bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of imprinting of the Prader–Willi/Angelman region
Authors: Horsthemke Bernhard , Wagstaff Joseph 
Published: July 2008

AbstractPrader–Willi syndrome (PWS) and Angelman syndrome (AS) are two distinct neurodevelopmental disorders, each caused by several genetic and epigenetic mechanisms involving the proximal long arm of chromosome 15. Lack of a functional paternal copy of 15q11–q13 causes PWS; lack of a functional maternal copy of UBE3A, a gene within 15q11–q13, causes AS. This region of chromosome 15 contains a number of imprinted genes that are coordinately regulated by an imprinting center (PWS/AS‐IC) that contains two functional elements, the PWS‐SRO and the AS‐SRO. A chromosome lacking the PWS‐SRO has the maternal state of gene activity and epigenetic modification after either maternal or paternal transmission; a chromosome lacking the AS‐SRO but containing the PWS‐SRO has the paternal state of gene activity and epigenetic modification after either maternal or paternal transmission. The maternal state of chromosome 15q11–q13 is associated with methylation of the PWS‐SRO, while the paternal state is associated with lack of methylation of the PWS‐SRO. Although most models of PWS/AS region imprinting assume that the PWS‐SRO is methylated during oogenesis and that this methylation of the maternal PWS‐SRO is maintained after fertilization, several lines of evidence suggest that the maternal PWS‐SRO is in fact not methylated until after fertilization. Imprinting defects affecting the PWS/AS region can arise from failure to demethylate the PWS‐SRO in the male germ line, from failure to methylate the maternal PWS‐SRO, or from failure to maintain PWS‐SRO methylation after fertilization. © 2008 Wiley‐Liss, Inc.
De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently “balanced” paracentric inversion of 14(q21q23)
Authors: Jiang Yong‐Hui , Martinez Jose E. , Ou Zhishuo , Cooper M. Lance , Kang Sung‐Hae L. , Pursley Amber , Cheung Sau W. 
Published: July 2008

AbstractParacentric inversions are one of the common chromosomal rearrangements typically associated with a normal phenotype. However, if dosage‐sensitive genes are disrupted by the breakpoints, an abnormal phenotype could result. Detection of paracentric inversions often relies on careful high resolution banding, which has limited sensitivity. We report here cytogenetic studies performed on a 4‐year‐old female patient with global developmental delay, hypotonia, and dysmorphic features. The initial cytogenetic evaluation by G‐banding revealed a de novo inversion of chromosome 14. Subsequent array CGH analysis using both a targeted BAC array and a high‐resolution oligonucleotide array revealed microdeletions at the breakpoints of 14q21.1 (0.8 Mb) and 14q23.1 (0.9 Mb). Unexpectedly, a microdeletion in the region of 16q23.1 (1.3 Mb) was also identified, which overlaps with the common fragile site FRA16D. Parental chromosome and FISH analyses were normal, supporting the conclusion that these microdeletions were de novo in the patient and likely contributed to her abnormal phenotype. The case report presented illustrates the value of using high‐resolution microarray analysis for phenotypically abnormal individuals with apparently balanced chromosomal rearrangements, including inversions. © 2008 Wiley‐Liss, Inc.
Analytical and clinical validity of whole‐genome oligonucleotide array comparative genomic hybridization for pediatric patients with mental retardation and developmental delay
Authors: Xiang Bixia , Li Ao , Valentin Dinu , Nowak Norma J. , Zhao Hongyu , Li Peining 
Published: July 2008

AbstractWe performed a pilot study to establish the analytical and clinical validity of whole genome oligonucleotide array comparative genomic hybridization (oaCGH) using the 44,000 oligonucleotide array from Agilent Technologies. DNA specimens from 10 patients with different chromosomal abnormalities were used as the test group and sex mismatched normal male or female DNA as references. A series of DNA mixtures containing 50%, 33%, and 25% of a known deletion was generated to evaluate the analytical capacity of oaCGH on detecting mosaic pattern. Receiver operating characteristic (ROC) curves were computed to evaluate sensitivity, specificity, and analytical resolution for detecting deletions, duplications, and mosaic patterns. The oaCGH detected the chromosomally recognized deletions, duplications, and additional genomic aberrations. Flurorescent in situ hybridization (FISH) assays using targeted BAC clone probes confirmed oaCGH findings. Failure in detecting marker chromosomes, a polymorphic inversion, and a Robertsonian translocation was also noted. The oaCGH achieved 99% sensitivity and 99% specificity with a resolution of 300–500 Kb. It also demonstrated 85% sensitivity and 95% specificity in detecting 50% mosaicism; however, increased test‐to‐test variations and reduced sensitivity were noted as the mosaic percentage decreased. Chromosome and oaCGH analyses on 50 pediatric patients with mental retardation (MR) and developmental delay (DD) delineated the genomic content of chromosomal abnormalities in nine cases, pathogenic genomic disorders in three cases and benign genomic variants in six cases. These results affirmed the analytical and clinical validity of oaCGH and prompted a cytogenomic algorithm to integrate oaCGH, chromosome and FISH analyses for genetic diagnosis. © 2008 Wiley‐Liss, Inc.
Subtelomeric 6p deletion: Clinical and array‐CGH characterization in two patients
Authors: Martinet Danielle , Filges Isabel , Besuchet Schmutz Nathalie , Morris Michael A. , Gaide Anne‐Claude , Dahoun Sophie , Bottani Armand , Addor Marie‐Claude , Antonarakis Stylianos E. , Beckmann Jacques S. , Béna Frédérique 
Published: July 2008

AbstractWe report on two patients with de novo subtelomeric terminal deletion of chromosome 6p. Patient 1 is an 8‐month‐old female born with normal growth parameters, typical facial features of 6pter deletion, bilateral corectopia, and protruding tongue. She has severe developmental delay, profound bilateral neurosensory deafness, poor visual contact, and hypsarrhythmia since the age of 6 months. Patient 2 is a 5‐year‐old male born with normal growth parameters and unilateral hip dysplasia; he has a characteristic facial phenotype, bilateral embryotoxon, and moderate mental retardation. Further characterization of the deletion, using high‐resolution array comparative genomic hybridization (array‐CGH; Agilent Human Genome kit 244 K), revealed that Patient 1 has a 8.1 Mb 6pter‐6p24.3 deletion associated with a contiguous 5.8 Mb 6p24.3‐6p24.1 duplication and Patient 2 a 5.7 Mb 6pter‐6p25.1 deletion partially overlapping with that of Patient 1. Complementary FISH and array analysis showed that the inv del dup(6) in Patient 1 originated de novo. Our results demonstrate that simple rearrangements are often more complex than defined by standard techniques. We also discuss genotype–phenotype correlations including previously reported cases of deletion 6p. © 2008 Wiley‐Liss, Inc.
Molecular and clinical characterization of two patients with Prader–Willi syndrome and atypical deletions of proximal chromosome 15q
Authors: Calounova Gabriela , Hedvicakova Petra , Silhanova Eva , Kreckova Gabriela , Sedlacek Zdenek 
Published: July 2008

AbstractPrader–Willi syndrome (PWS) is caused by the disturbed expression of genes from the imprinted region of 15q11‐q13, but the specific contributions of individual genes remain unknown. Most paternal PWS deletions are bracketed by recurrent breakpoints BP1 or BP2 and BP3. Atypical deletions are very rare. In the present work, we describe the molecular analysis of two patients with atypical deletions using microsatellite analysis, methylation‐specific MLPA, and microarray CGH. A deletion of about 2 Mb in Patient 1 started at BP2 and ended in the middle of the typically deleted region within the UBE3A gene. The deletion in Patient 2 started 1.3 Mb distal from BP2 within the C15ORF2 gene, extended over 9.5 Mb, and ended within the AVEN gene in proximal 15q14. In Patient 1 both deletion breakpoints involved repetitive regions, which precluded cloning of the junction and pointed to non‐allelic homologous recombination as a possible mechanism of this rearrangement. The breakpoints in Patient 2 were sequenced, and their structure suggested non‐homologous end joining as the most likely cause of this deletion. The phenotype of both patients did not depart significantly from the typical clinical picture of PWS, although some symptoms in Patient 2 were also reminiscent of the phenotype of individuals with the recently described 15q13.3 microdeletion syndrome. Our findings support previous observations of relatively mild phenotypic effects resulting from deletions that extend distally from the PWS region and observations of the modest effects of different types of genetic defects on the spectrum and severity of symptoms in PWS. © 2008 Wiley‐Liss, Inc.
Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt–Hopkins syndrome
Authors: Kalscheuer Vera M. , Feenstra Ilse , Van Ravenswaaij‐Arts Conny M.A. , Smeets Dominique F.C.M. , Menzel Corinna , Ullmann Reinhard , Musante Luciana , Ropers Hans‐Hilger 
Published: July 2008

AbstractWe have characterized a de novo balanced translocation t(18;20)(q21.1;q11.2) in a female patient with mild to moderate mental retardation (MR) and minor facial anomalies. Breakpoint‐mapping by fluorescence in situ hybridization indicated that on chromosome 18, the basic helix‐loop‐helix transcription factor TCF4 gene is disrupted by the breakpoint. TCF4 plays a role in cell fate determination and differentiation. Only recently, mutations in this gene have been shown to result in Pitt–Hopkins syndrome (PHS), defined by severe MR, epilepsy, mild growth retardation, microcephaly, daily bouts of hyperventilation starting in infancy, and distinctive facial features with deep‐set eyes, broad nasal bridge, and wide mouth with widely spaced teeth. Breakpoint mapping on the derivative chromosome 20 indicated that here the rearrangement disrupted the chromodomain helicase DNA binding protein 6 (CHD6) gene. To date, there is no indication that CHD6 is involved in disease. Our study indicates that TCF4 gene mutations are not always associated with classical PHS but can give rise to a much milder clinical phenotype. Thus, the possibility exists that more patients with a less severe encephalopathy carry a mutation in this gene. © 2008 Wiley‐Liss, Inc.
Mental health and quality of life after genetic testing for Huntington disease: A long‐term effect study in Germany
Authors: Licklederer Claudia , Wolff Gerhard , Barth Jürgen 
Published: July 2008

AbstractPredictive genetic testing for Huntington disease (HD) might cause severe short‐term psychological reactions in patients with poor mental health. Very few studies exist on the long‐term effects of genetic HD testing. The aim of this study was to assess mental health and quality of life in persons who were tested for HD mutation, to compare mental health depending on the result of the genetic test (non‐carriers, gene carriers, and patients with HD) and to identify predictors of mental health and quality of life via linear regression. The data were collected by self‐report questionnaires. In total, 121 individuals participated in this study: 52 were non‐carriers, 54 were gene carriers, and 15 were gene carriers suffering from HD. Non‐carriers and gene carriers showed better mental health and quality of life than HD‐patients but did not differ from each other. In non‐carriers four variables predicted increased depression and low mental quality of life: low perceived social support, no intimate relationship, female sex and younger age. For gene carriers three predictors were found: low perceived social support, the expectation of an unfavorable genetic test result before the testing procedure and being childless. To prevent detrimental effects of HD testing on mental health and mental quality of life, specific attention should be paid to persons with limited social networks during genetic counseling. Assessment of expectations related to the test result and mental health prior to a genetic testing procedure may help to identify gene carriers at risk of poor coping after an unfavorable test result. © 2008 Wiley‐Liss, Inc.
Radiological evolution in IMAGe association: A case report
Authors: Amano Naoko , Naoaki Hori , Ishii Tomohiro , Narumi Satoshi , Hachiya Rumi , Nishimura Gen , Hasegawa Tomonobu 
Published: July 2008

AbstractIMAGe association is a recently recognized multi‐system disorder of unknown etiology. IMAGe is a mnemonic acronym that stands for Intrauterine growth retardation, Metaphyseal dysplasia, Adrenal hypoplasia congenita, and Genital anomalies (OMIM 300290). Suspicion for the disorder is readily raised by the distinctive clinical and endocrinological constellation, and radiological identification of metaphyseal dysplasia is crucial for the diagnosis. However, knowledge of the onset, evolution, severity, and variation of the metaphyseal dysplasia is currently limited. We illustrate the radiological evolution of an affected girl from her premature birth to early childhood. Her initial skeletal changes included thin ribs, delayed ossification of the juxtatruncal bones, and delayed epiphyseal ossification. The former two became less conspicuous during infancy. Metaphyseal dysplasia was not discerned at birth. However, mild metaphyseal cupping, sclerosis and longitudinal striations became manifest in late infancy, and then progressed with age. It is thought that the skeletal alterations in IMAGe association encompass retarded endochondral ossification normalized later on and mild metaphyseal dysplasia of postnatal onset. © 2008 Wiley‐Liss, Inc.
Schilbach–Rott/blepharofacioskeletal syndrome in a Brazilian patient
Authors: Carvalho Daniel Rocha de , Rossi Natalia Freitas , Schellini Silvana , Moretti‐Ferreira Danilo , Richieri‐Costa Antônio 
Published: July 2008

AbstractWe report on a 4‐year‐old girl with blepharophimosis, a typical facial gestalt and skeletal abnormalities seen in the blepharofacioskeletal syndrome (BFSS). A comparative review with previous cases provides further evidence that BFSS and Schilbach–Rott syndrome (SRS) are the same condition. © 2008 Wiley‐Liss, Inc.
Monozygotic twins discordant for trisomy 21 and maternal 21q inheritance: A complex series of events
Authors: Dahoun Sophie , Gagos Sarantis , Gagnebin Maryline , Gehrig Corinne , Burgi Carole , Simon Fabienne , Vieux Chantal , Extermann Philippe , Lyle Robert , Morris Michael A. , Antonarakis Stylianos E. , Béna Frédérique , Blouin Jean‐Louis 
Published: July 2008

AbstractWe report on a monochorionic/diamniotic twin pregnancy discordant for trisomy 21. Amniocentesis (at ${\rm 13}{\raise0.5ex\hbox{$\scriptstyle {\rm 5}$}\kern-0.1em/\kern-0.15em\lower0.25ex\hbox{$\scriptstyle {\rm 7}$}}$ weeks) was performed following ultrasound signs of hydrops and cystic hygroma in twin 1 (T1). Prenatal karyotype showed non‐mosaic trisomy 21 in T1 (47,XX,+21[7]), and low‐grade mosaic trisomy 21 in twin 2 (T2) (47,XX,+21[2]/46,XX[19]). Post mortem examination of fetal skin, kidneys and lungs confirmed trisomy 21 in T1 (47,XX,+21[548]) and the placenta (47,XX,+21[200]). T2 had a normal karyotype (46,XX[648]). Analysis of microsatellite polymorphisms in multiple samples from the placenta, hand, lungs, kidneys and the umbilical cords of both twins confirmed monozygosity for all loci tested, and trisomy 21 in T1. Unexpectedly, T1 and T2 inherited different maternal alleles for markers of the most distal 4 Mbp of 21q. At least four successive events are needed to explain the genetic status of both twins and include maternal MI premature chromatids separation or maternal II meiotic nondisjunction and post‐zygotic events such as, chromosome rescue, nondisjunction, an/or recombination. © 2008 Wiley‐Liss, Inc.
Pierre Robin sequence associated with first trimester fetal tamoxifen exposure
Authors: Berger Joel C. , Clericuzio Carol L. 
Published: July 2008

AbstractTamoxifen is a nonsteroidal antiestrogen used as the current adjuvant endocrine treatment of choice for premenopausal women treated for breast cancer and its potential for causing fetal harm during pregnancy remains inconclusive. While the evidence of tamoxifen's effects on humans in utero is minimal, animal studies have shown evidence of teratogenicity, hence the FDA's class D categorization of the drug. In 1994 Cullins et al. published a case report entitled “Goldenhar's Syndrome Associated with Tamoxifen Given to the Mother During Gestation.” At the time of publication, the authors noted that the manufacturer of tamoxifen knew of two cases associated with tamoxifen administration which resulted in congenital craniofacial defects. Cullins' case of Goldenhar syndrome is also a craniofacial disorder and thus represented the third such case. We report on the fourth case of a tamoxifen‐associated craniofacial anomaly. The mother became pregnant while undergoing tamoxifen therapy for breast cancer. A child with severe micrognathia and cleft palate was born. It is noteworthy that the two patterns of craniofacial malformations in tamoxifen exposed infants—Goldenhar syndrome in Cullins' et al. case and Pierre Robin sequence reported here—have also both been observed in isotretinoin exposed infants. While a larger spectrum of anomalies is characteristic of retinoic acid embryopathy, the specific craniofacial anomalies include facial asymmetry, microtia, micrognatha and U‐shaped cleft of the secondary palate, that is, malformations seen in the two tamoxifen exposed infants. Therefore, it is conceivable that these two agents could produce comparable embryotoxic effects if they function in a like way during embryogenesis. While the majority of tamoxifen exposed infants are normal, the ascertainment of teratogenic effects from tamoxifen will best be determined by data from teratogen registries. © 2008 Wiley‐Liss, Inc.
The CASK gene harbored in a deletion detected by array‐CGH as a potential candidate for a gene causative of X‐linked dominant mental retardation
Authors: Hayashi Shin , Mizuno Seiji , Migita Ohsuke , Okuyama Torayuki , Makita Yoshio , Hata Akira , Imoto Issei , Inazawa Johji 
Published: July 2008

AbstractHere we report on a 5‐year‐old Japanese girl with developmental delay and microcephaly. Although she had a normal karyotype, a bacterial artificial chromosome‐based array‐comparative genome hybridization analysis detected a de novo 4.0‐Mb heterozygous deletion at Xp11.3–p11.4 harboring nine genes. By comparison with a healthy carrier mother of a boy with atypical Norrie disease having a smaller deletion in the same region, we excluded four genes as candidates whose haploinsufficiency would be causative for developmental delay. Among the other five genes, CASK seems to be the most likely candidate for a causative gene, because it is strongly expressed in fetal brain and plays important roles in neural development and synaptic function. We confirmed that the expression of CASK mRNA was decreased in the patient compared with healthy controls and the patient's X‐chromosomal inactivation was not skewed. These results suggested that the genetic deletion of CASK results in haploinsufficiency, which might be causative for the patient's developmental delay or mental retardation. © 2008 Wiley‐Liss, Inc.
Genetic disorders associated with macrocephaly
Authors: Williams Charles A. , Dagli Aditi , Battaglia Agatino 
Published: July 2008

AbstractMacrocephaly is associated with many genetic disorders and is a frequent cause of referral to the clinical geneticist. In this review we classify the commonly encountered macrocephaly disorders into useful categories and summarize recent genetic advances. Conditions where macrocephaly is a predominant aspect of the clinical presentation are discussed and a diagnostic approach to the common macrocephaly disorders is provided. Some emphasis is placed on familial macrocephaly (sometimes referred to as benign external hydrocephalus) and on the macrocephaly associated with autism spectrum disorders. The more recent conditions associated with the leukodystrophies and the organic acidurias are reviewed, but the well known conditions involving storage disorders and bone dysplasias are mentioned but not discussed. The genetic macrocephaly conditions cover a broad spectrum of gene disorders and their related proteins have diverse biological functions. As of yet it is not clear what precise biological pathways lead to generalized brain overgrowth. © 2008 Wiley‐Liss, Inc.
Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia
Authors: Douzgou Sofia , Lehmann Katarina , Mingarelli Rita , Mundlos Stefan , Dallapiccola Bruno 
Published: July 2008

AbstractDu Pan type chondrodysplasia (DPC) represents the milder end of homozygous growth differentiation factor 5 (GDF5) disorders. We report on a 20‐month‐old child with complex brachydactyly and mild proximal fibular hypoplasia, consistent with DPC, in the absence of other anomalies of long bones and joints. Mutational analysis disclosed two novel GDF5 mutations within the protein's mature domain and in the cleavage site of the prodomain which explains the distinct DPC phenotype found in this patient. The unaffected mother and the father who presented with mild brachybaso/mesophalangy of all digits were both heterozygous carriers. © 2008 Wiley‐Liss, Inc.
Deletion of 1 amino acid in Indian hedgehog leads to brachydactylyA1
Authors: Lodder E.M. , Hoogeboom A.J.M. , Coert J.H. , de Graaff E. 
Published: July 2008

AbstractBrachydactyly type A1 is a limb malformation characterized by a uniform shortening of the middle phalanges in all digits. Mutations in the Indian hedgehog (IHH) gene were shown to be the cause of this autosomal dominant disorder. The IHH protein is known to be an important signaling molecule involved in chondrocyte formation. So far, only missense mutations in IHH have been reported to cause BrachydactylyA1. We report here on the first deletion in IHH, p.delE95, causing mild BrachydactylyA1 in a small Dutch family. This brings the total number of different mutations found to cause BDA1 to 7. © 2008 Wiley‐Liss, Inc.
Clinical phenotype correlates to glycoprotein phenotype in a sib pair with CDG‐Ia
Authors: Barone Rita , Sturiale Luisa , Sofia Vito , Ignoto Antonella , Fiumara Agata , Sorge Giovanni , Garozzo Domenico , Zappia Mario 
Published: July 2008

AbstractCongenital disorder of glycosylation (CDG) type Ia (PMM2 mutations) is the most common genetic disorder of protein N‐glycosylation. The wide clinical spectrum with mild to severe impairment of neurological function and extensive allelic heterogeneity hamper phenotype‐genotype comparison. We report on two male adult siblings with the PMM2 mutations c. 385G > A (p.V129M) and c. 422G > A (p.R141H) and partially different clinical phenotype. Patient 2 has a more severe degree of neurological and systemic involvement and a more pronounced decrease in levels of serum glycoproteins. MALDI‐TOF mass spectrometry of serum transferrin and alpha‐1‐antitrypsin shows more pronounced glycosylation defects in the more severely affected patient. Glycoproteomic analysis may reveal differences in CDG‐Ia patients with different disease severity and might endorse clinical characterization of CDG‐Ia patients. © 2008 Wiley‐Liss, Inc.