bluuebunny/crossref_metadata_2025 huggingface dataset:
Carrier screening for cystic fibrosis in primary care: evaluation of a project in South Wales The South Wales Cystic Fibrosis Carrier Screening Research Team
Authors: Payne Y. , Williams M. , Cheadle J. , Stott N. C. H. , Rowlands M. , Shickle D. , West G. , Meredith L , Goodchild M. , Harper P. S. , Clarke A.
Published: July 2010

Population carrier screening for cystic fibrosis (CF) was offered to all patients aged 16–45 in one general practice in South Wales, excluding those in couples with a current pregnancy. Out of 1553 patients in this group, 481 subjects were tested, giving an overall uptake rate of more than 30%. The rate of uptake varied with the mode of invitation. Twenty‐six carriers were identified, giving a prevalence of identified carriers of 5.4% (1 in 18.5) for those with no family history of CF. A further 18 carriers were identified by cascade testing of these 26. We describe the practical difficulties encountered in setting up this programme in primary care in South Wales. Questionnaires were administered or distributed to all subjects before and after testing. The response rate for the pre‐test questionnaire was 95%, and 40–50% for the post‐test questionnaires. These showed that, at 3 months post‐test, 1 in 4 screen‐negative subjects did not appreciate that they had a residual risk of being a carrier. At the same time, 15% of this group thought that there was a 1 in 4 chance of a child being affected if one parent was screen‐positive (carried an identified mutation) and the other was screen‐negative, and 40% thought there was no risk. Anxiety in relation to testing did not appear to be a major problem, although individual patterns of response to carrier status varied widely and more sensitive indicators of psychosocial impact of genetic tests are required. A pilot study of couple screening showed that this approach is unlikely to be useful in primary care, although we did not assess couple testing during pregnancy. For any programme of CF carrier screening to be established in primary care, it will be necessary to involve the primary care team from the earliest planning stage, so that the opportunity costs, training needs and other costs of the programme can be fully resourced.
Prenatal growth retardation, microphthalmos/iris coloboma, cloudy cornea, urogenital anomalies and microcephaly. A possible new sublethal syndrome
Authors: Fryns Jean‐Pierre , Verresen Herman , Van den Berghe Herman
Published: July 2010

We present the findings of a “new” sublethal MCA syndrome in three siblings, one female and two boys, the only children of healthy, non‐consanguineous parents. In addition to prenatal growth retardation and early demise, they presented the same pattern of multiple malformations: relative microcephaly with bird‐headed face, microphthalmos/coloboma iris/cloudy corneae, genital anomalies with hypospadias and cryptorchidism in the two males. Associated anomalies included: cardiac defects (2/3), unilateral cleft lip/cleft palate (1/3), anal stenosis (2/3) and unilateral renal agenesis (1/3).
A study of possible deleterious effects of consanguinity
Authors: Abdulrazzaq Y. M. , Bener A. , Al‐Gazali L I. , Al‐Khayat A. I. , Micallef R. , Gaber T.
Published: July 2010

The aim of the study was to determine whether consanguineous marriages result in reproductive wastage and an increased incidence of illness in the offspring in a community with a long history of inbreeding and an expected high rate of consanguineous marriage. A representative sample of 2200 women aged > 15 years from Dubai and Al Ain, two cities in the United Arab Emirates, representing on the one hand a modern metropolis and on the other a traditional society, were studied. A questionnaire, which included questions on age, parity, gravidity, number of stillbirths, number of abortions, number of children alive, neonatal deaths and specific illnesses in children, was administered by nurses in antenatal and gynaecological clinics in the two cities. The rate of consanguineous marriage was 50.5% and parity, gravidity, ages and number of children were similar in consanguineous and non‐consanguineous groups. There was no significant difference in rates of abortion, stillbirth and neonatal death between the two groups. Overall, there was statistically significant higher reproductive wastage in consanguineous couples, but when the category of less than second cousins was excluded from the consanguineous group no difference was found in reproductive wastage between consanguineous and non‐consanguineous marriages. Children born to consanguineous unions also had significantly higher incidences of illnesses (37.1%) than those of non‐consanguineous unions (29%). The occurrence of malignancies, congenital abnormalities, mental retardation and physical handicap was significantly higher in offspring of consanguineous than non‐consanguineous marriages. In conclusion, consanguinity did not result in reproductive wastage, but was found to be an important factor in the causation of specific illnesses in offspring.
Identification of a point mutation (G727T) in the glucose‐6‐phosphatase gene in Japanese patients with glycogen storage disease type 1a, and carrier screening in healthy volunteers
Authors: Okubo Minoru , Aoyama Yoshiko , Kishimoto Masahiko , Shishiba Yoshimasa , Murase Toshio
Published: July 2010

Glycogen storage disease type 1a (GSD 1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose‐6‐phosphatase (G6Pase). We analyzed the G6Pase gene of two unrelated Japanese families with GSD 1a. DNA sequencing of all five exons and exon‐intron junctions revealed a G‐to‐T transversion at nucleotide 727 (G727T) in exon 5, which has been previously reported to cause abnormal splicing. Family studies using mismatch PCR showed that three patients were homozygous for the G727T mutation, while the parents were heterozygous. To investigate allele frequencies, we screened 216 Japanese healthy volunteers and found one asymptomatic carrier. Our findings suggest that the G727T mutation may be prevalent in Japan.
Supernumerary marker chromosomes (SMCs) in Turner syndrome are mostly derived from the Y chromosome
Authors: Patsalis Philippos C. , Hadjimarcou Michael I. , Velissariou Voula , Kitsiou‐Tzeli Sophia , Zera Christina , Syrrou Maria , Lyberatou Evangelia , Tsezou Aspasia , Galla Angeliki , Skordis Nicos
Published: July 2010

DNA and FISH (fluorescencein situhybridization) analysis were carried out in 12 patients with stigmata of Turner syndrome to determine whether the SupernumeraryMarkerChromosome (SMC) found cytogenetically in each of these patients was derived from the Y chromosome. The presence of a Y chromosome in these patients may predispose them to develop gonadoblastoma. PCR‐Southern blot analysis, followed by FISH, was used to detect the presence of Y chromosome material. TheSex determiningRegionY(SRY),TestisSpecificProteinY‐encoded (TSPY) andY‐chromosomeRNARecognitionMotif (YRRM) genes, which map at Yp11.31, Yp11.1–11.2 and Yp11.2/Yq11.21–11.23, respectively, were selected as markers, because they span the whole Y chromosome, and more importantly, they are considered to be involved in the development of gonadoblastoma. It was shown that in 12 patients, all of whom had an SMC, the SMC of 11 was derived from the Y chromosome. Furthermore, the presence of the SRY, TSPY and YRRM gene sequences was determined and FISH analysis confirmed the Y origin of the SMCs. The methodology described in this report is a rapid, reliable and sensitive approach which may be easily applied to determine the Y origin of an SMC carried in Turner syndrome. The identification of an SMC is important for the clinical management and prognostic counseling of these patients with Turner syndrome.
A novel point mutation (Pro84 ← Ser) of the low density lipoprotein receptor gene in a family with moderate hypercholesterolemia
Authors: Vuorio Alpo F. , Turtola Hannu , Kontula Kimmo
Published: July 2010

To obtain insight into the possibility that genetic variation of the structure of the low density lipoprotein (LDL) receptor protein could result in subtle changes of serum cholesterol levels, we used single‐strand conformation polymorphism (SSCP) to screen all 18 exons of the LDL receptor gene in a panel of subjects with moderate hypercholesterolemia. One novel mutation, replacing C to T at nucleotide 313 and predicted to cause a substitution of serine for proline at codon 84, was identified in a single proband. A convenient PCR assay based on the use of primer‐introduced restriction fragment length polymorphism was set up for the detection of this mutation. However, the pathophysiologic significance of the Pro84 → Ser replacement remains to be clarified, as serum LDL cholesterol levels were not significantly higher in mutation carriers vs. non‐carriers in the affected family, and no other proband was identified, on screening of DNA samples from 350 Finns. The Pro84 → Ser mutation represents the second single‐amino acid change of the LDL receptor protein so far reported which is not associated with the clinical phenotype of familial hypercholesterolemia.
Clinical manifestation of a severe neonatal progeroid syndrome
Authors: Mégarbané André , Loiselet Jacques
Published: July 2010

A girl with a progeroid appearance, with prominent occiput, blepharophimosis, cataract, arthrogryposis of the upper limbs and severe pulmonary stenosis is described. She died aged less than 6 months. An older sister was born 3 years before with the same appearance and underwent the same fatal evolution. The clinical appearance of this reported patient is compared to the previously published cases with severe neonatal progeroid syndromes.
De novo duplication of 12pter → p12.1: clinical and cytogenetic diagnosis confirmed by chromosome painting
Authors: Back E. , Kratzer W. , Zeitler S. , Schempp W.
Published: July 2010

A 12.5‐year‐old male patient with a de novo derivative chromosome 22 is reported. A detailed description of the clinical features and comparison with the results of conventional cytogenetic banding methods indicated that the derivative chromosome might have been caused by a translocation between the short arms of chromosomes 12 and 22: der(22)t(12;22)(p12.1;p11.2). Fluorescence in situ hybridization with a chromosome 12‐specific paint confirmed this supposition. The patient thus carries a pure duplication of 12pter → p12.1. The phenotype of the patient described is compared to cases in the literature.
Multiple epiphyseal dysplasia and pseudoachondroplasia due to novel mutations in the calmodulin‐like repeats of cartilage oligomeric matrix protein
Authors: Susie Slavovic , McGrory Joel , Ahier Janet , Cole William G.
Published: July 2010

A child with a mild form of pseudoachondroplasia was heterozygous for a deletion of 12 nucleotides from exon 10 of the cartilage oligomeric matrix protein (COMP) gene. It resulted in the deletion of valine 513 to lysine 516 from the eighth calmodulin‐like repeat of COMP monomers. A child with the Fairbank's type of multiple epiphyseal dysplasia was also heterozygous for a COMP mutation. It substituted cysteine 371 by serine in the fourth calmodulin‐like repeat. Both mutations were likely to alter the conformation and calcium binding of the mutant COMP protein chains. These findings support the proposal that deletions and insertions within the calmodulin‐like domain produce pseudoachondroplasia, while amino acid substitutions with this domain may produce either pseudoachondroplasia or multiple epiphyseal dysplasia.
Case Report: Two newborns with chromosome 4 imbalances: deletion 4q33 → q35 and ring r (4) (pterq35.2‐qter)
Authors: Calabrese G. , Giannotti A. , Mingarelli R. , Gilio M. C. Di , Piemontese M. R. , Palka G.
Published: July 2010

Two patients are reported who presented with 4q deletion and r(4), respectively. Cytogenetic and FISH analysis denned the breakpoints respectively at bands 4q33 → q35 proximal to the telomere, and 4pter and 4q35.2‐qter. Moreover in both cases rearranged chromosomes maintained telomeric sequences. The first patient showed some clinical features of deletion 4q and a pointed 5th finger, a characteristic finding in deletion 4q31 → qter. The second patient had mild dysmorphism associated with growth retardation.
Ohdo syndrome: report on a Brazilian girl with additional findings
Authors: Lopes Vera Lúcia Gil da Silva , Guion‐Almeida Maria Leine
Published: July 2010

We describe a Brazilian girl presenting Ohdo syndrome with cleft palate and diverticula of the bladder. Gestational history revealed the occurrence of fever for 12 days in the second month of gestation. To our knowledge, cleft palate and urinary abnormalites are hitherto undescribed features of this syndrome. Additional case reports could elucidate the fortuitous or causal association of these signs, the full phenotypic spectrum, as well as the pattern of transmission of the Ohdo syndrome.
Linkage studies exclude the AT‐V gene(s) from the translocation breakpoints in an AT‐V patient
Authors: Chrzanowska Krystina , Stumm Markus , Bialecka Magdalena , Saar Kathrin , Bernatowska‐Matuszkiewicz Ewa , Michalkiewicz Jacek , Barszcz Slawomir , Reis André , Wegner Rolf‐Dieter
Published: July 2010

An 8‐year‐old girl with severe microcephaly of prenatal onset, borderline intelligence, defects of skin pigmentation, deficiency of both humoral and cellular immunity, a normal serum α‐fetoprotein level and hypersensitivity to ionizing irradiation is described. Spontaneous chromosomal breakage in lymphocytes together with the clinical presentation led to the diagnosis of ataxia telangiectasia variant (AT‐V). In addition, the patient carried a constitutional translocation of paternal origin: 46,XX,t(3;7)(q12;q31.3) pat. In subsequent linkage and haplotype studies in 12 AT‐V families with microsatellite markers from each of the translocation breakpoint regions, we could clearly exclude the localization of an AT‐V gene to these regions.
Molecular studies of an X;Y translocation chromosome in a woman with deletion of the pseudoautosomal region but normal height
Authors: Spranger S. , Kirsch S. , Mertz A. , Schiebel K. , Tariverdian G. , Rappold G.A.
Published: July 2010

A translocation chromosome in a woman with the karyotype 46,X,der(X)t(X;Y)(p22.3; q11.2) was investigated by FISH and STS analysis with molecular probes derived from the sex chromosomes. Due to the partial deletion of the short arm pseudoautosomal region (PARI) from DXYS14 to DXYS147 in the translocation chromosome, the proband is hemizygous for the gene responsible for growth control (SS) located in this region, yet does not show growth retardation. Molecular analysis of the Yq arm of the translocation chromosome revealed the presence of markers DYS273 to DYS246 harboring the hypothesized growth control gene critical region (GCY) on Yq, thereby placing the deletion breakpoint between markers DYS11 and DYS273. These results suggest that the Y‐specific growth gene GCY on Yq compensates for the missing growth gene SS on Xp22.3.
Female pseudohermaphroditism due to classical 21‐hydroxylase deficiency in a girl with Turner syndrome
Authors: Maciel‐Guerra Andréa Trevas , Jr Gil Guerra , Marini Sofia Helena V L , Baptista Maria Tereza Matias , Marques‐de‐Faria Antonia Paula
Published: July 2010

We report on a rare case of female pseudohermaphroditism due to classical 21‐hydroxylase deficiency associated with Turner syndrome (45,X/46,XX). Difficulties in the management of both diseases are briefly discussed. We regard this rare combination as a coincidental occurrence.
Extending the overlap of three congenital overgrowth syndromes
Authors: Coppin Brian , Moore Isabella , Hatchwell Eli
Published: July 2010

We present the case of a male infant, born prematurely (at 33 weeks gestation) with macrosomia, disproportionate macrocephaly, facial dysmorphism, short penis and a small umbilical defect. He had a large ASD and was ventilated from birth for respiratory distress syndrome. He died at 12 hours of age despite neonatal ITU care. Post‐mortem examination showed highly lobulated kidneys with nodules of blastema and foci of hamartomatous change in the medulla. Prominence of pancreatic islet cells and expansion of hepatic portal tracts were also noted. His mother has minor cervical spine abnormalities. We discuss the differential diagnosis and the difficulty in confidently assigning a diagnosis to this patient, as considerable overlap is becoming evident between Simpson‐Golabi‐Behmel syndrome and Perlman syndrome.
Photoanthropometric study of craniofacial traits in individuals with Williams syndrome
Authors: Hovis Christopher L , Butler Merlin G.
Published: July 2010

A photoanthropometric method, which enables an objective description of facial structures, was used to better delineate the craniofacial characteristics of 29 individuals with Williams syndrome (WS; 18 males and 11 females) between the ages of 0 to 10 years, with an average age of 4.0 years. Facial parameters were measured from strict frontal and profile photographic 35‐mm slides and compared with other facial measurements from the same face (e.g., palpebral fissure width to bizygomatic diameter). Sixteen photoanthropometric craniofacial indices were developed from 20 measurements (3 from the frontal face, 2 from the eye region, 3 from the nose region, 2 from the mouth region, 4 from the profile face, and 6 from the ear region). Based on our measurements of 29 Williams syndrome individuals, two parameters (e.g. nose length to midface height and palpebral fissure width to bizygomatic diameter) were outside the normal range when compared with photoanthropometric index standards for age established by Stengel‐Rutkowski et al. from white control children. Overall, our data supported a high midface height, broad palpebral fissure width, broad interalar distance, short length of back of nose, prominent ears with long narrow conchae, increased chin height, increased inclination of the ears and a narrow bizygomatic diameter in WS patients. These craniofacial parameters (many not previously evaluated in WS patients) may become useful for early detection, and aid in the diagnosis and study of the development of the characteristic face in Williams syndrome subjects.
On the many faces of Leber hereditary optic neuropathy
Authors: Oostra R.J. , Tijmes N.T. , Cobben J.M. , Boihuis P.A. , van Nesselrooij B.P.M. , Houtman W.A. , de Kok‐Nazaruk M.M. , Bleeker‐Wagemakers E.M.
Published: July 2010

Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.
Codon 89 polymorphism of the human 5α‐steroid reductase type 2 gene
Authors: Vilchis F. , Hernández D. , Canto P. , Méndez J.P. , Chávez B.
Published: July 2010

The existence of a genetic polymorphism within the coding region of the human 5α‐steroid reductase type 2 (5α‐SR2) gene is reported in a Mexican population. Genotypic variation was assessed in 100 unrelated, healthy volunteers (50 males; 50 females), using single‐stranded conformational polymorphism and direct sequencing analysis. Examination of exon 1 DNAs disclosed the presence of sequences encoding for valine (GTA) or leucine (CTA) at codon 89 of the gene. Of the subjects screened, 45% were homozygous for GTA (89Val), 50% had a heterozygous pattern GTA/CTA (89Val/89Leu) and the remaining 5% were homozygous for CTA (89Leu). These data support the view that the G/C condition at codon 89 of the 5α‐SR2 gene represents a silent polymorphism which does not alter phenotypical development in the human.
Three cases of trisomy 13 mosaicism and a review of the literature
Authors: Delatycki M. , Gardner R. J. M.
Published: July 2010

We describe three cases of trisomy 13 mosaicism and review the literature. The phenotype ranges from a severe form similar to Patau syndrome, through to physical and mental normality. This range presumably reflects the proportion and tissue distribution of the trisomic cell line. The percentage of trisomic cells in lymphocytes correlates poorly with the observed phenotype.
Polycystic kidney disease, biliary dysgenesis in a patient with Larsen's syndrome
Authors: Kurtoglu Selim , Dundar Munis , Hallaç I. Kuttulus. , Üzüm Kazim , Okumus Yüksel , Öktem Turhan
Published: July 2010

Larsen's syndrome is characterised by multiple joint dislocations, flat face and talipes equinovarus. There is an autosomal dominant form and also a more severe autosomal recessive form. Several types of polycystic kidney disease have been reported in children. In this report we present an infant with a severe form of Larsen's syndrome (thought to be lethal Larsen‐like), infantile‐type polycystic kidney disease, biliary dysgenesis and osteosclerosis.
A case of Carpenter syndrome diagnosed in a 20‐week‐old fetus with postmortem examination
Authors: Balci S. , Önol B. , Eryilmaz M. , Haytoglu T.
Published: July 2010

Carpenter syndrome (acrocephalopolysyndactyly type II) is an autosomal recessive syndrome. The case we present was diagnosed prenatally at 20 weeks. Postmortem examination revealed severe central nervous system malformations. The central nervous system anomalies in this 23‐week‐old fetus merit emphasis, since these anomalies in such a young fetus may explain Carpenter syndrome cases, which do not improve in spite of early surgical intervention.
A case of mosaic trisomy 2 diagnosed at amniocentesis in an abnormal fetus and confirmed in multiple fetal tissues
Authors: Robinson Jacqueline , Stewart Helen , Moore Lynette , Gaunt Lorraine
Published: July 2010

Pseudomosaicism for trisomy 2 is a relatively common finding at amniocentesis. However, genuine trisomy 2 mosaicism is extremely rare. As a result, very few cases have been described and little information is available with which to counsel the parents of an affected fetus. We describe a case of mosaic trisomy 2 diagnosed at amniocentesis in a fetus with multiple anomalies on ultrasound scan. Following termination of pregnancy, the fetus was found to have mild dysmorphic features, together with an absent gall bladder, cystic left kidney, a 13th left rib and mild unilateral talipes. The presence of trisomy 2 cells was confirmed by both standard cytogenetic analysis and fluorescent in‐situ hybridisation techniques in multiple fetal tissues, as well as in the cord and placenta.
Identification of the parental origin of polysomy in two 49,XXXXY cases
Authors: Çelik Arzu , Eraslan Serpil , Gökgöz Nalan , Ilgin Hatice , Baçaran Seher , Bökesoy Işik , Kayserili Hülya , Yüksel‐Apak Memnune , Kirdar Betül
Published: July 2010

The parental origin and mechanism of formation of polysomy X were studied in two polysomic cases, using four X‐linked restriction fragment length polymorphisms, three (CA)n dinucleotide repeat sequences and one variable number tandem repeat (VNTR) locus as genetic markers. A nonradioactive technique based on the hybridization of the polymerase chain reaction (PCR) product was developed for the analysis of dinucleotide repeats. Segregation analysis using different nonradioactive approaches based on the PCR, revealed that all four X chromosomes were of maternal origin. These data provide additional evidence of an identical mechanism of successive nondisjunctions in maternal meiosis I and II.
Scintigraphic evaluation of Tc‐99m‐low‐density lipoprotein (LDL) distribution in patients with Gaucher disease
Authors: Lorberboym Mordechai , Vallabhajosula Shankar , Lipszyc Helena , Pastores Gregory
Published: July 2010

Gaucher disease (GD) is frequently associated with reduced plasma levels of low density lipoproteins, presumably due to increased catabolism of LDL. The purpose of this study was to determine the distribution of Tc‐99m LDL (Tc‐LDL) in Gaucher patients, and compare the findings to bone marrow distribution. Four patients with non‐neuropathic Gaucher disease (type 1) underwent baseline whole body imaging at 4 and 24 h after injection of dialyzed autologous LDL labeled with 10–20 mCi Tc‐99m‐pertechnetate. Three of the four patients were treated with macrophage‐targeted alglucerase (Ceredase). The LDL studies were compared to concurrent bone marrow scans performed with 10 mCi Tc‐99m sulfur colloid (Tc‐SC). Follow‐up Tc‐LDL and Tc‐SC scans were obtained 12–14 months later. Tc‐LDL activity was abnormally increased in the spleen and long bones of the upper and lower extremities. Liver activity was also increased. Prominent blood pool activity 4 h after injection mostly cleared on the 24‐hour images. The distribution of Tc‐SC was congruent with Tc‐LDL activity. All patients had mild‐to‐moderate hepatomegaly and peripheral bone marrow expansion. One patient had been previously splenectomized and the remaining three had moderate‐to‐severe splenomegaly. Two of the three treated patients showed regression of peripheral bone marrow activity with therapy, along with a comparable decrease in Tc‐LDL uptake. Our study with Tc‐LDL and Tc‐SC suggests that in patients with Gaucher disease native LDL is taken up by the reticuloendothelial system (RES) of the spleen and bone marrow in addition to increased uptake by the liver. This abnormal uptake (presumably by macrophages of the RES) may account for accelerated LDL catabolism and reduced plasma levels of LDL. Serial LDL studies can be performed, allowing for longitudinal follow‐up after drug or enzyme therapies.
Detection of dystrophin deletion carriers using FISH analysis
Authors: Calvano S. , Memeo E. , Piemontese M. R. , Melchionda S. , Bisceglia L. , Gasparini P. , Zelante L.
Published: July 2010

The detection of carrier status in female relatives of Duchenne/Becker muscular dystrophy patients is not always possible and this poses a problem in genetic counseling. We have developed a simple method that can be used in families in which affected males are characterized by the presence of a deletion within the dystrophin gene. PCR fragments, corresponding to the deleted regions are used as fluorescent probes for hybridization of peripheral lymphocytes nuclei of female relatives. The results obtained clearly demonstrate the feasibility of this method for detecting female DMD/BMD carriers.
Oto‐facio‐osseous‐gonadal syndrome: a new form of syndromic deafness?
Authors: Da‐Silva Elias O. , Duarte Andréa R. , Lins Thereza S. S.
Published: July 2010

In this study, we report on two brothers, born to consanguineous parents, with a syndrome of sensorineural deafness, short stature, cryptorchidism, inguinal hernia, brachycephaly, prominent forehead, flat face, downslanting palpebral fissures, low nasal root, hypoplastic alae and round tip to the nose, low‐set prominent ears, narrow thorax, genu valgum, wormian bones, fusion of carpal bones, delayed bone age and congenital clubfeet. This combination of anomalies appears to be a previously undescribed syndrome, with probable autosomal recessive inheritance.
Analyses of mutations in the human renal kallikrein (hKLKl) gene and their possible relevance to blood pressure regulation and risk of myocardial infarction
Authors: Berge K. E. , Bakken A. , Bøhn M. , Erikssen J. , Berg K.
Published: July 2010

The kallikrein‐kinin system is involved in the maintenance of blood pressure (BP), and studies have shown an inverse correlation between BP and urinary kallikrein levels. These and other effects, make the human tissue kallikrein (hKLKl) gene a candidate gene with respect to BP regulation as well as risk of myocardial infarction (MI). By analysis for single‐stranded conformation polymorphisms (SSCPs), patterns consistent with four different variants of the gene were detected and further characterized by DNA sequencing. Three of the variants have not been described before. Two of the polymorphisms changed the codon for an amino acid. Methods based on the polymerase chain reaction (PCR) were developed to analyze these polymorphisms at the hKLKl locus. We found no evidence of association between any genotype in the polymorphisms and normal BP level in two series of healthy, unrelated individuals. In a third series, diastolic BP exhibited a weak association with genotypes in three of the four polymorphisms. Since no such association was detected in the other two series, we conclude that no effect on normal BP level is exerted by variants in the hKLKl as expressed in these polymorphisms. In two series of monozygotic (MZ) twin pairs, there were no differences between genotypes in within‐pair difference in systolic BP or diastolic BP. Finally, no differences in allele frequencies or genotype frequencies in the four polymorphisms at the hKLKl locus were found between a series of young MI survivors and a series of controls. Thus, genes in the four polymorphisms at the hKLKl locus detected by SSCP and DNA sequencing did not exhibit associations with MI. and had neither “level gene” nor “variability gene” effects on normal blood pressure.
Combined partial trisomy 3p/monosomy 5p resulting in sonographic abnormalities
Authors: Entezami Michael , Coumbos Alexandra , Runkel Sanyukta , Vogel Martin , Wegner Rolf
Published: July 2010

We report here a case of partial trisomy of the short arm of chromosome 3 combined with partial monosomy 5p due to malsegregation of a balanced maternal translocation t(3;5). The newborn demonstrated esophageal atresia and complex cerebral malformations. Conspicuous sonographic findings offering the chance of prenatal detection included polyhydramnios without visualization of the stomach, as well as a single umbilical artery. The child died 8 days postpartum.
Earlier finishing of Xp21.2 subband replication of the inactive X chromosome in Rett syndrome girl but not in her 47,XXX mother
Authors: Panasiuk Barbara , Midro Alina T. , Zadrożna‐Tolwińska Barbara
Published: July 2010

X‐inactivation mosaicism has been proposed to explain the origin of Rett syndrome. We present the results of the cytogenetic analysis, including RBG dynamic replication pattern, in a girl with Rett syndrome. The late replicating X chromosome (LRX) showed the earlier replication of subband Xp21.2 in 36% of analysed cells. Unexpectedly the maternal karyotype 47,XXX was found. Replication timing of both maternal LRX chromosomes was normal. The critical region of Xp essential for RS is proposed.
Partial trisomy 6p from a de novo translocation (6; 18) with variable mosaicism in different tissues
Authors: Rudnik‐Schönebom Sabine , Schubert Regine , Majewski Frank , Haverkamp Fritz , Schwanitz Gesa
Published: July 2010

Partial trisomy 6p is regarded as a distinct phenotype with short stature, failure to thrive, facial dysmorphisms with blepharophimosis, mental retardation and other malformations. An 18‐month‐old girl with typical features of partial trisomy 6p showed a de novo unbalanced translocation resulting in partial trisomy 6p21 to pter and partial monosomy 18p11 to pter. The translocation was observed in all fibroblasts analyzed, but only in 6% of the peripheral lymphocytes.
Consanguineous marriage and its clinical consequences in migrants to Australia
Authors: Nelson J. , Smith M. , Bittles A. H.
Published: July 2010

Marriage between close biological relatives is strongly favoured in many countries in Asia and Africa. Although substantial numbers of migrants from these regions are now living in Australia, little information is available either on the prevalence of consanguineous unions among migrants or on their clinical outcome. Data are presented on a range of generally rare autosomal recessive genetic disorders diagnosed in the children of parents of Eastern Mediterranean origin who attended Westmead Hospital, Sydney for genetic counselling during the period 1990 to 1994. The effects of parental consanguinity are assessed both in terms of the specific recessive disorders detected, and the perceived role of consanguineous marriage in the communities investigated.
Familial inv(X)(p22q22): ovarian dysgenesis in two sisters with del Xq and fertility in one male carrier
Authors: Madariaga M. L. , Rivera H.
Published: July 2010

A recombinant chromosome with Xp duplication and Xq deletion was found in two sisters with normal height and gonadal dysgenesis. Their mother and other four relatives, including a fertile male, carried an inv(X)(p22q22); the inverted X was randomly inactivated in one female carrier. The abnormal X chromosome showed inactivation in all the examined cells. This is the tenth report of a recombinant X chromosome. A review of the literature shows that: i) most female carriers of inv(X) are phenotypically normal and fertile; ii) recombinants having short‐arm duplication and long‐arm deletion are associated with ovarian failure and normal or tall stature, whereas the reciprocal recombinants are compatible with fertility but cause short stature; and (ü) except for one index case, all male carriers have a normal phenotype and 11 of them (from eight families) are of proven fertility. Moreover, no instance of male infertility has been documented.
Applicability of a checklist for clinical screening of the fragile X syndrome
Authors: Arvio M. , Peippo M. , Simola K. O. J.
Published: July 2010

In a population of 340000 in Southern Häme, Finland, there were 541 intellectually disabled adult males (> 16 years) known to the District Organisation for the Care of the Mentally Retarded in August 1993. Of these, 197 already had a confirmed etiological diagnosis, with 20 having the fragile X syndrome. The other 344 males were screened for the fragile X syndrome using a three‐step method: a clinical checklist used by a specialist nurse, a clinical examination by a physician who was very familiar with the fragile X syndrome, and the FRAXA‐locus gene test. Six new fragile X males were found. The minimum prevalence of the fragile X syndrome in the district was calculated to be 1:4400.
Greig cephalopolysyndactyly syndrome: altered phenotype of a microdeletion syndrome due to the presence of a cytogenetic abnormality
Authors: Williams Patricia Gail , Hersh Joseph H. , Yen Frank F. , Barch Margaret J. , Kleinert Harold E. , Kunz J. , Kalff‐Suske M.
Published: July 2010

A male had several features of Greig cephalopolysyndactyly syndrome (GCPS) and significant developmental delay. He was found to have a de novo chromosomal deletion of chromosome no. 7 involving p13; this resulted in loss of the zinc finger gene, GLI3, which is the candidate gene in this syndrome. Modification of the CGPS phenotype in a sporadic case emphasizes the importance of searching for a chromosomal origin of this autosomal dominant disorder. Detection of a chromosomal deletion in these patients may be associated with a poor prognosis from the standpoint of cognitive development, and the potential for other structural abnormalities not normally associated with GCPS.
Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study
Authors: Berg Kåre , Dahlén Gösta , Christophersen Bjørn , Cook Thomas , Kjekshus John , Pedersen Terje
Published: July 2010

The Scandinavian Simvastatin Survival Study (4S) was a double‐blind. randomized placebo‐controlled multi‐centre clinical trial of long‐term Simvastatin therapy in patients with coronary heart disease who had total cholesterol levels between 5.5 and 8.0 mmol/1, comprising 4444 patients, equally distributed to a Simvastatin and a placebo group. Patients achieved a significant 30% relative reduction in overall mortality with Simvastatin therapy through a 42% relative reduction in coronary heart disease mortality. Lp(a) lipoprotein levels in Scandinavian coronary heart disease patients were strikingly higher than in healthy controls. Numbers of deaths in the Simvastatin group differed significantly between quartiles of Lp(a) lipoprotein levels, the reduction in deaths being most pronounced in the second (next to lowest) quartile. Subjects with major coronary events had significantly higher Lp(a) lipoprotein levels than subjects without such events, in all groups. The relationship between Lp(a) lipoprotein level and total mortality as well as between Lp(a) lipoprotein level and major coronary events was significantly different from zero, in logistic regression analyses. The findings show that Lp(a) lipoprotein predicts major coronary events as well as death in secondary prevention with Simvastatin. This prospective study provides independent confirmation that a high Lp(a) lipoprotein level is a significant coronary heart disease risk factor.
High‐degree sequence conservation in LPA kringle IV‐type 2 exons and introns
Authors: Rösby Oddveig , Aleström Peter , Berg Kåre
Published: July 2010

In the search for factors contributing to the regulation of the Lp(a) lipoprotein concentration, we have sequenced the kringle IV‐type 2 encoding exons 1 and 2 together with the flanking intron sequences of the LPA gene in individuals with different serum concentrations of Lp(a) lipoprotein. The high degree of sequence identity between the kringle IV‐type 2 repeats made it possible to analyse all the 3–42 kringles simultaneously by polymerase chain reaction and direct DNA sequencing. The strategy used allowed us to determine approximately 700 bp from each kringle IV‐type 2 repeat, resulting in a rapid screen of on average 28 000 bp of the LPA gene from each individual. Comparing these bipartite kringle IV‐type 2 repeat sequences from 12 individuals with high and 11 individuals with low Lp(a) lipoprotein level revealed that: 1. no sequence polymorphism could be detected in the exons examined; 2. no sequence polymorphism could be detected in the consensus GT/AG splicing signals of exon/intron junctions; and 3. the proximal intron sequences seemed almost completely conserved in the 76–135 bp analysed. Only one position in the intron sequences exhibited the pattern of a G/A polymorphism. We observed no differences between the group with high and the group with low Lp(a) lipoprotein level. The very high conservation of intron sequences could support the hypothesis that the LPA gene evolved relatively recently. The contradictory finding of a corresponding sequence conservation between the human LPA and the plasminogen gene suggests that an evolutionary pressure has preserved these intron sequences over the last 40–90 million years.
Reporter gene analysis of four DNasel hypersensitive sites in the plasminogen/apolipoprotein(a) intergenic region
Authors: Acquati Francesco , Rönicke Volker , Taramelli Roberto , Müller Hans‐Joachim
Published: July 2010

We have previously described four DNasel hypersensitive sites (DH1 to DH4) in the 40‐kb intergenic region between the plasminogen gene and the apo(a) gene. Here, we wanted to analyse whether any of these sites, located 4, 21, 28 and 34 kb upstream of the apo(a) transcriptional start site, would act as an enhancer on a minimal apo(a) promoter. Starting from a cloned, highly expressed apo(a) allele, we obtained four fragments comprising the DH1 to DH4 sites, respectively. These fragments were cloned in both orientations into a luciferase reporter gene plasmid comprising a minimal apo(a) promoter (—100 to +141 with respect to the transcriptional start site). Our results from transfection studies with the resulting series of reporter gene plasmids into liver (HepG2) and non‐liver (HeLa) cells suggest that the four DH sites from the selected apo(a) allele do not provide a strong, liver‐specific enhancer activity.
Metabolism of Lp(a): assembly and excretion
Authors: Kostner Gert M. , Wo Xingde , Frank Sasa , Kostner Karam , Zimmermann Robert , Steyrer Ernst
Published: July 2010

Lp(a) is one of the most atherogenic lipoproteins, and we know much more about the pathophysiology of Lp(a) than about its physiological function and metabolism. From our previous investigations and the new results reported here, we propose the following model of Lp(a) metabolism: apo(a) is biosynthesized in liver cells and the size of the isoform determines its rate of synthesis and excretion. Specific kringle‐4 domains in apo(a), mainly T‐6 and T‐7, bind in a first step to circulating LDL, followed by the stabilization of the newly formed Lp(a) complex by a disulfide bridge. Circulating Lp(a) interacts specifically with kidney cells, or possibly other tissues, causing cleavage of 2/3–3/4 of the N‐terminal part of apo(a) by a collagenase‐type protease. Part of the apo(a) fragments is found in the urine, but there are indications that they in fact represent the biologically active form of apo(a). The core portion of Lp(a) in turn is cleared by the LDL‐receptor or another specific binding system of the liver. Strategies for reducing plasma Lp(a) levels with medication should aim at interfering with the assembly of Lp(a) on one hand and the stimulation of apo(a) fragmentation on the other hand.
Vascular accumulation of Lp(a): in vivo analysis of the role of lysine‐binding sites using recombinant adenovirus
Authors: Hughes Steven D. , Rubin Edward M.
Published: July 2010

Despite the importance of lipoprotein(a) [Lp(a)] as an atherogenic risk factor, very little information, especially from in vivo studies, is available concerning which structural features of apo(a) contribute to the interactions of Lp(a) with the vessel wall and its proatherogenic properties. Nearly all the proposed and proven activities of apolipoprotein(a) [apo(a)] focus on its high degree of sequence homology with plasminogen and the possibility that structural features shared by these two molecules contribute to the atherogenesis associated with high Lp(a) plasma levels in humans. In these studies, we examined the properties of three forms of Lp(a) differing at postulated lysine‐binding domains contained in the constituent apo(a). We used the recombinant adenoviral gene delivery system to produce apo(a) in the plasma of human apoB transgenic mice, resulting in high levels of Lp(a) similar to those found in the plasma of humans. By comparison of in vitro lysine‐binding properties of these forms of Lp(a) with measurements of Lp(a) vascular accumulation in the mice, we have demonstrated that lysine‐binding defective forms of Lp(a) have a diminished capacity for vascular accumulation in vivo.
Lipoprotein(a): identification of subjects with a superbinding capacity for fibrinogen
Authors: Scanu Angelo M. , Atzeni Maria Maddalena , Edelstein Celina , Tonolo Giancarlo , Maioli Mario , Kiezovitch Olga
Published: July 2010

We have previously shown that the binding of lipoprotein (a) [Lp(a)] to immobilized fibrinogen involves the domain located in kringles IV‐5 to IV‐8, but not kringle IV‐10. In extending those studies to subjects living in Chicago and in the island of Sardinia, we found that about 6% of them had an Lp(a) with Bmax values of 27.7 + 6.0 fmol, which were about 5–8‐fold higher than those of controls (3.4 + 2.8 fmol) and in the range of those observed for free apo(a) derived from the Lp(a) of controls (36.6 + 2.9 fmol). This superbinding phenotype was unaffected by age, sex, type of lipid disorder and hypolipidemic agents, and also had a familial incidence. We are currently exploring the hypothesis that this fibrinogen superbinding phenotype is due to conformational changes of apolipoprotein(a) [apo(a)] resulting from the lipid content and composition of the Lp(a) particle and/or sequence anomalies in the kringle domain IV‐5 to IV‐8.
Apolipoprotein E type ε4 allele, heritability and age at onset in twins with Alzheimer disease and vascular dementia
Authors: Bergem A. L. Mina , Lannfelt Lars
Published: July 2010

The apolipoprotein E (APOE) ε4 allele is a risk factor in Alzheimer disease (AD), but not in vascular dementia (VaD). We have investigated whether the ε4 allele is more common in twin pairs concordant for AD, compared with those discordant for AD, and whether the ε4 allele is more common in AD twins than in VaD twins. In addition, we have investigated the relationship of the ε4 allele and the age at onset in AD and VaD. APOE genotype was analysed in 29 senile demented twin pairs. The ε4 allele was associated with AD and not with VaD. However, there was no difference in the frequency of the APOE ε4 allele in concordant (33.3%) and discordant (31.3%) AD dizygotic twin pairs. Age at onset in AD was significantly lower in ε4 homozygotes than in individuals with one or no copies of ε4 (62.4 vs. 73.5, p < 0.01). In concordant AD twin pairs, the ε4 allele frequency was somewhat higher in the twins with earlier onset (41.7% vs. 25%), but the difference was not statistically significant. In the VaD group the age at onset was not significantly different between individuals with or without ε4 in their genotypes.
The Asn9 variant of lipoprotein lipase is associated with the — 93G promoter mutation and an increased risk of coronary artery disease
Authors: Kastelein John JP , Groenemeyer Bjöm E. , Hallman D Michael , Henderson Howard , Reymer PWA , Gagné S Eric , Jansen Hans , Seidell Jaap C. , Kromhouf Daan , Jukema J Wouter , Bruschke Albert VG , Boerwinkle Eric , Hayden Michael R. , Group The Regress Study
Published: July 2010

Two mutations in the lipoprotein lipase (LPL) gene, a T to G transition at position — 93 of the proximal promoter region and an Asp9Asn substitution in exon 2, were examined in 762 Dutch males with angiographically‐diagnosed coronary artery disease (CAD) and 296 healthy normolipidemic Dutch males. The two mutations exhibited strong linkage disequilibrium (D' = 0.975). A significantly higher proportion of cases (4.86%) than controls (1.37%) carried the ‐93G/Asn9 allele (p = 0.008). In the combined sample of cases and controls, adjusted mean plasma total cholesterol (TC) levels were significantly higher in — 93G/Asn9 carriers (6.20 ± 0.13 mmol/1) than in non‐carriers (5.93 + 0.03 mmol/1; p = 0.048), while mean high‐density lipoprotein cholesterol (HDL‐C) levels were lower in carriers (0.88 ± 0.03 mmol/1) than in non‐carriers (0.98 ± 0.01 mmol/1; p = 0.002). There was a trend towards higher triglyceride (TG) levels in carriers (1.96 + 0.14 mmol/1) compared with non‐carriers (1.73 ± 0.03 mmol/1) (p = 0.08). Additionally, carrier frequencies in tertiles of TC, HDL‐C, TG, and LPL activity, suggested an association of the — 93G/Asn9 variant with higher TC and TG levels, and with lower HDL‐C and LPL activity levels. Logistic regression revealed a significant odds ratio (OR) for the combined — 93G/Asn9 genotype in CAD cases relative to controls (OR: 5.36; 95% CI: 1.57–18.24), with age, body mass index (BMI), smoking, and plasma total‐ and HDL‐cholesterol levels included in the model. In conclusion, we show that the LPL Asp9Asn mutation is in non‐random association with aTG substitution at position — 93 of the proximal promoter region and that the combined — 93G/Asn9 genotype predisposes to decreased HDL‐C levels and an increased risk of CAD.
Complete identification of cystic fibrosis transmembrane conductance regulator mutations in the CF population of Saguenay Lac‐Saint‐Jean (Quebec, Canada)
Authors: Braekeleer Marc De , Man Cécile , Verlingue Claudine , Allard Christian , Leblanc Jean‐Pierre , Simard Fernand , Aubin Gervais , Férec Claude
Published: July 2010

Over the past few years, we have conducted a systematic study of 230 cystic fibrosis (CF) chromosomes in the Saguenay Lac‐Saint‐Jean (SLSJ) population which has a high CF incidence (1/936 live births). We identified 11 mutations accounting for 100% of the CF chromosomes found in patients born in SLSJ. Our results indicate that denaturing gradient gel electrophoresis (DGGE) is a powerful method of identifying CF mutations. They have also considerable implications for genetic counselling and molecular characterization of doubtful patients. They make carrier screening technically feasible in this population.