRY alone can induce normal male sexual differentiation
Authors: López Marisol , Torres Leda , Méndez Juan P. , Cervantes Alicia , Alfaro Guillermo , Pérez‐Palacios Gregorio , Erickson Robert P. , Kofman‐Alfaro Susana
Published: June 2005

Most individuals with the rare 46,XX male “syndrome” arise due to an unequal interchange between Xp and Yp termini during paternal meiosis. The pattern of Y‐sequences in these patients varies considerably, but very few cases have been reported showing only SRY. The phenotype in these patients is also variable ranging from severe impairment of the external genitalia through hypospadias and/or cryptorchidism to occasional normal male phenotype.

We report a Mexican 46,XX male patient without genital ambiguities in whom DNA analysis showed the presence of SRY and the absence of ZFY. We conclude that in this case SRY alone was enough for complete male sexual differentiation. © 1995 Wiley‐Liss, Inc.
In‐frame deletion in the proteolipid protein gene of a family with Pelizaeus‐Merzbacher disease
Authors: Kleindorfer Dawn Olson , Dlouhy Stephen R. , Pratt Victoria M. , Jones Marylin C. , Trofatter James A. , Hodes M. E.
Published: June 2005

We describe an in‐frame deletion of parts of exons 3 and 4 of the proteolipid protein gene (PLP), with all of the intervening sequence, in a 3‐generation family with Pelizaeus‐Merzbacher disease. The mutation removes 49 amino acids of the PLP. © 1995 Wiley‐Liss, Inc.
Numerical syndromology: A mathematical approach to the nosology of complex phenotypes
Authors: Verloes Alain
Published: June 2005

Numerical taxonomy is defined by Sneath and Sokal as the grouping of taxonomic units on the basis of their character states by numerical methods of multivariate data analysis, and syndromology as the study of multiple congenital anomaly (MCA) syndromes and of their nosology. We present here an application of those methods to the analysis of overlapping syndromes. The main advantage of numerical taxonomy is that it allows simultaneous objective and unweighted analysis of multiple traits, giving the possibility to test mathematically the clinical hypotheses about the heterogeneity between closely resembling syndromes and uncovering objective patterns of anomalies, to be compared with the subjective pattern recognition process which characterizes most of the diagnostic approach in syndromology. In this paper, we explored 5 syndromes whose most severe expression belongs to the cerebroacrovisceral early lethality (CAVE) phenotype: hydrolethalus, severe Smith‐Lemli‐Opitz, orofaciodigital type VI (Varadi‐Papp), holoprosencephaly‐polydactyly, and Pallister‐Hall syndromes, Fifty‐five published cases, including many overlapping cases, were submitted to principal factor analysis followed by hierarchical clustering and graphical scaling. Results show that the 5 syndromes clearly constitute independent phenotypic entities, that some of the original diagnoses have to be reconsidered, and that many of the overlapping cases may be unambiguously set in one category. Hypothalamic hamartoblastoma appears to be a nonspecific dysplasia occurring in any of the 5 disorders. © 1995 Wiley‐Liss, Inc.