bluuebunny/crossref_metadata_2025 huggingface dataset:
Severe cystic fibrosis associated with a AF508/R347H + D979A compound heterozygous genotype
Authors: Hojo Satoko , Fujita Jiro , Miyawaki Hiroshi , Obayashi Yuka , Takahara Jiro , Bartholomew Dennis W.
Published: July 2010

This report is concerned with twins with cystic fibrosis (CF). They are of mixed parentage: Japanese mother and German father. One case is presented with meconium ileus as a neonate. The other patient did relatively well until the age of 6 years when she was first hospitalized and diagnosed with pulmonary aspergillosis. They have been receiving standard therapies for CF including digestive enzymes, vitamins and periodic antibiotic therapy in the US. At 19 years of age, they were tested for common mutations and one ΔF508 cystic fibrosis transmem‐brane conductance regulator (CFTR) allele was found. Further testing of their CFTR gene as well as those of their Japanese mother and grandmother revealed missense mutations in exon 7 (R347H) and exon 16 (D979A). Although the D979A mutant is very rare, this mutation combination seemed to be responsible for severe CF phenotypes.
Evaluation of a clinically applicable mutation screening technique for genetic diagnosis of familial hypercholesterolemia and familial defective apolipoprotein B
Authors: Nissen Henrik , Hansen Annebirthe B. , Guldberg Per , Hansen Torben S. , Petersen Niels E. , Harder Mogens
Published: July 2010

We have recently developed a simple mutation screening assay based on the denaturing gradient gel electrophoresis (DGGE) technique for detection of mutations in the coding and regulatory regions of the low density lipoprotein receptor (LDLR) gene and the codon 3500 region of the apolipoprotein (apo) B‐100 gene leading to familial hypercholesterolemia (FH) and familial defective apo B‐100 (FDB), respectively. To evaluate the assay, 14 Danish families suspected of FH were studied. In ten families, the DGGE assay detected seven different point mutations, including mutations undescribed prior to establishing the assay. In addition, in one of these ten families and in one of the remaining four families, Southern blotting detected the FH‐DK3 exon 5 deletion. Based on segregation analysis and clinical data, the FH diagnosis was dubious in the remaining three families without DGGE or Southern blotting detectable mutations.

In conclusion, a simple DGGE based mutation screening assay may detect underlying mutations in most FH/FDB families, thus allowing its routine use in genetic counselling of FH‐families.
Ehlers‐Danlos syndrome and type III collagen abnormalities: a variable clinical
Authors: Hamel BCJ , Pals G. , Engels CHAM , van den Akker E. , Boers GHJ , van Dongen PWJ , Steijlen PM
Published: July 2010

Ehlers‐Danlos syndrome (EDS) comprises ten types. EDS IV is the most severe type because of its often lethal complications, such as arterial rupture. EDS IV is caused by an abnormality of collagen type III as a result of mutations in the corresponding gene COL3A1. A collagen type III abnormality is also seen in patients with EDS without the classical severe EDS IV phenotype. We report on 11 patients with type III collagen abnormality and normal collagen V in whom clinically EDS II, III, and IV were diagnosed. There is no correlation between the type of collagen III anomaly and the clinical phenotype. It is concluded that type III collagen abnormality may lead to a phenotypic spectrum and that it does not predict the severity and course of the disease.
Detection of factor V Leiden mutation in severe pre‐eclamptic Hungarian women
Authors: Nagy Bálint , Tóth Tamás , Jr János Rigó , Karádi István , Romics László , Papp Zoltán
Published: July 2010

Pre‐eclampsia is a pregnancy‐related disorder that complicates approximately 5% of all pregnancies and is cited as the primary cause of worldwide maternal and fetal mortality. The factor V Leiden mutation has been implicated in the development of severe pre‐eclampsia. In order to investigate this association, a sample of 198 Hungarian women was recruited and enrolled in one of the three groups based on reproductive and health status: those as classified as pregnant and healthy (n = 71), those diagnosed as pregnant and severe pre‐eclamptic (n = 69), and those found to be healthy and non‐pregnant (n = 58). The presence of factor V Leiden mutation was determined by using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism analysis (RFLP). We identified three (5.2%) heterozygous among healthy non‐pregnant participants, five (7.0%) heterozygous among healthy pregnant participants and 13 (18.8%) heterozygous among preeclamptic women (p < 0.05, 95% CI). Our result supports the previous observation that carriers of factor V Leiden mutation are at increased risk for developing severe pre‐eclampsia.
Prenatal identification ofde novomarker chromosomes using micro‐FISH approach
Authors: Xu Jia , Fong Chin‐To , Cedrone1 Edward , Sullivan Julie , Wang Nancy
Published: July 2010

Chromosome microdissection combined with polymerase chain reaction (PCR) and reverse chromosome painting (‘micro‐FISH’) is a powerful technique for the unequivocal identification of complex or subtle chromosomal aberrations. We have applied this technique to the prenatal diagnosis of three fetuses withde novomarker chromosomes. One small supernumerary satellited marker chromosome was shown to have originated from the fusion of the centromeric heterochromatin of one or both of chromosomes 14 and 22. The second marker was identified as i(9)(p10) while the third marker chromosome was shown to have been derived from the 1p13.1–1q21.3 region. At birth, the clinical outcome correlated well with that expected from the prenatal cytogenetic findings. Our study highlights the importance of the application of ‘micro‐FISH’ to prenatal diagnosis.
Brother/sister siblings affected with Hunter disease: evidence for skewed X chromosome inactivation
Authors: Sukegawa Kazuko , Matsuzaki Tetuo , Fukuda Seiji , Masuno Mitsuo , Fukao Toshiyuki , Kokuryu Mie , Iwata Shoko , Tomatsu Shunji , Orii Tadao , Kondo Naomi
Published: July 2010

Hunter disease is an X‐linked recessive disorder caused by a deficiency of iduronate‐2‐sulfatase activity. We describe a pair of brother/sister siblings with a typical feature of Hunter disease (mucopolysaccharidosis type II). They had normal karyotypes but a marked deficiency of iduronate‐2‐sulfatase activity in both lymphocytes and fibroblasts. The molecular analysis of the iduronate‐2‐sulfatase gene revealed the R468L(G1403→ T) substitution in their genes. Although the sister's genomic DNA was heterozygous for the mutant allele, the sister's cDNA was found to be homogeneous for this mutation. The mother was found to be a heterozygote. The analysis of X chromosome inactivation by comparison of the methylation patterns of the androgen‐receptor (AR) gene which was isolated from the sister's fibroblasts and leucocytes revealed a skewed X chromosome inactivation of the paternal allele. These findings indicate that a skewed X chromosome inactivation of the paternal gene and a point mutation in the maternal gene were responsible for the lack of iduronate‐2‐sulfatase activity in the sister.
Skewed X inactivation in manifesting carriers of Duchenne muscular dystrophy
Authors: Yoshioka Mieko , Yorifuji Tohru , Mituyoshi Izuru
Published: July 2010

We studied X inactivation patterns in manifesting carriers of familial and sporadic Duchenne muscular dystrophy (DMD) or unaffected carriers of DMD by analysis of the methylation of Hpall sites in the first exon of the human androgen‐receptor gene (HUMARA) from peripheral blood samples. Three of the four manifesting carriers, four of the five asymptomatic carriers, and 31 of the 32 female controls were heterozygous for the CAG repeat of HUMARA. All manifesting carriers showed skewed X inactivation, while all unaffected carriers showed almost symmetrical inactivation. One family studied over three generations is noteworthy because it includes two mother/daughter pairs, one an affected pair with skewed X inactivation, and the other a phenotypically normal carrier pair with random X inactivation. On the other hand, the extent of X inactivation for each X chromosome in 31 female controls was widely distributed. These data suggest that in carriers of DMD, both affected and unaffected, it is valuable to analyze the pattern of skewed X inactivation because it provides important prognostic information. Carriers of DMD with skewed X inactivation might show slowly progressive myopathy with advancing age.
Clinical, morphological and biochemical features in the familial articular hypermobility syndrome (FAHS): a family study
Authors: Garcia‐Cruz D. , Cano‐Colin S. , Sánchez‐Corona J. , Gallegos MP , Chimal‐Monroy J. , Díaz‐de‐León L.
Published: July 2010

A female with clinical features of familial articular hypermobility syndrome (FAHS) and her family were studied. The subject showed generalized hypermobility, except for a painful shoulder which presented functional limitation with a diagnosis of painful shoulder syndrome. Biochemical studies demonstrated that collagen and glycosaminoglycans (GAGs) contents from skin biopsies of the subject and her family were almost normal. Nevertheless, the densitometric analysis of electrophoretic patterns showed differences in the relative proportions of their collagenous components. They were characterized by changes in type I and III collagens and the presence of type V collagen, in the subject, her father and brother. Also, they presented changes in the types of GAGs, when compared with those of normal skin. Morphological studies revealed a general disorganization of dermal components, a loose collagen network characterized by thick bundles. Also, besides cellular elements, the presence of an abundant darkly staining material was observed.

Biochemical and morphological findings permit us to suggest a connective tissue defect, initially described in the FAHS, otherwise known as Ehlers‐Danlos syndrome (EDS) type XI.
Maternal cell contamination of buccal smear samples in nursing neonates
Authors: Babovic‐Vuksanovic Dusica , Michels Virginia V , Law Mark E , Lindor Noralane M , Jalal Syed M
Published: July 2010

Buccal smear analysis is a non‐invasive method which is being popularized by new fluorescence in situ hybridization (FISH) techniques. It is frequently used for gender identification and detection of sex chromosome aneuploidy in neonates. We attempted to determine whether or not buccal smears of nursing infants can be contaminated by maternal cells from breast feeding. FISH involving centromere specific directly labeled, multicolor probes for chromosomes X, Y and 18 were used for analysis of buccal smear samples. Buccal smear samples from 22 breast fed and 20 formula fed male neonates were analyzed in a blinded fashion. Twenty‐seven percent of samples from breast fed infants had some (0.5–2.5%) XX signal pattern while the samples from formula fed infants had no XX signal pattern (difference statistically significant, p < 0.02, at 95% confidence interval). Our results indicate that breast feeding can cause maternal cell contamination of buccal smear samples that can lead to misinterpretation of results involving FISH analysis or other DNA based diagnostic studies. We have also modified the FISH technique to suit the neonates.
Inherited microdeletion in Xp21.3–22.1 involved in non‐specific mental retardation
Authors: des Portes Vincent , Carrié Alain , Billuare Pierre , Kieffer Virginie , Bienvenu Thierry , Vinet Marie Claude , Beldjord Cherif , Kahn Axel , Ponsot Gérard , Chelly Jamel , Moutard Marie Laure
Published: July 2010

X‐linked mental retardation (XLMR) is a genetically and clinically neterogenous common disorder. A cumulative frequency of about 1/600 male births was estimated by different authors, including the fragile X syndrome, which affects 1/4000 males. Given this very high cumulative frequency, identification of genes and molecular mechanisms involved in other XLMRs, represents a challenging task of considerable medical importance. In this report we describe clinical and molecular investigations in the family of a mentally retarded boy for whom a microdeletion in Xp21.3–22.1 was detected within the frame of a previously reported systematic search for deletion using STS‐PCR screening. Thorough clinical investigation of the sibling showed that two affected brothers exhibit a moderate non‐specific mental retardation without any additional neurological impairment, statural growth deficiency or characteristic dysmorphy. Molecular analysis revealed that the microdeletion observed in this family is an inherited defect which cosegregates with mental retardation as an X‐linked recessive condition, since both non‐deleted boys and transmitting mother are normal. These results and the inherited microdeletion detected within the same region associated with non‐specific MR, reported by Raeymaekers et al., suggest that Xp21.3 MR locus is prone to deletions. Therefore, search for microdeletions in the eight families assigned by linkage analysis to this region might allow a better definition of the critical region and an identification of the gene involved in this X‐linked mental retardation.
Deletion of chromosome 3q proximal region gives rise to a variable phenotype
Authors: Ogilvie Caroline Mackie , Rooney Susan C , Hodgson Shirley V , Berry A Caroline
Published: July 2010

We report two new cases with interstitial deletions of chromosome 3. Both had breakpoints established as q 12q21. Despite an apparently identical abnormal karyotype, their phenotypes were different although hypotonia, severe developmental delay, lack of speech, high arched palate and pointed chin were common features. One patient had corpus cajlosum agenesis (ACC), also present in two of the only four previously reported cases with a deletion in this region.
Normal growth in Angelman syndrome due to paternal UPD
Authors: Smith A. , Robson L. , Buchholz B.
Published: July 2010

We describe 2 patients with Angelman syndrome (AS) due to paternal uniparental disomy (UPD). One patient is a female aged 30 years and the other a male aged 41/2 years. Both have the characteristic wide mouth and big chin, moderate mental retardation, virtually no speech but some 30 words of sign language and a happy disposition with outbursts of laughter. Ataxia is minimal in both patients, manifesting mainly when they are excited or running. Both patients are tall (height around 90th percentile), have a head circumference around 75th percentile and are overweight (weight over the 97th percentile). These cases add to the knowledge of the possibility of normal or increased growth parameters, particularly weight, in AS when the genetic mechanism is paternal UPD.
Prenatal diagnosis of low level trisomy 15 mosaicism: review of the literature
Authors: Zaslav AL , Fallet S. , Brown S. , Ebert R. , Fleischer A. , Valderama E. , Fox JE
Published: July 2010

Low level chromosome mosaicism found at amniocentesis is problematic for clinicians and patients. We report prenatal diagnosis of a fetus with a rare karyotype of 47.XX, + 15/46, XX. Second trimester amniocentesis was performed for advanced maternal age. Fetal ultrasound revealed a hypoplastic right ventricle and intrauterine growth retardation (IUGR). The rest of the fetal anatomy was within normal limits. A mosaic karyotype of 47.XX, + 15/46, XX was observed. The couple interrupted the pregnancy at 19 weeks by dilation and suction evacuation. Careful evaluation of multiple pieces of fetal parts and placenta revealed one abnormal finding: a single umbilical artery. Cytogenetic metaphase and fluorescent in situ hybridization (FISH) interphase analyses of cells from fetal lung, heart, placenta, and skin revealed the presence of the trisomic line in all tissues. Molecular analysis demonstrated that the origin of the extra chromosome 15 was maternal, the error most likely occurred in meiosis I and the diploid line was of biparental inheritance. This case report discusses the associated findings in this fetus and reviews the literature describing other cases of mosaic trisomy 15.
Internet databases for clinical geneticists ‐ an overview1
Authors: van Steensel MAM , Winter RM
Published: July 2010

In this paper, we provide an overview of databases that are of importance to clinical geneticists. Some suggestions for the fruitful use for both research and diagnosis are given. For beginning ‘web‐surfers’ we also list some well‐known search engines and give a short overview of how to use these and other services. In addition, the URLs of some of the most important databases, gateways and tutorials are listed.
Identification of iduronate sulfatase gene alterations in 70 unrelated Hunter patients
Authors: Froissart Roseline , Maire Irène , Millat Gilles , Cudry Stéphane , Birot Anne‐Marie , Bonnet Véronique , Bouton Olivier , Bozon Dominique
Published: July 2010

We studied 70 unrelated Hunter patients and found a gene alteration in every patient. The molecular heterogeneity was very important. Large gene rearrangements were identified in 14 patients. Forty‐three different mutations were identified in the 56 other patients and 31 were not previously described. Deletions and insertions, splice site mutations were associated with a severe phenotype as nonsense mutations except Q531X. Only a few mutations were present in several patients making difficult genotype‐phenotype correlations. Mutation identification allows accurate carrier detection improving prenatal diagnosis. The mother was not found to be a carrier in five cases among the 44 sporadic cases. Haplotype analysis demonstrated a higher frequency of mutations in male meiosis.
Glycogen storage disease type II: identification of a dinucleotide deletion and a common missense mutation in the lysosomal α‐glucosidase gene
Authors: Kroos Marian A , van Leenen Dik , Verbiest Jan , Reuser Arnold JJ , Hermans Monique MP
Published: July 2010

In nine Dutch patients with the infantile form of glycogen storage disease type II (GSDII), who were compound heterozygous for either 525delT or exon18del (1), sequence analysis was performed to search for the mutations in the second lysosomal a‐glucosidase allele. One patient had a novel TG deletion at cDNA position 379 + 380. Surprisingly five of the nine patients had the same two base pair changes: A921 ± T and G925 ±A. The first change is a well‐known polymorphism but the second one is a novel mutation and results in the substitution of Gly309 by Arg. By screening 43 other GSDII patients the same mutation was found in two other cases, one from The Netherlands and one from France. To verify its deleterious effect, the mutation was introduced in the wild type lysosomal α‐glucosidase cDNA and expressed in COS cells.
Linkage analysis in a large Spanish family with X‐linked retinitis pigmentosa: phenotype—genotype correlation
Authors: Capeans C. , Blanco M. J. , Lareu M. V. , Barros F. , Piñeiro A. , Sanchez‐Salorio M. , Carracedo A.
Published: July 2010

X‐linked retinitis pigmentosa (XLRP) accounts for 10–25% of RP families and causes the most severe form of the disease in terms of onset and progression. Although three different loci (RP3, RP2 and RP15) have been proposed on the short arm of the X‐chromosome by linkage analysis, RP3 represents the disease locus in the majority of XLRP families.

The identification of female carriers of X‐linked RP is important for genetic counselling. The presence of fundus and electroretinogram (ERG) abnormalities have been reported to be as high as 87 and 90%, respectively. However, in clinical practice it has not always been possible to know the carrier state of females at risk.

Thirty‐five members of a Spanish family with X‐linked RP were evaluated by linkage analysis using nine polymorphic markers (CYBB, DXS1110, M6, DXS6679, DXS1068, DXS1058, MAOA, MAOB and DXS6849) that map to the X‐chromosome region Xp21.1 to Xp11.3, in an attempt to determine the carrier state of these females at risk. It was possible to establish that a RP3 mutation is, most likely, segregating in this family.
Low frequency of RET mutations in Hirschsprung disease in Sweden
Authors: Svensson Pär‐Johan , Molander Marie‐Louise , Eng Charis , Anvret Maria , Nordenskjöld Agneta
Published: July 2010

Hirschsprung disease is a congenital malformation, where absence of intramural ganglia in the hindgut results in a defect in the coordination of peristaltic movement. This leads to ileus in the newborn or, more often, constipation in children and adults. The disease affects one in 5000 live births. Siblings of affected cases are at an increased risk (4%) of developing the disease. Among cases, males are affected more often than females.

The first major susceptibility gene for Hirschsprung disease is the RET proto‐oncogene on 10q11.2. Germline RET mutations in Hirschsprung disease are mainly inactivating, and have been reported to account for up to 20 and 50% of sporadic and familial cases, respectively. We have screened Swedish population‐based samples from 62 sporadic cases and seven familial cases of Hirschsprung disease with single strand conformation polymorphism (SSCP), and found five mutations.
Analysis of an interstitial deletion in a patient with Kallmann syndrome, X‐linked ichthyosis and mental retardation
Authors: Weissörtel R. , Strom T. M. , Dörr H. G. , Rauch A. , Meitinger T.
Published: July 2010

Contiguous gene syndromes are an interesting clinical phenomenon, resulting from interstitial or terminal deletions of several adjacent genes. The phenotype results in a combination of two or more monogenic disorders and relates clinical findings to corresponding genotypes. We present the case of a male patient with Kallmann syndrome (KS), X‐linked ichthyosis (XLI) and X‐linked mental retardation (MRX). He was referred at the age of 15.4 years for delayed puberty and obesity. He had a previous history of pyloric stenosis, bilateral orchidopexy and surgical correction of a pes equinovarus adductus. On physical examination, generalised ichthyosis and hypoplastic external genitalia were found. KS was evident with hypogonadotropic hypogonadism, hyposmia and a hypoplastic anlage of the olfactory tract in magnetic resonance imaging. Lipoprotein electrophoresis, and lack of steroid sulfatase and arylsulfatase‐C activity in leucocytes confirmed XLI. DNA investigation established an interstitial deletion in Xp22.3 involving the Kallmann (KAL) gene, the steroid sulfatase (STS) gene and a putative mental retardation locus (MRX). The novel MRX locus maps to a 1‐Mb region between DXS1060 and GS1.
Familial hypercholesterolemia: potential diagnostic value of mutation screening in a pediatric population of South Africa
Authors: Kotze Maritha J. , Peeters Armand V. , Loubser Odell , Theart Leonora , du Plessis Lana , Hayes Vanessa M. , de Jong Greetje , de Villiers J. Nico P. , Lombard Carl J. , Hansen Peter S. , Raal Frederick J.
Published: July 2010

Three founder‐related low‐density lipoprotein receptor (LDLR) gene mutations, D154N, D206E and V408M, cause familial hypercholesterolemia (FH) in approximately 90% of South African Afrikaners. Two hundred and twenty‐one South African children, from 85 affected families, were screened for the specific mutation identified previously in the index case. Sixty boys and 56 girls were heterozygous for mutation D154N (FH3), D206E (FH1) or V408M (FH2). Total and LDL cholesterol (LDLC) levels were similar among the children heterozygous for the three founder mutations, and mean values were significantly higher compared to those without a known mutation (p < 0.0001). Plasma cholesterol levels overlapped considerably between the different groups, suggesting that modifiable lifestyle factors remain important in children with FH. This study demonstrates the potential diagnostic value of mutation screening in a pediatric population with an enrichment of particular gene mutations.
SKALP/elafin gene polymorphisms are not associated with pustular forms of psoriasis
Authors: Kuijpers Astrid LA. , Pfundt Rolph , Zeeuwen Patrick LJM , Molhuizen Henri OF. , Mariman Edwin CM. , van de Kerkhof Peter CM. , Schalkwijk Joost
Published: July 2010

Psoriasis is a multifactorial skin disease characterised by epidermal abnormalities and infiltration by lymphocytes and polymorphonuclear leukocytes (PMN). Skin‐derived antileukoproteinase (SKALP), also known as elafin, is a potent inhibitor of human leukocyte elastase and proteinase 3, two PMN‐derived proteinases implicated in tissue destruction and leukocyte migration. We have shown that, at least at the protein level, SKALP is significantly decreased in lesional skin of patients with pustular psoriasis compared with plaque‐type psoriasis. This finding raised the possibility that SKALP could be one of the candidate genes for pustular forms of psoriasis. We therefore performed single strand conformation polymorphism (SSCP) analysis on the SKALP gene to screen for mutations/polymorphisms in the exons of 30 patients with plaque‐type psoriasis, 15 patients with pustular psoriasis and 48 healthy controls. In exon 1 a polymorphism was detected at position + 43 relative to the translation start site, resulting in a substitution of threonine for alanine in the signal peptide. In the promoter region a dinucleotide repeat polymorphism was identified. Both polymorphisms were not associated with pustular psoriasis, or psoriasis in general. Our data indicate that the decrease in SKALP activity in pustular psoriasis is not caused by mutations in the coding region of the gene, and that there is no allelic association between pustular psoriasis and SKALP gene polymorphisms.
Molecular analysis of the BRCA2 gene in 16 breast/ovarian cancer Spanish families
Authors: Osorio Ana , Robledo Mercedes , Martínez Beatriz , Cebrián Arancha , Román Juan Manuel San , Albertos Jose , Lobo Francisco , Benitez Javier
Published: July 2010

The recent isolated gene BRCA2 is responsible for about 45% of familial breast cancer and the majority of male breast cancer families. In order to evaluate the role of inherited BRCA2 mutations in Spanish families, the complete coding sequence of the gene was screened by SSCP/sequencing in 16 high‐risk breast/ovarian cancer families. Four mutations were found that cause a premature termination codon. Two of them have been reported elsewhere and one is a novel mutation. In addition we have found seven polymorphisms, two of which have not been previously described. One of the mutations, 936delAAAC was found in two of our high‐risk families. Because this mutation is considered as recurrent, we have tried to estimate its frequency in our breast cancer population. A total of 127 moderate‐ high‐risk families were screened for this mutation and it was also found in another high‐risk family. All the families carrying the 936delAAAC mutation harboured part of a common haplotype shared by other reported carriers, suggesting a possible founder effect for this mutation.
Map refinement of the Usher syndrome type 1B gene, MYO7A, relative to 11q13.5 microsatellite markers
Authors: Mouglabey Yolla Bou , Nimri Sawsan , Sayegh Fouad , Zir Elie El , Slim Rima
Published: July 2010

Usher syndrome (US) is clinically and genetically a heterogeneous group of disorders characterized by the association of deafness with retinitis pigmentosa. So far, eight genes responsible for US have been mapped, of which only the gene responsible for the most common form, USH1B, has been identified. The USH1B is a large gene containing 49 exons and encoding for an unconventional myosin‐VIIA (MYO7A). Mutation analysis within the MYO7A gene showed a wide variety of mutations dispersed all over the gene. The present report refines the location of the MYO7A gene relative to microsatellite markers mapped to this region, thereby allowing a reliable and efficient carrier detection by linkage analysis.
Pallister—Killian syndrome [i(12p)]: first pre‐natal diagnosis using cordocentesis in the second trimester confirmed by in situ hybridization
Authors: Chiesa J. , Hoffet M. , Rousseau O. , Bourgeois JM , Sarda P. , Mares P. , Bureau JP
Published: July 2010

Pallister–Killian syndrome (PKS) is the most frequent form of partial autosomal tetrasomy 12p in humans. Sufferers have a mosaic of isochromosome 12p [i(12p)]. We report the first pre‐natal diagnosis on fetal blood cells after cordocentesis during the second trimester. The extra chromosome was first diagnosed by in situ hybridization. Fluorescence in situ hybridization (FISH) was used to count the interphase and/or metaphase cells containing the isochromosome. A review of the literature identified 27 other reports of PKS diagnosed pre‐natally. We showed that the most consistent pre‐natal ultrasound findings include hypertelorism, broad neck, shorts limbs, abnormal hands or feet, diaphragmatic hernia and hydramnios. Recognition of this congenital malformation pattern pre‐natally may allow utilization of FISH.
Isolation of a 370 kb YAC fragment spanning a translocation breakpoint at 3p14.1 associated with holoprosencephaly
Authors: Pete Erwin , Kroisel Peter Michael , Wagner Klaus
Published: July 2010

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face. HPE is extremely heterogeneous, some cases being associated with structural anomalies of the short arm of chromosome 3. For a detailed characterization of a t(3;19)(p14.1;p13.1) breakpoint associated with HPE, we performed fluorescence in situ hybridization (FISH) analysis using yeast artificial chromosomes (YACs) mapped to the short arm of chromosome 3 from the Le Centre d'Etude du Polymorphisme Humain (CEPH) library. Three YACs mapped proximal, and one was located distal to the described breakpoint on chromosome 3. One of the chromosome 3 ‘Mega‐YACs’ spanned the translocation breakpoint. From this chimeric YAC we generated a site specific probe of about 370 kb by digestion of the YAC‐DNA, which will be assessed for gene alterations that could underlie HPE in this patient.
Charcot‐Marie‐Tooth phenotype produced by a duplicated PMP22 gene as part of a 17P trisomy‐translocation to the X chromosome
Authors: King PH , Waldrop R. , Lupski JR , Shaffer LG
Published: July 2010

The Charcot‐Mane‐Tooth disease type 1A (CMTlA) phenotype is most often associated with a 1.5 megabase (mb), tandem duplication of chromosome 17 band p12 (17˜12). The prevailing hypothesis is that the demyelinating neuropathy results from a dosage effect of the peripheral myelin protein gene PMP22 which is included within this duplication. We present a patient with clinical and electrophysiological features ofCMTlA in whom an extra PMP22 gene resulted from a rare unbalanced translocation of 17p to the X chromosome. This finding further supports the hypothesis of gene dosage as the basis for CMTlA. More‐over, this case highlights the importance of fluorescence in siiu hybridization (FISH) as an alternative molecular technique in the diagnosis of CMTlA.
Prenatal diagnosis of a trisomy 17p derived from a de novo non‐mosaic satellited marker
Authors: Kulharya Anita S , Garcia‐Heras Jaime , Radtke Heather B , Norris Karen S , Keppen Laura D , Flannery David B
Published: July 2010

A trisomy 17pter→p11.2 derived from a supernumerary de novo satellited marker was identified by GTG bands and fluorescent in situ hybridisation (FISH) in amniocytes of a fetus with malformations and intrauterine growth retardation (IUGR). At 39 weeks a male infant with a phenotype similar to other postnatal cases of ‘pure.’ complete trisomy 17p was born. Some additional clinical features, however, make him more severely affected than previous patients.
The long and the short of it: developmental genetics of the skeletal dysplasias
Authors: Dreyer Sandra D , Zhou Guang , Lee Brendan
Published: July 2010

The skeletal dysplasias are a large heterogeneous group of genetic conditions characterized by abnormal shape, growth, or integrity of bones. Often, there may be prominent features associated with other organ systems as part of a more encompassing skeletal malformation syndrome. Tremendous advances have been made in the clinical and molecular delineation of these conditions over the past 20–30 years. We have progressed from initial broad clinical classifications of these conditions in the first two‐thirds of this century, to extensive delineation based on radiographic features in the 1970s and 1980s, to the present reconsideration and grouping of these conditions according to their molecular pathogenesis. This has in part been spurred on by advances in the understanding of the developmental pathways which govern skeletal development, as well as by the human genome sequencing effort, which has provided a plethora of positional candidate genes for many of these conditions. The pathogenetic correlations derived from such studies are often based on parallels between the human phenotype and mouse models of the human condition, and have sometimes revealed novel developmental functions.
Carrier detection in Duchenne and Becker muscular dystrophy Argentine families
Authors: Baranzini Sergio E , Giliberto Florencia , Dalamon Viviana , Barreiro Cristina , García‐Erro Marcela , Grippo Jorge , Szijan Irene
Published: July 2010

In order to offer carrier detection, genetic counseling, and prenatal diagnosis to families with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) in our country, segregation analysis of highly polymorphic short tandem repeats (STR) (dC‐dA)n: (dG‐dT)n loci was utilized. The risks to females of 15 DMD/BMD families (9 familial and 6 sporadic) were evaluated on STR, pedigree and serum creatine kinase (SCK) data. From the 36 females at risk of being carriers (not including 8 obligate carriers), results of STR analysis were compatible with carrier status in 7 and not compatible in 20. In 9 females, no information regarding carriership was derived from the STR analysis. Prenatal diagnosis is now possible on the carrier females. Previously identified deletions in the central part of the gene were confirmed by STR analysis in 3 families. Five new alleles were identified in Argentine individuals; allele frequencies differed from those of North American people. Results derived from this study are useful for carrier detection and genetic counseling in DMD/BMD. One case of probable mosaicism in an unaffected father was detected on a pedigree basis in a family with DMD patients.
The evaluation of 15q proximal duplications by FISH
Authors: Riordan D. , Dawson AJ
Published: July 2010

Six patients from the clinical cytogenetics laboratory identified as having the normal variant dup(15)(q12) were further evaluated using fluorescence in situ hybridization (FISH). The purpose of this study was to ascertain whether any of the Prader–Willi/Angelman Chromosome Region (PWCR and ANCR, respectively) loci were duplicated in these patients. The results indicated that the patients could be categorized into two groups. The first group showed no duplication of the PWCR/ANCR loci and appeared to belong to the dup(15)(q12) class which is phenotypically silent and is therefore called the normal variant. The second group also showed no duplication of the PWCR/ANCR loci, but had a large alpha satellite variant with D15Z. It is hypothesized that these patients do not have a duplication of 15q12 but rather a centromeric variant which mimics the dup(15)(q12). This study confirms the importance of evaluating apparent variations in the proximal region of chromosome 15 with FISH.
Ethical considerations for enzyme replacement therapy in neuronopathic Gaucher disease
Authors: Elstein Deborah , Abrahamov Ayala , Zimran Ari
Published: July 2010

Elstein D, Abrahamov A, Zimran A. Ethical considerations for enzyme replacement therapy in neuronopathic Gaucher disease. Clin Genet 1998: 54: 179–184. 0 Munksgaard, 1998

Enzyme replacement therapy for Gaucher diseases, the most prevalent lysosmal storage disease, was originally approved by the FDA for type I patients and has proven to be both safe and effective in reducing hepatosplenomegaly and improving the hematological parameters. However, the use of enzyme treatment in both neuronopathic forms has heretofore been on an investigational or trial basis, with reports of progression of neurological deterioration even at very high doses. To date, there are no guidelines for clinicians with regard to enzyme replacement therapy in the neuronopathic forms of metabolic diseases. Herein, we discuss strategies derived from the literature ub‐his treatment of very premature babies and from the Jewish Halachic point of view. In conclusion, we describe recommendations for the ethical treatment and/or withdrawal of treatment. as well as practical guidelines for dosage regimens, in children with neuronopathic Gaucher disease.
Severe classical congenital muscular dystrophy and merosin expression
Authors: Vajsar Jiri , Chitayat David , Becker Laurence E. , Ho Michael , Ben‐Zeev Bruria , Jay Venita
Published: July 2010

Vajsar J, Chitayat D, Becker LE, Ho M, Ben‐Zeev B, Jay V. Severe classical congenital muscular dystrophy and merosin expression. Clin Genet 1998: 54: 193–198. 0 Munksgaard, 1998

It has been suggested that patients with autosomal recessive merosin deficient congenital muscular dystrophy (CMD), as opposed to the merosin positive cases form a homogeneous subgroup of a clinically more severe form of CMD. We examined merosin expression in muscle biopsies from five children with the severe classical form of CMD. Merosin deficiency was found only in 1 patient, a 6–year‐old female, with abnormal brain myelination. However, her initial biopsy did not reveal the classical picture of dystrophy. The four merosin positive cases exhibited severe muscle weakness but their brain imagings were normal. There were no familial cases, except for the mother of 1 patient who had a milder form of the disease, suggesting an autosomal dominant mode of inheritance.

In contrast to previous reports, the merosin deficient CMD cases were rare in our group. Furthermore, merosin positive cases were also associated with severe phenotype suggesting that a severe phenotype is not exclusive to merosin deficient cases. Finally, the absence of merosin in a neonate with hypotonia and weakness can be helpful in making a definitive diagnosis of CMD, even though the dystrophic process may not be evident yet and histology may be non‐specific.
Molecular basis of cystic fibrosis in the Republic of Macedonia
Authors: Petreska L. , Koceva S. , Plaseska D. , Chernick M. , Gordova‐Muratovska A. , Fustic S. , Nestorov R. , Efremov GD
Published: July 2010

Petreska L, Koceva S, Plaseska D, Chernick M, Gordova‐Muratovska A, Fustic S, Nestorov R, Efremov GD. Molecular basis of cystic fibrosis in the Republic of Macedonia. Clin Genet 1998: 54: 203–209. 0 Munksgaard, 1998

Eighty‐three cystic fibrosis (CF) patients and their families, belonging to various ethnic groups living in the Republic of Macedonia were studied for molecular defects in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and for the associated extragenic marker loci XV‐2c and KM 19. The DNA methodology used included characterization of CFTR mutations in 19 exons (and flanking sequences) of the gene and analysis of distribution of the XV‐2c/KM19 haplotypes among normal (N) and CF chromosomes by polymerase chain reaction (PCR) amplification followed by dot blot hybridization, restriction digestion, single‐strand conformational polymorphism, constant denaturing gel electrophoresis, denaturing gradient gel elec‐trophoresis, and sequencing. We identified 58.4% (97/166) of the CF chromosomes. Nine different CFTR gene mutations, including three novel ones. were found. Eight known and one new CFTR intragene polymorphisrns were also characterized. The haplotype analysis of the XV‐2c/TaqI and KM19/PstI polymorphic loci have shown that haplotype C is the most frequently found haplotype among the non‐AF508 CF chromosomes from Macedonia (36.5%). The results demonstrate the broad heterogeneity of CF origin in this part of the Balkan Peninsula.
A family with three germline mutations in BRCAl and BRCA2
Authors: Liede Alexander , Metcalfe Kelly , Offit Kenneth , Brown Karen , Miller Shari , Narod Steven A. , Moslehi Roxana
Published: July 2010

Liede A, Metcalfe K, Offit K, Brown K, Miller S, Narod SA, Moslehi R. A family with three germline mutations in BRCAl and BRCA2. Clin Genet 1998: 54: 215–218. 0 Munksgaard. 1998

Several cancer genetics centres offer testing for specific BRCAl and BRCAZ mutations to Ashkenazi Jewish individuals with a family history of breast and ovarian cancers. Testing involves screening for three common mutations found in this population, namely BRCA I 185delAG, 5382insC and BRCA2 6174delT (Struewing et al., Nat Genet 1995: 11: 198–200; Roa et al., Nat Genet 1996: 14 185–187; Oddoux et al., Nat Genet 1996: 14 188–190). We have identified a large Ashkenazi Jewish kindred (W9170) with ten cases of breast cancer and four cases of ovarian carcinoma. Initially, mutation analysis for this family identified a BRCAl 185delAG mutation in the proband diagnosed with three separate primary cancers of the breast, ovary and colon. Another individual in this family diagnosed with two primary cancers of the ovary and breast, was identified as having a second mutation, BRCA I 5382insC. Subsequent work found that two sisters (cousins of the proband), both diagnosed with carcinoma of the breast, had a third mutation, BRCAZ 6174delT. These three mutations have previously been found to be more common in the Ashkenazi Jewish population (References as above). The identification of all three mutations in one family, raised new implications for the manner in which testing and counselling should be offered. In our opinion, Ashkenazi Jewish individuals in breast‐ovarian cancer families should be offered complete testing for the three common Ashkenazi Jewish mutations regardless of previous identification of one of these mutations in the family.
Dinucleotide repeat polymorphism within the tumor suppressor gene PTCH at 9q22
Authors: Louhelainen Jari , Lindströrn Erica , Hemrninki Kari , Toftgård Rune
Published: July 2010

Louhelainen J, Lindström E, Hemminki K, Toftgård R. Dinucleotide repeat polymorphism within the tumor suppressor gene PTCH at 9q22.
Cryptic chromosome rearrangements detected by subtelomere assay in patients with mental retardation and dysmorphic features
Authors: Dawson AJ , Putnam S. , Schultz J. , Riordan D. , Prasad C. , Greenberg CR , Chodirker BN , Mhanni AA , Chudley AE
Published: July 2010

The regions near telomeres of human chromosomes are gene rich. Chromosome subtelomere rearrangements occur with a frequency of 7–10% in children with mild‐to‐moderate mental retardation (MR) and approximately 50% of cases are familial. Clinical investigation of subtelomere rearrangements is now prompted by fluorescence in situ hybridization (FISH) analysis using specific DNA probes from all relevant chromosome ends. In our study, 40 children were selected for subtelomere assay using either the Chromophore Multiprobe‐T Cytocell device or the VYSIS TelVision probes. Inclusion criteria were: developmental delay or MR; a normal 550 G‐band karyotype; FRAXA negative; and at least one other clinical criterion. Exclusion criteria included an identified genetic or environmental diagnosis. Of the 40 patients analysed, four (10%) were found to have subtelomere rearrangements. Three of 40 (7.5%) were found to have an unbalanced subtelomere rearrangement and one of 40 (2.5%) was found to have an apparently normal variant subtelomere deletion. The first of the three with an unbalanced karyotype was the result of a familial translocation, the second was a de novo finding, and the origin of the third could not be determined. The subtelomere FISH assay detected almost twice the frequency of unbalanced karyotypes as those detected by 550 G‐banding in our cytogenetics laboratory (4.7%). In addition, subtelomere screening was eight times more likely than fragile X screening in our DNA laboratory (1%) to detect genetic abnormalities in mentally handicapped individuals. Our findings support the view that screening for subtelomere rearrangements has a greater positive yield than other commonly used genetic investigations and, if cost and resources permit, should be the next diagnostic test of choice in a child with unexplained MR/dysmorphisms and a normal 550 G‐band karyotype.
GFAP mutations and polymorphisms in 13 unrelated Italian patients affected by Alexander disease
Authors: Caroli F , Biancheri R , Seri M , Rossi A , Pessagno A , Bugiani M , Corsolini F , Savasta S , Romano S , Antonelli C , Romano A , Pareyson D , Gambero P , Uziel G , Ravazzolo R , Ceccherini I , Filocamo M
Published: July 2010

Alexander disease (AD), a rare neurodegenerative disorder of the central nervous system, is characterized by the accumulation of cytoplasmic protein aggregates (Rosenthal fibers) composed of glial fibrillary acidic protein (GFAP) and small heat‐shock proteins within astrocytes. To date, more than 40 different GFAP mutations have been reported in AD. The present study is aimed at the molecular diagnosis of Italian patients suspected to be affected by AD. By analyzing the GFAP gene of 13 unrelated patients (eight with infantile form, two with juvenile form and three with adult form), we found 11 different alleles, including four new ones. Among the novel mutations, three (p.R70Q, p.R73K, and p.R79P) were identified in exon 1 and p.L359P in exon 6. The sequence analysis also detected six different single nucleotide polymorphic variants, including two previously unreported ones, spread throughout non‐coding regions (introns 2, 3, 5, 6, and 3′UTR) of the gene. All patients were heterozygous for the mutations, thus confirming their dominant effect.
DMPK‐associated myotonic dystrophy and CTG repeats in Alabama African Americans
Authors: Acton RT , Rivers CA , Watson B , Oh SJ
Published: July 2010

Myotonic dystrophy type 1 (DM1) is a result of a CTG expansion in the 3′‐untranslated region of the DMPK gene. DM1 is rare among African blacks who have fewer large CTG repeats in the normal range than other racial/ethnic groups. Neither the prevalence of DM1 nor the relationship of CTG expansion to clinical status in African Americans (AAs) is well documented. We describe two AA brothers with DM1, each of whom had CTG repeats of 5/639; their father was reported to have DM1 and had CTG repeats of 5/60. Other family members had CTG repeats of 5–14. An unrelated AA patient from a second kinship also had DM1; an analysis revealed CTG repeats of 27/191. In 161 Alabama AA control subjects, we observed 18 CTG alleles from 5 to 28 repeats; the most common allele had five CTG repeats. The frequency of CTG repeats ≥15 were greater (p < 0.0003) in Pygmy, Amhara Ethiopian, Ashkenazi Jewish, North African Jewish, Israeli Muslim Arab, European white, and Japanese populations than in the Alabama AA population. These data suggest that the risk for DM1 in AAs is intermediate between that of African blacks and whites of European descent.