bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring gene—gene interactions in the etiology of neural tube defects
Authors: Botto Lorenzo D. , Mastroiacovo Pierpaolo
Published: July 2010

The role of susceptibility genes in the etiology of birth defects is unclear, but may involve in some cases multiple alleles at multiple loci. We suggest a simple epidemiologic approach to explore gene‐gene interactions, and use it to reevaluate data from a recent case‐control study on the possible association of neural tube defects (NTDs) with specific mutations of two genes, 5,10‐methylene‐tetrahydrofolate reductase (MTHFR) and cystathionine‐β synthase (CBS). We found that, compared with the common genotype, homozygosity for the MTHFR mutation alone was associated with a two‐fold increased risk for NTDs, while homozygosity for the CBS mutation alone was not a risk factor. However, homozygous individuals for the mutations at both loci had a five‐fold greater risk for NTDs than those with the reference genotype. Though the original study was too small to detect statistically significant differences among most of the risk estimates, these results, if confirmed by independent and larger studies, suggest that gene‐gene interaction may play a role in modulating the susceptibility to NTDs in a proportion of affected individuals. This approach, moreover, could be a valuable adjunct to the study of gene‐gene interactions in the etiology of human disease.
A deletion involving exons 2–4 in the iduronate‐2‐sulfatase gene of a patient with intermediate Hunter syndrome
Authors: Bonuccelli Gloria , Regis Stefano , Filocamo Mirella , Corsolini Fabio , Caroli Francesco , Gatti Rosanna
Published: July 2010

A large deletion in the iduronate‐2‐sulfatase (IDS) gene has been found in a patient affected by an intermediate form of Hunter syndrome (mucopolysaccharidosis II). The deletion involves exons 2–4, the breakpoints lying respectively in intron 1, at position 376, and in intron 4, at position 5725. cDNA analysis revealed a direct exon 1‐exon 5 junction due to the deletion resulting in a frameshift mutation.
Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate‐dehydrogenase, methenyltetrahydrofolate‐cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects
Authors: Hol Frans A , van der Put Nathalie MJ , Geurds Monique PA , Heil Sandra G , Trijbels Frans JM , Hamel Ben CJ , Mariman Edwin CM , Blom Henk J
Published: July 2010

It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate‐dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD.
DGGE screening of mutations in mismatch repair genes (hMSH2 and hMLH1) in 34 Swedish families with colorectal cancer
Authors: Liu Tao , Wahlberg Siobhan , Rubio Carlos , Holmberg Eva , Grönberg Henrik , Lindblom Annika
Published: July 2010

Hereditary non‐polyposis colorectal cancer (HNPCC) is an autosomal dominantly inherited syndrome which confers an increased risk for colorectal cancer and endometrial cancer as well as other tumors. It is caused by germline DNA mismatch repair (MMR) gene mutations in five MMR genes, hMSH2, hMLH1, hPMS1, hPMS2 and hMSH6. Finding mutations in these high risk families means that you can offer presymptomatic carrier diagnosis and thereby identify individuals with a very high risk for cancer. These persons benefit from counseling and should be offered surveillance. We have used DGGE to screen members from 34 families for mutations in hMLHl and hMSH2. Six mutations in five families were found, five of these mutations are new. Besides, three new polymorphisms were identified. The mutations were found in two of seven Amsterdam criteria HNPCC families and in three of four families with at least one case of early onset of CRC (before 35), suggesting there are apporopriate families to be chosen for mutation screening in MMR genes.
High frequency of IgE receptor FcεRIß variant (Leu181/Leu183) in Kuwaiti Arabs and its association with asthma
Authors: Hijazi Z. , Haider MZ , Khan MR , AI‐Dowaisan AA
Published: July 2010

The presence of IgE receptor FcεRIβ polymorphism (181/183) was investigated in Kuwaiti asthmatic patients and controls using an allele refractory mutation screening (ARMS) test. The variant sequence (Leu181/Leu183) was detected in 72% (320/442) chromosomes analysed. Homozygous LL genotype was detected in 48% (46/96) asthmatic subjects compared to 31% (39/125) in non‐asthmatics. In 11/52 families mothers of the asthmatic children were themselves asthmatic and 3/11 asthmatic mothers had homozygous LL genotype. 80% of the homozygous LL asthmatics showed a positive skin prick test (SPT) compared with 28% of non‐asthmatics with the same genotype. In heterozygous NL asthmatics a positive SPT was found in 60% cases compared to 17% in non asthmatics with the same genotype. The incidence of hay fever (HF) and eczema (E) was also found to be higher in homozygous LL asthmatics compared with the non‐asthmatics with the same genotype. This study reports a high prevalence of IgE receptor FcεRIβ variants in Kuwaiti Arabs compared with British, Australian and Austrian populations studied before. The association of Leu181/Leu183 variant with asthma in Kuwaitis underlines its significance as a risk factor in manifesting the clinical phenotype in this population.
Implications of genotyping of spouses to limit investigation of children in genetic hemochromatosis
Authors: Adams Paul C
Published: July 2010

Background: A genetic test for hemochromatosis has allowed for the first time, genotypic identification of heterozygotes. The purpose of this study is to determine whether genotyping of spouses of homozygotes results in fewer investigations of children and subsequent cost savings.

Methods: Two hundred and ninety one children of homozygotes were studied using HLA typing, transferrin saturation and serum ferritin. Ninety six percent of the probands were homozygous for the C282Y mutation of the HFE gene. Pedigrees were reviewed to determine cost savings incurred if the spouse had been genotyped to guide follow‐up studies in the children. Paternity was confirmed by HLA studies.

Results: There were 13 homozygotes identified. All homozygous children tested (10/10) were homozygous for the C282Y mutation. There were no iron loaded children identified in homozygotes negative for the C282Y mutation. Genotyping of the spouse eliminated the need for the investigation of 269 children. The cost savings of this strategy were modeled using the cost of the family studies (consultation, iron studies) minus the cost of spouse assessment (consultation, genotyping) plus the cost of assessment of children in families in which the spouse was a heterozygote. The spousal genotyping strategy resulted in a cost savings of 39%.

Conclusion: Genotying the spouse of a homozygote is the best cost‐efficient strategy in pedigree studies because it leads to more selective investigation of children for the hemochromatosis gene.
Glucose‐6‐phosphatase gene (727G→T) splicing mutation is prevalent in Hong Kong Chinese patients with glycogen storage disease type la
Authors: Lam Ching‐Wan , But Wai‐Man , Shek Chi‐Chung , Tong Sui‐Fan , Chan Yuen‐Shan , Choy Kwong‐Wai , Tse Wing‐Yee , Pang Chi‐Pui , Hjelm Nils Magnus
Published: July 2010

Glycogen storage disease type la (GSD1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose‐6‐phosphatase (GóPase). We analyzed the GóPase genes of two unrelated Chinese families with GSD1a. DNA sequencing of all five exons and the exonintron boundaries revealed a G → T transversion at nucleotide 727 (727G→T) in exon 5, which has previously been reported to cause abnormal splicing. In one family, the subject and her affected sister were confirmed to be homozygous for this mutation and their parents to be heterozygotes. In the other family, the proband was identified to be heterozygous for this mutation, and a novel mutation, the 341delG in exon 2, was identified. This mutation alters the reading frame and creates a stop codon TAA 15 codons downstream from the mutation, resulting in a truncated protein. Family studies revealed that the father was heterozygous for the 727G → T mutation and that the mother was heterozygous for the 341delG mutation. This is the first time that the 727G→T mutation has been found in Chinese patients or outside Japan. Since we only tested two GSDla families and found 727G→T in both, we believe that this mutation may also be prevalent in our local Chinese population. To investigate allele frequencies, we screened 385 Chinese healthy volunteers and found two asymptomatic carriers. Our findings suggest that the 727G → T mutation is indeed prevalent in Hong Kong.
Serum lipids and apolipoprotein E phenotypes in identical twins reared apart1
Authors: Kervinen Kari , Kaprio Jaakko , Koskenvuo Markku , Juntunen Juhani , Kesäniemi Y Antero
Published: July 2010

Lipid and lipoprotein metabolism is controlled by genes, the environment and the gene‐environment interaction. We studied monozygotic twin pairs reared apart (MZA) and an age‐sex matched group of twins reared together (MZT) to evaluate the effects of the genotype and the rearing environment on lipids. The intraclass correlations for low density lipoprotein (LDL) cholesterol were 0.21 and 0.50 for the MZA and MZT groups, respectively, suggesting that the rearing environment possibly had an impact on the variability in LDL cholesterol later in life. The intraclass correlations for total cholesterol (0.26 and 0.47 for the MZA and MZT groups, respectively) reflected those for LDL cholesterol. The intraclass correlations for high density lipoprotein (HDL) cholesterol did not show any difference between the twin groups, suggesting that the rearing environment does not have major long‐term effects on the variability of HDL levels. The intrapair differences for LDL cholesterol were smallest in the twins heterozygous for the apolipoprotein E allele ε2 (E2/3 and E2/4 phenotypes), intermediate in the pairs with the common E3/3 phenotype and enhanced in the pairs with E4/3 phenotype. To conclude, these data suggest that the rearing environment may play a role in the variability of LDL cholesterol levels, although variance difference between MZAs and MZTs, and the small number of available monozygotic twins reared apart limits the generalizability of the results.
Detection and incidence of cryptic Y chromosome sequences in Turner syndrome patients
Authors: Patsalis Philippos C , Sismani Carolina , Hadjimarcou Michael I , Kitsiou‐Tzeli Sophia , Tzezou Aspasia , Hadjiathanasiou Charalambos G , Velissariou Voula , Lymberatou Evangelia , Moschonas Nicholas K , Skordis Nicos
Published: July 2010

The presence of Y chromosome sequences in Turner syndrome (TS) patients may predispose them to gonadoblastoma formation with an estimated risk of 15–25%. The aim of this study was to determine the presence and the incidence of cryptic Y chromosome material in the genome of TS patients. The methodology involved a combination of polymerase chain reaction (PCR) and nested PCR followed by Southern blot analysis of three genes—the sex determining region Y (SRY), testis specific protein Y encoded (TSPY) and RNA binding motif protein (RBM) (previously designated as YRRM) and nine additional STSs spanning all seven intervals of the Y chromosome. The methodology has a high sensitivity as it detects one 46, XY cell among 105 46, XX cells. Reliability was ensured by taking several precautions to avoid false positive results. We report the results of screening 50 TS patients and the identification of cryptic Y chromosome material in 12 (24%) of them. Karyotypes were divided in four groups: 5 (23.8%) patients out of the 21 TS patients which have the 45, X karyotype (group A) also have cryptic Y sequences; none (0%) of the 7 patients who have karyotypes with anomalies on one of the X chromosomes have Y mosaicism (group B); 1 (6.3%) of the 16 patients with a mosaic karyotype have Y material (group C); and 6 (100%) out of 6 patients with a supernumerary marker chromosome (SMC) have Y chromosome sequences (group D). Nine of the 12 patients positive for cryptic Y material were recalled for a repeat study. Following new DNA extraction, molecular analysis was repeated and, in conjunction with fluorescent in situ hybridization (FISH) analysis using the Y centromeric specific probe Yc‐2, confirmed the initial positive DNA findings. This study used a reliable and sensitive methodology to identify the presence of Y chromosome material in TS patients thus providing not only a better estimate of a patient's risk in developing either gonadoblastoma or another form of gonadal tumor but also the overall incidence of cryptic Y mosaicism.
Sex ratio and absence of uniparental disomy in spontaneous abortions with a normal karyotype
Authors: Smith Martin J , Creasy Michael R , Clarke Angus , Upadhyaya Meena
Published: July 2010

A series of spontaneous abortions collected in the South Wales region over a period of 18 months was karyotyped to identify those with a normal chromosome complement. Microsatellite polymorphisms distributed throughout all autosomes were typed by the polymerase chain reaction to determine the parental origin of each autosome pair in karyotypically normal spontaneous abortions. In 35 cases biparental inheritance of every autosome pair was demonstrated. The sex ratio of the normal spontaneous abortions of proven biparental origin was 0.77, but this was not significantly different from 1.00.
G2 repair in Nijmegen breakage syndrome: G2 duration and effect of caffeine and cycloheximide in control and X‐ray irradiated lymphocytes
Authors: Pincheira J. , Bravo M. , Santos M.J
Published: July 2010

Lymphocytes from a patient with the Nijmegen breakage syndrome (NBS/NBS) and his parents (NBS/+) have been analyzed to identify possible disturbances in chromosomal G2 repair. The study included the determination of G2 duration and the analysis of the chromosomal aberration frequencies in lymphocytes with/without caffeine and cyclohexemide (CHM) treatments during G2, under control and X‐irradiated conditions. Under control conditions, NBS/NBS lymphocytes showed that the basal chromosomal damage as well as the damage detected in G2, with caffeine treatment, and the G2 duration were higher than cells from an age‐matched control. In X‐irradiated NBS/NBS lymphocytes. the basal and G2 chromosome aberration frequencies were higher than in the controls; however, no significant differences in G2 duration were detected between these two type of cells.

Under X‐irradiated conditions, NBS/+ lymphocytes showed that while the level of chromosomal damage in G2 and the duration of this cell cycle phase were similar to the control cells, the frequency of unrepaired chromosomal lesions was higher than in the control lymphocytes. No significant differences in chromosomal damage and G2 duration were detected in NBS/+ lymphocytes compared to the control cells, under control conditions.

CHM treatment, which induces an increase in G2 duration, decreased the basal spontaneous and X‐ray induced chromosome aberration frequency in NBS/NBS and NBS/+ lymphocytes. These results suggest that NBS lymphocytes might be affected by some disturbances in their ability to extend the G2 duration, which may be influencing their DNA repair efficiency in this phase of the cell cycle.
Discordant repeat size and phenotype in Kennedy syndrome
Authors: Morrison PJ , Mirakhur M. , Patterson VH
Published: July 2010

Previous reports in the literature have described correlation of increasing repeat length with severity of the phenotype, in Kennedy syndrome. We describe male siblings with different repeat lengths, with lack of expression of the phenotype in the sibling with the longer repeat length. The phenotype was identical to motor neurone disease. There is variability of expression in Kennedy syndrome and repeat length even in siblings cannot be taken as a conclusive indicator of severity. CAG repeat length cannot be used to predict the natural history of Kennedy disease. The diagnosis of Kennedy syndrome should be considered in male patients presenting with atypical motor neurone disease.
Molecular and cytogenate analysis of an X/autosomal translocation: 45, X, dic(X;17)(p22.2;p13)
Authors: Eggermann Thomas , Mau Ulrike , Klein‐Vogler Ute , Kendziorra Heidemarie , Mackensen‐Haen Susanne , Sieverding Ludger , Enders Herbert , Kaiser Peter
Published: July 2010

We present an unusual case of monosomy 17p13‐pter and monosomy Xp22.2‐pter due to a dicentric translocation chromosome X/17 in a female newborn with severe anomalies. The karyotype was identified as 45, X, dic(X;17)(p22.2;p13) by high resolution GTG banding in lymphocytes. R banding showed the translocational X‐chromosome to be late replicating, and there was no spreading of X‐inactivation onto the autosomal segment. Furthermore, it could be demonstrated by C banding that the X‐centromere in the translocation chromosome was inactive.

The results of short tandem repeat (STR) typing confirmed the partial monosomy X and 17 as well as the paternal origin of the two chromosomes X and 17 which were involved in the translocation chromosome formation. The cell stage of the structural rearrangement was consistent with paternal meiosis as well as with postzygotic mitosis. The monosomy was confirmed in lymphocytes and fibroblasts, and mosaicism was not detected.
Apolipoprotein E genotypes in offspring with a positive and negative family history of premature myocardial infarction
Authors: Rašlová Katarina , Smolková Božena , Vohnout Branislav , Schifferdecker Branislav , Poledne Rudolf , Dusinšká Maria
Published: July 2010

Apolipoprotein E (apo‐E) aliele and genotype frequencies were evaluated in offspring with positive (MI‐offspring) and negative (control‐offspring) parental history of myocardial infarction (MI). The apo‐E allele frequencies in MI‐and control‐offspring were as follows: ε2: 9.04 and 2.08% (p < 0.02), ε3: 84.04 and 87.5%. ε4: 6.91 and 10.41%, respectively. The frequencies of the E2‐genotypes were significantly lower in offspring of controls (4.2%, 17.0%, respectively, p < 0.03). The ε2‐allele is associated with raised plasma triglyceride concentrations in subjects on a diet high in saturated fat. We therefore hypothesize that offspring carrying an ε2‐allele are predisposed to develop disturbance of plasma triglyceride metabolism when exposed to a traditional Slovak high‐fat diet and/or weight gain, resulting in altered lipid levels and increased predisposition to atherosclerosis.
Partners with reciprocal translocations: genetic counseling for the ‘double translocation’
Authors: Cook Lola , Hartsfield James K , Vance Gail H
Published: July 2010

SV at age 2 years presented with multiple congenital anomalies including an absent left kidney, anal stenosis, vertebral abnormalities, partial sacral agenesis, microcephaly, dysmorphic facial features, growth deficiency, and developmental delay. She was found to have a complex chromosomal rearrangement derived from balanced translocations in each parent.
Jumping translocation with partial duplications and triplications of chromosomes 7 and 15
Authors: Jewett T. , Marnane D. , Stewart W. , Hayworth‐Hodge R. , Finklea L. , Klinepeter K. , Rao PN , Pettenati MJ
Published: July 2010

We report a 2‐year‐old female with seizures, mild dysmorphic features and a jumping translocation involving chromosome 15 that results in multiple cell lines with partial duplications and triplications of chromosomes 7 and 15. Fluorescent in situ hybridization (FISH) and chromosome microdissection were used to identify the complex nature of the jumping translocation. Interstitial telomeres were observed at the jumping translocation sites. The jumping chromosome rearrangement was also found to have a partial duplication of 7p as demonstrated by chromosome microdissection. Despite these paritial duplications and triplications of chromosomes 7 and 15, the child does not have major birth defects. She does have mild sensorimotor delays. A review of non‐Robertsonian jumping translocations is provided.
Association of long variants of the dopamine D4 receptor exon 3 repeat polymorphism with Parkinson's disease
Authors: Ricketts Michael H. , Hamer Robert M. , Manowitz Paul , Feng Fei , Sage Jacob I. , Paola Rocco Di , Menza Matthew A.
Published: July 2010

The dopamine D4 receptor (D4DR) has a highly polymorphic region in the third exon which has been associated with novelty seeking (NS) behavior. Due to the central position of dopamine and the documented low NS in Parkinson's disease (PD), the frequency of the exon 3 variants of D4DR in 95 PD patients and 47 controls was investigated. A significantly higher frequency of exon 3 alleles with six or more repeat units was found in the PD group (p = 0.039). This provides evidence that some forms of the highly polymorphic D4DR may represent a genetic susceptibility factor for PD.
Female external genitalia, absent uterus, and probable agonadism in a 46,XY infant with bilateral upper amelia
Authors: Ohro Yo‐ichiro , Suzuki Yoshimi , Tsutsumi Yoshiyuki , Ogata Tsutomu
Published: July 2010

This report describes a 46,XY phenotypic female infant with absent uterus, probable agonadism, and bilateral upper amelia. The constellation of anomalies is similar to that of the patient described by Temocin et al. (Acta Paediatr Jpn 1997: 39: 631–633), and may suggest a developmental link between genital region and upper limbs.
A case of Prader – Willi syndrome arising as a result of familial unbalanced translocation t(11;15)(q25;q13)
Authors: Walasek Malgorzata Krajewska , Gutkowska Anna , Bielińska Beata , Goryluk‐Kozakiewicz Bozenna , Popowska Ewa
Published: July 2010

We report on a case of Prader‐Willi syndrome (PWS) with a true reciprocal unbalanced translocation, 45,XX,‐15,der(11)t(11;15)pat. The proposita was diagnosed clinically as having severe PWS. Molecular studies revealed loss of the paternal methylation pattern at locus D15S63 and a deletion encompassing the loci from at least D15S10 to D15S97 of paternal chromosome 15. FISH studies confirmed the deletion of 15q11‐q13 region and the presence of two telomeres on all chromosomes. The proposita's father, the father's sister and their mother are all carriers of the same balanced translocation t(11;15)(q25;q13). By genomic imprinting we would expect that if the father's sister were to give birth to a child with the same unbalanced translocation as the proband, it would be affected by Angelman syndrome.

To date, a similar familial unbalanced translocation due to loss of the small chromosome 15 derivative has not been described.
Failure to identify the ryanodine receptor G1021A mutation in a large North American population with malignant hyperthermia
Authors: Stewart Sherri L , Rosenberg Henry , Fletcher Jeffrey E
Published: July 2010

Anesthesia‐induced malignant hyperthermia (MH) is a rare inherited disorder of skeletal muscle. Several mutations in the ryanodine receptor (RYR1) have been found to be causative of MH. The G1021A mutation in the RYR1 is one of the most frequently occurring mutations in European populations. MH normal (165) and MH susceptible (114) North American patients were screened for the presence of the G1021A mutation. This mutation was not found in any of the patients tested. These studies support the absence of this mutation in the normal population. Furthermore, these findings emphasize the importance of viewing the distribution of MH mutations as variable gene pools with frequencies dependent on the geographical location of the population examined.
Risk factors for mortality in young children living under various socio‐economic conditions in Lahore, Pakistan: with particular reference to inbreeding
Authors: Yaqoob Muhammad , Cnattingius Sven , Jalil Fehmida , Zaman Shakila , Iselius Lennart , Gustavson Karl‐Henrik
Published: July 2010

Risk factors such as maternal age, parity, previous siblings' death, inbreeding of parents, birth weight, birth length were examined in a population‐based prospective study in four population groups at different levels of urbanization in and round Lahore, Pakistan. From September 1984 to March 1995, 2967 full‐term, single born infants were followed from the 5th month of gestation to 12 months of age. Logistic regression analysis showed a significant relative risk (RR) of infant death associated with parents' consanguinity (RR = 1.8), birth weight (RR = 1.8) and elder siblings' death (RR = 1.7). The risk attributed to these factors was 28, 17 and 25%, respectively. The number of lethal equivalents per gamete is about one. The B/A ratio 10.36 suggests that the genetic load is likely to be mutational. In countries like Pakistan, where consanguinity is favourably practiced, a substantial proportion of infant deaths may be prevented by cessation of such marriages. The implications of this finding for the Pakistani community are discussed.
Paternal uniparental disomy of chromosome 6 and transient neonatal diabetes mellitus
Authors: Gardner RJ , Robinson DO , Lamont L. , Shield JPH , Temple IK
Published: July 2010

Transient neonatal diabetes mellitus occurs in growth‐retarded infants, has an incidence of 1 in 400000 live births and has been associated with both paternal uniparental disomy of chromosome 6 and paternal duplications of 6q. We analysed samples from our cohort of patients with transient neonatal diabetes mellitus for uniparental disomy of chromosome 6 using polymorphic microsatellite repeat analysis. We report here the fifth case of paternal uniparental disomy of chromosome 6 associated with classic transient neonatal diabetes mellitus and estimate that uniparental disomy of chromosome 6 accounts for approximately one fifth of cases of transient neonatal diabetes mellitus.
New insights into the molecular and genetic mechanisms underlying idiopathic epilepsies
Authors: Steinlein Ortrud K.
Published: July 2010

Steinlein OK. New insights into the molecular and genetic mechanisms underlying idiopathic epilepsies.

For many years, idiopathic epilepsies have been known to have a strong genetic background. In most subtypes, the mode of inheritance appears to be complex, with only some rare idiopathic epilepsies being monogenic disorders. Thus far, several gene loci have been reported for the common subtypes, such as juvenile myoclonic epilepsy, but the results of linkage studies in independent samples have often been conflicting. Recently, the gene defects underlying two monogenic epilepsies, autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions. have been identified. Both diseases are caused by ion channel mutations, a similarity which may shed light on the understanding of the basic mechanisms of epileptogenesk.
Three novel PROC gene lesions causing protein C deficiency
Authors: Hallam PJ , Mannucci P. , Tripodi A. , Bevan D. , Lawsen B. , Tengborn L. , Wacey A. , Coopel DN
Published: July 2010

Hallam PJ, Mannucci P, Tripodi A, Bevan D, Laursen B, Tengborn L, Wacey A, Cooper DN. Three novel PROC gene lesions causing protein C deficiency. Clin Genet 1998: 54: 231–233. 0 Munksgaard, 1998

Missense mutations. three of them novel (Am210→Val, Asn248→ Ile, Ah355→Val), were found in the protein c (PROC) genes of 7 patients with inherited protein C deficiency associated with venous thrombosis. Comparison with the phenotypic effects of mutations in the analogous residues of factor IX causing hdernophilia B and the use of molecular modelling has provided explanations as to how these lesions might alter either the structure, function or secretion of the protein C molecules encoded.
Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipoluscinosis
Authors: Zhong Nan , Krystyna  , Wisniewski E. , Hartikainen Jaana , Ju Weina , Moroziewicz Dorota N. , McLendon Lucille , Brooks Susan Sklower , Brown W Ted
Published: July 2010

Zhong N, Wisniewski KE, Hartikainen J, Ju W, Moroziewicz DN, McLendon L, Sklower Brooks S, Brown WT. Two common mutations in the CLN2 gene underlie late infantile neuronal ceroid lipofuscinosis

Late infantile neuronal ceroid lipofuscinosis (LINCL) is one of the most common pediatric neuronal degenerative disorders. A candidate gene underlying this disease, designated CLN2, was recently cloned and the gene product was characterized as a lysosomal pepstatin‐insensitive carboxypeptidase (LPIC). Four mutations were identified in CLN2 from three unrelated LINCL individuals. To investigate further the mutation frequency in LINCL, we screened 16 LINCL probands for these four mutations. The previously reported intronic mutation, T523–1 G°C, was found in 56% (9/16) of the cases, of which two were homozygous and accounted for 34% (11/32) of LINCL chromosomes. The previously reported nonsense mutation, 636 C→T leading to R208stop, was found in 31% (5/16) of the cases, including one ho‐mozygote and accounted for 19% (6/32) of LINCL chromosomes. Two previously described missense mutations, 1107 T°C and 1108 G→A, were not detected in any of these 16 probands. In total, the two observed mutations, T523–1 G°C and 636 C→T, accounted for 53% (17/32) of LINCL alleles. Thus, one or both mutations were seen in 11 (69%) cases and no mutation has yet been identified in five. Our finding that these two mutations are common in LINCL cases adds further evidence in support of the idea that dysfunction of LPIC underlies LINCL. Positive molecular testing can now complement clinical diagnosis of LPIC and will allow for pre‐natal diagnosis for subsequent pregnancies.
Cytogenetically invisible microdeletions involving PITX2 in Rieger syndrome
Authors: Engenheiro E , Saraiva J , Carreira I , Ramos L , Ropers HH , Silva E , Tommerup N , Tümer Z
Published: July 2010

Axenfeld–Rieger syndrome (ARS) is a genetically heterogeneous autosomal dominant disorder mainly characterized by developmental defects of the anterior segment and extraocular anomalies. ARS shows great clinical variability and encompasses several conditions with overlapping phenotypes, including Rieger syndrome (RS). RS is characterized by developmental defects of the eyes, teeth and umbilicus, and the main causative gene is PITX2 (paired‐like homeodomain transcription factor 2, or RIEG1) at 4q25. PITX2 mutations show great variety, from point mutations to microscopic or submicroscopic deletions, and apparently balanced translocations in few cases. We identified cytogenetically undetectable submicroscopic deletions at 4q25 in two unrelated patients diagnosed with RS. One patient had a t(4;17)(q25;q22)dn translocation with a deletion at the 4q breakpoint, and the other patient had an interstitial deletion of 4q25. Both deletions included only the PITX2 and ENPEP (glutamyl aminopeptidase) genes.
A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late‐onset non‐syndromic hearing loss in a Chinese family
Authors: Cheng J , Han DY , Dai P , Sun HJ , Tao R , Sun Q , Yan D , Qin W , Wang HY , Ouyang XM , Yang SZ , Cao JY , Feng GY , Du LL , Zhang YZ , Zhai SQ , Yang WY , Liu XZ , He L , Yuan HJ
Published: July 2010

We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non‐syndromic, late‐onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age‐at‐onset of disease in these subjects. Genome‐wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two‐point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase–polymerase chain reaction (RT–PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5‐associated hearing loss is caused by a very specific gain‐of‐function mutation.
TBX22 mutations are a frequent cause of non‐syndromic cleft palate in the Thai population
Authors: Suphapeetiporn K , Tongkobpetch S , Siriwan P , Shotelersuk V
Published: July 2010

Mutations in the TBX22 gene underlie an X‐linked malformation syndrome with cleft palate (CP) and ankyloglossia. Its mutations also result in non‐syndromic CP in some populations. To investigate whether mutations in TBX22 play a part in the formation of non‐syndromic CP in the Thai population, we performed mutation analysis covering all the coding regions of the TBX22 gene in 53 unrelated Thai patients with non‐syndromic CP. We identified four potentially pathogenic mutations, 359G→A (R120Q), 452G→T (R151L), 1166C→A (P389Q), and 1252delG in four different patients. All mutations were not detected in at least 112 unaffected ethnic‐matched control chromosomes and had never been previously reported. R120Q and R151L, found in two sporadic cases, were located in the DNA binding T‐box domain. P389Q and 1252delG, found in two familial cases, were at the carboxy‐terminal region, which has never been described. Our study indicates that TBX22 mutations are responsible for a significant proportion of Thai non‐syndromic CP cases confirming its importance as a frequent cause of non‐syndromic CP across different populations.
Colorectal cancer survivors undergoing genetic testing for hereditary non‐polyposis colorectal cancer: motivational factors and psychosocial functioning
Authors: Esplen MJ , Madlensky L , Aronson M , Rothenmund H , Gallinger S , Butler K , Toner B , Wong J , Manno M , McLaughlin J
Published: July 2010

Hereditary non‐polyposis colorectal cancer (HNPCC) represents about 1–3% of all cases of colorectal cancer (CRC). The objectives of the study were to examine motivational factors, expectations and psychosocial functioning in a sample of CRC survivors undergoing genetic testing for HNPCC. A cross‐sectional survey of 314 colorectal cancer patients recruited through a population‐based colon cancer family registry was conducted. Motivations for genetic testing for hereditary cancer were similar to those of clinic‐based samples of CRC patients and included learning of the increased risk to offspring and finding out if additional screening was needed. While age at diagnosis and sex were associated with psychological functioning, significant predictors of post‐counseling distress were perceived lower satisfaction with social support, an escape‐avoidant coping style and the anticipation of becoming depressed if a mutation was present. Most cancer survivors anticipated disclosing test results to relatives and physicians. Cancer survivors reported several motivations for genetic testing for HNPCC that varied by sex. A subgroup of survivors with lower satisfaction with social support and an escape‐avoidant coping style were worried about the potential impact of genetic test results and demonstrated more distress following counseling. Findings have implications for future research and potential support needs during the genetic counseling and testing process.
Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan
Authors: Kitajiri S‐i , McNamara R , Makishima T , Husnain T , Zafar AU , Kittles RA , Ahmed ZM , Friedman TB , Riazuddin S , Griffith AJ
Published: July 2010

Non‐syndromic deafness is genetically heterogeneous. We previously reported that mutations of transmembrane channel‐like gene 1 (TMC1) cause non‐syndromic recessive deafness at the DFNB7/B11 locus on chromosome 9q13–q21 in nine Pakistani families. The goal of this study was to define the identities, origins and frequencies of TMC1 mutations in an expanded cohort of 557 large Pakistani families segregating recessive deafness. We screened affected family members for homozygosity at short‐tandem repeats flanking known autosomal recessive (DFNB) deafness loci, followed by TMC1 sequence analysis in families segregating deafness linked to DFNB7/B11. We identified 10 new families segregating DFNB7/B11 deafness and TMC1 mutations, including three novel alleles. Overall, 9 different TMC1 mutations account for deafness in 19 (3.4%) of the 557 Pakistani families. A single mutation, p.R34X, causes deafness in 10 (1.8%) of the families. Genotype analysis of p.R34X‐linked markers indicates that it arose from a common founder. We also detected p.R34X among normal control samples of African‐American and northern European origins, raising the possibility that p.R34X and other mutations of TMC1 are prevalent contributors to the genetic load of deafness across a variety of populations and continents.
Characterization of de novo microdeletions involving 17q11.2q12 identified through chromosomal comparative genomic hybridization
Authors: Brunetti‐Pierri N , Grange DK , Ou Z , Peiffer DA , Peacock SKG , Cooper ML , Eng PA , Lalani SR , Chinault AC , Gunderson KL , Craigen WJ , Cheung S‐W
Published: July 2010

High‐resolution array‐comparative genome hybridization (CGH) is a powerful tool for detection of submicroscopic chromosome deletions and duplications. We describe two patients with mild mental retardation (MR) and de novo microdeletions of 17q11.2q12. Although the deletions did not involve the neurofibromatosis type 1 (NF1) gene, they overlap with long‐range deletions of the NF1 region which have been encountered in a small group of NF1 patients with more severe MR. Given the overlap of the deletions in our two patients with the large‐sized NF1 microdeletions but not with the more frequent and smaller NF1 deletions, we hypothesize that more than one gene in the 17q11.2q12 region may be involved in MR. We discuss candidate genes for MR within this interval that was precisely defined through array‐CGH analysis.
A novel duplication in the FMR1 gene: implications for molecular analysis in fragile X syndrome and repeat instability
Authors: Mononen T , von Koskull H , Airaksinen R‐L , Juvonen V
Published: July 2010

We have observed a 49 bp tandem duplication adjacent to the triplet repeat of the FMR1 gene and have shown it to occur as a variant in Finland. It affects the primers commonly used in molecular analysis of fragile X syndrome by polymerase chain reaction (PCR) methods. One concern is that females with the full mutation and variant alleles might be missed because of the two PCR products generated by the variant. We suggest that the duplication has arisen by a misalignment of the proximal end of the repeat tract and the non‐adjacent GGCGGCGGCGG‐sequence located 37 bp upstream and may indicate a mutation hot spot. The discovery of this duplication and the previous observations on deletions associated with full mutations in FMR1 indicate that realignment between the repeat tract and dispersed non‐adjacent homologous repetitive sequences may also play a role in repeat instability in fragile X.
Contiguous gene deletions involving EFNB1, OPHN1, PJA1 and EDA in patients with craniofrontonasal syndrome
Authors: Wieland I , Weidner C , Ciccone R , Lapi E , McDonald‐McGinn D , Kress W , Jakubiczka S , Collmann H , Zuffardi O , Zackai E , Wieacker P
Published: July 2010

Craniofrontonasal syndrome (CFNS [MIM 304110]) is an X‐linked malformation syndrome characterized by craniofrontonasal dysplasia and extracranial manifestations in heterozygous females. In the majority of patients CFNS is caused by mutations in the EFNB1 gene (MIM 300035). We identified three girls with classical CFNS and mild developmental delay harboring de novo deletions of the EFNB1 gene. Applying haplotype analysis, Southern blot hybridization and array‐comparative genomic hybridization, deletion of EFNB1 was found to be part of contiguous gene deletions in the patients. In one patient the deletion interval includes the genes for oligophrenin‐1 (OPHN1 [MIM 300127]) and praja 1 (PJA1 [MIM 300420]). In the second patient the deletion includes OPHN1, PJA1 and the gene for ectodysplasin A (EDA [MIM 300451]). In the third patient EFNB1 gene deletion may include deletion of regulatory regions 5′ of OPHN1. Previously, the OPHN1 gene has been shown to be responsible for recessive X‐linked mental retardation. Although it is too early to predict the future cognitive performance of the two infant patients with contiguous gene deletions of OPHN1–EFNB1–PJA1, mild learning disabilities have been recognized in the older, third patient. It is important for genetic counseling to be aware that their male offspring may not only be carriers of CFNS but may also be affected by mental retardation and anhidrotic ectodermal dysplasia.
Genetic defects underlying Peutz–Jeghers syndrome (PJS) and exclusion of the polarity‐associated MARK/Par1 gene family as potential PJS candidates
Authors: de Leng WWJ , Jansen M , Carvalho R , Polak M , Musler AR , Milne ANA , Keller JJ , Menko FH , de Rooij FWM , Iacobuzio‐Donahue CA , Giardiello FM , Weterman MAJ , Offerhaus GJA
Published: July 2010

LKB1/STK11 germline inactivations are identified in the majority (66–94%) of Peutz–Jeghers syndrome (PJS) patients. Therefore, defects in other genes or so far unidentified ways of LKB1 inactivation may cause PJS. The genes encoding the MARK proteins, homologues of the Par1 polarity protein that associates with Par4/Lkb1, were analyzed in this study because of their link to LKB1 and cell polarity. The genetic defect underlying PJS was determined through analysis of both LKB1 and all four MARK genes. LKB1 point mutations and small deletions were identified in 18 of 23 PJS families using direct sequencing and multiplex ligation‐dependent probe amplification analysis identified exon deletions in 3 of 23 families. In total, 91% of the studied families showed LKB1 inactivation. Furthermore, a MARK1, MARK2, MARK3 and MARK4 mutation analysis and an MARK4 quantitative multiplex polymerase chain reaction analysis to identify exon deletions on another eight PJS families without identified LKB1 germline mutation did not identify mutations in the MARK genes. LKB1 defects are the major cause of PJS and genes of the MARK family do not represent alternative PJS genes. Other mechanisms of inactivation of LKB1 may cause PJS in the remaining families.
Do carriers of POLG mutation W748S have disease manifestations?
Authors: Rantamäki M , Luoma P , Virta JJ , Rinne JO , Paetau A , Suomalainen A , Udd B
Published: July 2010

Mitochondrial recessive ataxia syndrome (MIRAS) is a common cause of autosomal recessive juvenile‐ or adult‐onset ataxia, at least in Scandinavia. MIRAS patients are homozygous or compound heterozygous for POLG mutations W748S and A467T. Because many first‐degree relatives of MIRAS patients in the studied families have reported neurological symptoms and some recent studies have suggested dominant negative effect of these mutations, a careful family study of heterozygotes was needed. We investigated all available members of the original large MIRAS family with W748S mutation. Neurological symptoms and signs were present in a number of carriers, but clearly defined neurological diseases did not segregate consistently with the mutation. Sensory polyneuropathy as a subclinical finding was observed in the majority of carriers examined. By positron emission tomography, cerebral glucose metabolism was moderately reduced in two out of four heterozygotes compared with severe reduction in one MIRAS patient. In conclusion, W748S heterozygotes showed no clinically manifesting phenotype.
Susceptibility genes in breast cancer: more is less?
Authors: Willems Patrick J
Published: July 2010

PALB2, which encodes a BRCA2‐interacting protein, is a breast cancer susceptibility gene Rahman et al. (2007) Nature Genetics 39: 165–167

A common coding variant in CASP8 is associated with breast cancer risk Cox et al. (2007) Nature Genetics 39: 352–358

A genome‐wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer Hunter et al. (2007) Nature Genetics 39: 870–874

Genome‐wide association study identifies novel breast cancer susceptibility loci Easton et al. (2007) Nature 447: 1087–1093

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer Stacey et al. (2007) Nature Genetics 39: 865–869
Survival estimates for patients with Machado–Joseph disease (SCA3)
Authors: Kieling C , Prestes PR , Saraiva‐Pereira ML , Jardim LB
Published: July 2010

Machado–Joseph disease (MJD), one of the most prevalent autosomal dominant cerebellar ataxias, is a neurodegenerative disease that starts during adulthood, with patients showing difficulties in gait, later becoming bedridden, and ultimately presenting premature death. There is, however, scarce data quantifying disease impact on patient survival. We investigated the overall survival of a large series of MJD patients and compared it with the survival of their asymptomatic relatives. A total of 412 affected and 413 unaffected individuals were ascertained from a consecutive sample of 82 families with a molecular diagnosis of MJD. Estimated mean survival time was 63.96 years [95% confidence interval (CI), 62.09–65.83] for the affected group and 78.61 years (95% CI, 74.75–82.47) for the unaffected group (p < 0.001). For a subset of 366 patients, mean age at onset was 36.37 years (95% CI, 35.21–37.53) and survival after disease onset was estimated as 21.18 years. Early onset and large CAG length predicted shorter overall survival times. This study presents quantitative data on the impact of MJD on overall survival, a phenomenon that is related to CAG length, age at onset, and year of birth.