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M Pembrey

Publications and source records attributed to M Pembrey.

At least 19 recordsLinked to original sources
PubMed2006

An investigation of FRAXA intermediate allele phenotype in a longitudinal sample.

The FRAXA trinucleotide repeat at Xq27.3 gives rise to fragile X syndrome when fully expanded, and both premature ovarian failure (POF) and fragile X tremor and ataxia syndrome (FXTAS) when in the premutation range. Reports of phenotypic effects extending into the intermediate repeat range are inconsistent but some studies suggest that these smaller expansions predispose to special educational needs (SEN). This study utilises the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort to investigate cognitive and behavioural variables that might be associated with FRAXA intermediate alleles. The current study failed to find any strong evidence of association of FRAXA intermediate alleles with SEN, behavioural problems or cognitive difficulties. However, our findings illustrate some of the difficulties encountered in identifying individuals with SEN. The power to identify specific components of cognitive and behavioural difficulties was reduced due to elective drop-out, which is characteristic of longitudinal studies. Our findings demonstrate the non-random loss of participants from this cohort and highlight problems that may arise when such data are used in genetic association studies.

Alleles↗
PubMed2002

An interaction between the IL-4Ralpha gene and infection is associated with atopic eczema in young children.

BACKGROUND: A gain of function mutation (Q551- > R) in the IL-4 receptor alpha-chain (IL-4Ralpha) has been found to be associated with atopy in some studies but not others. The different results may be explained by interactions between the IL-4Ralpha polymorphism and environmental factors. OBJECTIVES: To identify interactions between the R551 mutation and environmental factors that are associated with atopy. METHODS: DNA from the Children in Focus (CiF) cohort of the Avon Longitudinal Study of Parents and Children (ALSPAC) was genotyped by heteroduplex formation for the presence of the R551 polymorphism. The data were then analysed for associations with flexural eczema as an indicator of atopic eczema, skin prick tests to allergens and serum IgE levels, and for interactions with environmental factors. RESULTS: A significant (P = 0.02) positive association was seen between the R551 polymorphism and flexural eczema in children up to 6 months of age who had not been given antibiotics, but not in children who had been given antibiotics. This association was maintained as a trend until 30 to 42 months of age but was no longer statistically significant. There was no significant association between the R551 polymorphism and positive skin prick tests or levels of serum IgE at 61 months of age, consistent with the effect of the R551 polymorphism being restricted to early life. CONCLUSION: There is an association between the R551 polymorphism and flexural eczema in children at 6 months of age who have not had infection requiring treatment with antibiotics. Restriction of the R551 association with eczema to children who have not had antibiotics lends support to the 'hygiene hypothesis', which states that exposure to infection in childhood can protect against allergic disease.

Bacterial Infections↗
PubMed2001

Disruption of the bipartite imprinting center in a family with Angelman syndrome.

Imprinting in 15q11-q13 is controlled by a bipartite imprinting center (IC), which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome (PWS). Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome (AS). So far, in all affected sibs with an imprinting defect, an inherited IC deletion was identified. We report on two sibs with AS who do not have an IC deletion but instead have a 1-1.5 Mb inversion separating the two IC elements. The inversion is transmitted silently through the male germline but impairs maternal imprinting after transmission through the female germline. Our findings suggest that the close proximity and/or the correct orientation of the two IC elements are/is necessary for the establishment of a maternal imprint.

Angelman Syndrome↗
PubMed2001

ALSPAC--the Avon Longitudinal Study of Parents and Children. I. Study methodology.

ALSPAC (The Avon Longitudinal Study of Parents and Children, formerly the Avon Longitudinal Study of Pregnancy and Childhood) was specifically designed to determine ways in which the individual's genotype combines with environmental pressures to influence health and development. To date, there are comprehensive data on approximately 10,000 children and their parents, from early pregnancy until the children are aged between 8 and 9. The study aims to continue to collect detailed data on the children as they go through puberty noting, in particular, changes in anthropometry, attitudes and behaviour, fitness and other cardiovascular risk factors, bone mineralisation, allergic symptoms and mental health. The study started early during pregnancy and collected very detailed data from the mother and her partner before the child was born. This not only provided accurate data on concurrent features, especially medication, symptoms, diet and lifestyle, attitudes and behaviour, social and environmental features, but was unbiased by parental knowledge of any problems that the child might develop. From the time of the child's birth many different aspects of the child's environment have been monitored and a wide range of phenotypic data collected. By virtue of being based in one geographic area, linkage to medical and educational records is relatively simple, and hands-on assessments of children and parents using local facilities has the advantage of high quality control. The comprehensiveness of the ALSPAC approach with a total population sample unselected by disease status, and the availability of parental genotypes, provides an adequate sample for statistical analysis and for avoiding spurious results. The study has an open policy in regard to collaboration within strict confidentiality rules.

Adult↗
PubMed2001

The association of aneuploidy and mild fetal pyelectasis in an unselected population: the results of a multicenter study.

INTRODUCTION: Mild pyelectasis is a common finding and there is some debate as to its association with aneuploidy. The results of a large, prospective, multicenter study of mild pyelectasis designed to determine the incidence and association with aneuploidy in an unselected population are reported. METHODS: A large multicenter, prospective observational study of unselected fetuses with mild pyelectasis identified between 16 and 26 weeks' gestation in routine ultrasound departments. RESULTS: There were 737 fetuses with mild pyelectasis of which 12 had an abnormal karyotype. Pyelectasis was isolated in three fetuses with Down syndrome, but in one the mother was older (36 years). CONCLUSION: These data confirm the fact that the presence of mild fetal pyelectasis increases the risk for aneuploidy, in particular trisomy 21. However, other risk factors should be considered before embarking on fetal karyotyping, as for most pregnancies complicated by isolated mild pyelectasis, risks of aneuploidy will remain small.

Adult↗
PubMed2001

Hyperphagic short stature and Prader--Willi syndrome: a comparison of behavioural phenotypes, genotypes and indices of stress.

BACKGROUND: The clinical features of hyperphagic short stature (HSS) include short stature secondary to growth hormone insufficiency, excessive appetite (hyperphagia) and mild learning disabilities. Affected children characteristically live in conditions of high psychosocial stress. Symptoms resolve when the child is removed from the stressful environment. Family studies indicate a genetic predisposition. AIMS: To compare the behavioural and stress profiles of HSS with those of Prader--Willi syndrome (PWS), and to test the hypothesis that the genetic locus that predisposes to HSS co-inherits with the PWS locus at 15q11--13. METHOD: Twenty-five children with HSS, mean age 9.1 (s.d. 3.8) years, 28% female, were compared with 30 children with PWS, mean age 8.8 (s.d. 2.8) years, 33% female. RESULTS: The clinical profiles were largely similar across the conditions, but no evidence was found in HSS of co-inheritance of the PWS critical region. CONCLUSIONS: Hyperphagic short stature is one of the very few behavioural diseases associated with a pathognomonic physiological abnormality. Investigations of the suggested genetic dysregulation, which is so sensitive to environmental influences, may well be of importance in a broader context.

Child↗
PubMed2000

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: a second FG locus [FGS2]?

FG syndrome is an X-linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints.

Abnormalities, Multiple↗
PubMed2000

A new human genetic resource: a DNA bank established as part of the Avon longitudinal study of pregnancy and childhood (ALSPAC).

We describe a unique human DNA resource forming part of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC), a longitudinal cohort study involving 14 000 children and their families living in a geographically defined area of England. The DNA bank will underpin the search for associations between genetic polymorphisms and common health outcomes. The opportunities to collect blood samples suitable for DNA extraction are necessarily limited, and the samples themselves have often been treated in different ways and have varied storage histories. With the need to maximise yields, the choice of DNA extraction method is critical to the success of the bank and we have investigated the suitability of various commercial and in-house methods of DNA extraction. Various steps have been taken to minimise errors in sample address and identification, including the use of a pipetting robot for dilution and transfer of samples between 96-well arrays to provide aliquots suitable for PCR. The robot has been programmed to cope with concentrated viscous DNA solutions.

Animals↗
PubMed1999

Diagnosis of fragile-X syndrome: the experiences of parents.

In order to assess some aspects of the quality of care for families seeking the cause of their child(ren)s intellectual disability, a postal questionnaire was sent to parents of children with fragile-X syndrome, who were members of the UK Fragile-X Society. Although the interval taken to get a diagnosis ('lagtime') has fallen over time, other aspects of care could still be improved. Most families feel that having a diagnosis is an advantage, but many still find the diagnostic process distressing and feel unsupported. Not all families are referred for genetic counselling, and even those who are do not always understand or retain the information given. Most families feel that having a diagnosis is a benefit rather than a disadvantage.

Child↗
PubMed1998

Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study.

BACKGROUND: Congenital heart defects are generally assumed to have a multifactorial aetiology. We have tested this hypothesis by studying adults with heart defects and their families. METHODS: We identified 1094 patients who survived surgery for major cardiac defects before 1970. We chose individuals with disturbance of situs or segmental connection, with atrioventricular septal defect or with tetralogy of Fallot. After exclusion and non-participation, 727 individuals were traced. Each was visited by an investigator and completed a detailed questionnaire. If possible, all "normal" offspring were examined by a paediatric cardiologist. FINDINGS: The 727 individuals had 393 live offspring. There were 71 miscarriages and five terminated pregnancies. Overall, we found recurrent heart defects in 16 liveborn offspring--a recurrence risk of 4.1%. This result differed significantly from sibling risk (2.1%; p=0.021). More congenital heart defects occurred in the offspring of affected women than in those of affected men (p=0.047); when all malformations (cardiac and non-cardiac) in the offspring were taken into account the excess was more significant (p=0.032). We found an excess of miscarriages in the offspring of affected women (p=0.001). In tetralogy of Fallot, heart defects occurred in seven (3.1%) of 223 offspring, 12 (2.2%) of 539 siblings, five (0.3%) of 1575 second-degree relatives, and eight (0.3%) of 2728 third-degree relatives. INTERPRETATION: Our findings do not support a polygenic basis for all heart defects. Atrioventricular septal defect seems to be a single-gene defect and tetralogy of Fallot a polygenic disorder with a small number of interacting genes. Our data suggest that isolated transposition of the great arteries is a sporadic defect.

Adult↗
PubMed1998

The significance of choroid plexus cysts in an unselected population: results of a multicenter study.

OBJECTIVES: Choroid plexus cysts are commonly found at the time of a routine second-trimester scan, but there is much debate as to their clinical significance. The aims of this study were to define the incidence of choroid plexus cysts in an unselected population and describe their association with aneuploidy. DESIGN: This was a prospective, observational multicenter study. SUBJECTS: Subjects were all fetuses found to have choroid plexus cysts with a maximum diameter of 3 mm or greater and who were between 14 and 24 weeks' gestation when scanned in the routine ultrasound department at any of the 13 participating hospitals. RESULTS: There were 658 fetuses with choroid plexus cysts in a total of 101,600 births. The overall incidence of aneuploidy was 2.1%, but in fetuses with isolated choroid plexus cysts the incidence of proven aneuploidy was 0.5% (95% confidence interval (CI), 0.1-1.4%). If age is taken into consideration, then the incidence of aneuploidy in fetuses with isolated choroid plexus cysts where the mother is under the age of 36 years was 0.36% (95% CI, 0.04-1.3%), and 2.4% (95% CI, 0.06-12.6%) in older women. CONCLUSIONS: We conclude that the presence of choroid plexus cysts increases the risk for aneuploidy, mainly trisomy 18. In the majority of cases, the final risk will remain small, but will increase as maternal age increases.

Aneuploidy↗
PubMed1997

A gene for FG syndrome maps in the Xq12-q21.31 region.

FG syndrome is an X-linked recessive condition in which mental retardation is associated with congenital hypotonia, macrocephaly, characteristic face, and constipation. This syndrome was mapped by Zhu et al. [Cytogenet Cell Genet 1991;58:2091A] to Xq21.31-q22 by linkage analysis with a max lod score of 1.2 for the DXYS1X, DXS178, DXS101, and DXS94 loci and crossovers at DXS16 (Xp22.31) and DXS287 (Xq22.3). However, this mapping was only provisional and needed to be refined. In this paper, we report the results of a new linkage analysis performed on 10 families including that studied by Zhu et al. [1991]. Two-point analysis demonstrated linkage with DXS441 (Zmax = 3.39 at theta = 0.12) at Xq13. In addition, separate analysis of the lod scores obtained for the Xq13 markers suggested linkage exclusion for three families. Genetic heterogeneity was confirmed by analysis of the linkage results with the HOMOG program (max logL = 4.07, theta = 0, alpha = 0.65). Localization of one FG gene between DXS135 and DXS1066 was suggested by analysis of crossovers found in those three families which were assumed to be linked to Xq13 with a probability of 0.95 or more. This region could be reduced to the DXS135-DXS72 interval after combining our data with those from deletions previously described in males in the Xq13-q21 region.

Abnormalities, Multiple↗
PubMed1997

IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome.

The Jervell and Lange-Nielsen syndrome (JLNS) comprises profound congenital sensorineural deafness associated with syncopal episodes. These are caused by ventricular arrhythmias secondary to abnormal repolarisation, manifested by a prolonged QT interval on the electrocardiogram. Recently, in families with JLNS, Neyroud et al. reported homozygosity for a single mutation in KVLQT1 , a gene which has previously been shown to be mutated in families with dominantly inherited isolated long QT syndrome [Neyroud et al . (1997) Nature Genet ., 15, 186-189]. We have analysed a group of families with JLNS and shown that the majority are consistent with mutation at this locus: five families of differing ethnic backgrounds were homozygous by descent for markers close to the KVLQT1 gene and a further three families from the same geographical region were shown to be homozygous for a common haplotype and to have the same homozygous mutation of the KVLQT1 gene. However, analysis of a single small consanguineous family excluded linkage to the KVLQT1 gene, establishing genetic heterogeneity in JLNS. The affected children in this family were homozygous by descent for markers on chromosome 21, in a region containing the gene IsK . This codes for a transmembrane protein known to associate with KVLQT1 to form the slow component of the delayed rectifier potassium channel. Sequencing of the affected boys showed a homozygous mutation, demonstrating that mutation in the IsK gene may be a rare cause of JLNS and that an indistinguishable phenotype can arise from mutations in either of the two interacting molecules.

Chromosomes, Human, Pair 21↗
PubMed1996

Imprinting and transgenerational modulation of gene expression; human growth as a model.

It is proposed that transgenerational modulation of gene expression might be possible, if the metabolic response of the parent to some physiological or social stress modified imprint setting. Transcription regulators could theoretically mediate this process. The nature of imprinted genes poised, as it were, between a transcriptionally active and silent state, makes them good candidates for incorporation into the evolution of transgenerational adaption systems where coordinated changes in gene expression over the generations is a selective advantage. The coordination of human fetal (head) growth with the existing size of the mother's pelvis is suggested as just such a circumstance. The reduce birth weight of Dutch babies where their grandmothers suffered acute starvation in mid pregnancy, supports the notion of transgenerational adaption to nutrition, as does the secular change (increase) in child growth over the last century. The recent indication that there may be functional polymorphism in the imprinting of the human IGF2 and IGF2R genes suggests these ideas could be explored using association studies at the population and individual level.

Adaptation, Physiological↗
PubMed1996

Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4.

Inherited causes account for about 50% of individuals presenting with childhood (prelingual) hearing loss, of which 70% are due to mutation in numerous single genes which impair auditory function alone (non-syndromic). The remainder are associated with other developmental anomalies termed syndromic deafness. Genes responsible for syndromic forms of hearing loss include the COL4A5 gene in Alport syndrome and the PAX3 and MITF genes in Waardenburg syndrome. Pendred syndrome is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss and diffuse thyroid enlargement (goitre). Pendred syndrome is the most common syndromal form of deafness, yet the primary defect remains unknown. We have established a panel of 12 families with two or more affected individuals and used them to search for the location of the Pendred gene by linkage analysis. We excluded localization to four previously mapped nonsyndromic deafness loci but obtained conclusive evidence for linkage of the Pendred syndrome gene to microsatellite markers on chromosome 7q31 (D7S495 Zmax 7.32, Qmax = 0). This region contains a gene, DFNBL, for autosomal recessive non-syndromic sensorineural hearing loss. Multipoint analysis indicates that DFNB4 and Pendred syndrome co-localize to the same 5.5 centiMorgan (cM) interval flanked by D7S501 and D7S523. These data raise the possibility that Pendred syndrome is either allelic with DFNB4 or may represent an inherited contiguous gene disorder, not clinically manifest in the heterozygote.

Chromosome Mapping↗
PubMed1996

Thyroid peroxidase: evidence for disease gene exclusion in Pendred's syndrome.

OBJECTIVE: Pendred's syndrome is an association between congenital neurosensory deafness and goitre with abnormal discharge of iodide following perchlorate challenge, indicating a defect of iodide organification. Although Pendred's syndrome may cause up to 7.5% of all cases of congenital deafness, the molecular basis of the association between the hearing loss and the thyroid organification defect remains unknown. We chose to investigate the role of the thyroid peroxidase (TPO) gene as the genetic defect in Pendred's syndrome. DESIGN: A highly informative variable number tandem repeat (VNTR), located 1.5 kb downstream of exon 10 of the TPO gene, was used to search for genetic linkage in multiple sibships affected by Pendred's syndrome. PATIENTS: Seven kindreds were recruited from the UK, each with at least two affected members. We have also examined a large inbred Israeli family with two affected offspring and five unaffected children. MEASUREMENTS: Individuals were assigned affected status based on the characteristic clinical features of Pendred's syndrome, namely the presence of congenital sensorineural hearing loss and the appearance in early life of a goitre. Additionally, at least one affected member from each sibship had a characteristic positive perchlorate discharge test (Morgans & Trotter, 1958). PCR amplification of genomic DNA at the TPO VNTR allowed assignment of genotypes to each individual and the calculation of a two-point LOD score. RESULTS: In six of the nine sibships analysed we found obligatory recombination between TPO and Pendred's syndrome. Non-complementation observed in affected parents with an affected offspring excluded TPO in an affected sibship with genotype sharing and supports a hypothesis of genetic homogeneity for Pendred's syndrome. In two sibships, mutation of the TPO gene as the cause of Pendred's syndrome could not be excluded. CONCLUSIONS: These data suggest that defects at the thyroid peroxidase locus on chromosome 2 are not the major cause of Pendred's syndrome.

Base Sequence↗