Showing papers in "American Journal of Medical Genetics in 2002"

Expression of the dopamine transporter gene is regulated by the 3' UTR VNTR: Evidence from brain and lymphocytes using quantitative RT-PCR.

Abstract: Genetic association studies provide considerable evidence that the 10-repeat allele of a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'-UTR) of the dopamine transporter gene (DAT1) is associated with a range of psychiatric phenotypes, most notably, attention deficit hyperactivity disorder. The mechanism for this association is not yet understood, although several lines of evidence implicate variation in gene expression. In this study, we measured DAT1 messenger RNA levels in cerebellum, temporal lobe, and lymphocytes using quantitative real-time reverse-transcription polymerase chain reaction. Relative to a set of four control housekeeping genes (beta-actin, GAPD, ribosomal 18S, and beta2-microglobulin) we observed that increased levels of DAT1 expression were associated with the number of 10-repeat alleles. These data provide direct evidence that the VNTR, or another polymorphism in linkage disequilibrium with the VNTR, is involved in regulating expression of this gene.

Environmental factors in the etiology of type 1 diabetes

Abstract: Type 1 diabetes is considered to be an autoimmune disease in which T lymphocytes infiltrate the islets of pancreas and destroy the insulin producing beta cell population. Besides antigen specificity, the quality of immune reactivity against islet cell antigen(s) is an important determinant of the beta cell destruction. Much evidence indicates that the function of the gut immune system is central in the pathogenesis, as the regulation of the gut immune system may be aberrant in type 1 diabetes. The role of virus infections in the pathogenesis of type 1 diabetes has been supported by substantial new evidence suggesting that one virus group, enteroviruses, may trigger the beta-cell damaging process in a considerable proportion of patients. The latest evidence comes from studies indicating the presence of viral genome in diabetic patients and from prospective studies confirming epidemiological risk effect. If this association holds still true in ongoing large-scale studies, intervention trials should be considered to confirm causality. Of the dietary putative etiological factors, cow's milk proteins have received the main attention. Many studies indicate an association between early exposure to dietary cow's milk proteins and an increased risk of type 1 diabetes. The question will be answered by a large scale, prospective, randomized, international intervention trial Another dietary factor in need of more studies is the deficiency of vitamin D. Among toxins, N-nitroso compounds are the main candidates. An interaction of genetic and environmental factors is important in evaluating the possible role of a certain environmental factor in the etiology of type 1 diabetes. © 2002 Wiley-Liss, Inc.

A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population.

Abstract: Van Buchem disease is an autosomal recessive sclerosing bone dysplasia characterized by skeletal hyperostosis, overgrowth of the mandible, and a liability to entrapment of the seventh and eighth cranial nerves. The genetic determinant maps to chromosome 17q12-q21. We refined the critical interval to the < 1-Mb region between D17S2250 and D17S2253 in 15 affected individuals, all of whom shared a common disease haplotype. Furthermore, we report here the identification of a 52-kb deletion located within the interval and encompassing D17S1789 that is 100% concordant with the disorder. Although the deletion itself does not appear to disrupt the coding region of any known or novel gene(s), the closest flanking genes are MEOX1 on the proximal side, and SOST on the distal side of the deletion. MEOX1 is known to be important for the development of the axial skeleton, whereas the SOST gene is the determinant of sclerosteosis, a disorder that shares many features with van Buchem disease, thus raising the possibility that van Buchem disease results from dysregulation of the expression of one or both of these genes.

Familial paraganglioma and gastric stromal sarcoma: A new syndrome distinct from the Carney triad

Abstract: Paragangliomas may be inherited in an autosomal dominant manner either alone (as in PGL1, PGL2, and PGL3 syndromes) or as a component of a multiple tumor syndrome (as in von Hippel-Lindau disease and neurofibromatosis type 1). In this article, we describe 12 patients (7 male and 5 female) with an average age of 23 years from five unrelated families that manifested paraganglioma and gastric stromal sarcoma; the tumors were inherited in an apparent autosomal dominant manner, with incomplete penetrance. Seven patients had paraganglioma, four had paraganglioma and gastric stromal sarcoma, and one had gastric stromal sarcoma. The paraganglioma was multicentric and the gastric stromal sarcoma multifocal. Because of the rarity of gastric stromal sarcoma and its multifocality, the young age of the patients, and the unlikelihood of coincidental co-occurrence of paragangliomas and gastric stromal sarcomas, we suggest that a new syndrome exists with these two main components, a condition that is familial and distinct from the Carney triad.

Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice

Abstract: Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. The specific function of this protein is unknown; however, it has been proposed to play a role in developmental synaptic plasticity. Examination of human brain autopsy material has shown that fragile-X patients exhibit abnormalities in dendritic spine structure and number, suggesting a failure of normal developmental dendritic spine maturation and pruning in this syndrome. Similar results using a knockout mouse model have previously been described; however, it was noted in retrospect that the mice used in that study may have carried a mutation for retinal degeneration, which may have affected cell morphology in the visual cortex of those animals. In this study, dendritic spines on layer V pyramidal cells of visual cortices, taken from fragile-X knockout and wild-type control mice without the retinal degeneration mutation and stained using the Golgi-Cox method, were investigated for comparison with the human condition. Quantitative analyses of the lengths, morphologies, and numbers of dendritic spines, as well as amount of dendritic arbor and dendritic branching complexity, were conducted. The fragile-X mice exhibited significantly more long dendritic spines and significantly fewer short dendritic spines than control mice. Similarly, fragile-X mice exhibited significantly more dendritic spines with an immature-like morphology and significantly fewer with a more mature type morphology. However, unlike the human condition, fragile-X mice did not exhibit statistically significant dendritic spine density differences from controls. Fragile-X mice also did not demonstrate any significant differences from controls in dendritic tree complexity or dendritic arbor. Long dendritic spines with immature morphologies are characteristic of early development or a lack of sensory experience. These results are similar to those found in the human condition and further support a role for the fragile-X mental retardation protein specifically in normal dendritic spine developmental processes. They also support the validity of these mice as a model of fragile-X syndrome.

Endophenotypes in bipolar disorder

Abstract: The search for genes in bipolar disorder has provided numerous genetic loci that have been linked to susceptibility to developing the disorder. However, because of the genetic heterogeneity inherent in bipolar disorder, additional strategies may need to be employed to fully dissect the genetic underpinnings. One such strategy involves reducing complex behaviors into their component parts (endophenotypes). Abnormal neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, and neuropsychological findings are characteristics that often accompany psychiatric illness. It is possible that some of these may eventually be useful in subdefining complex genetic disorders, allowing for improvements in diagnostic assessment, genetic linkage studies, and development of animal models. Findings in patients with bipolar disorder that may eventually be useful as endophenotypes include abnormal regulation of circadian rhythms (the sleep/wake cycle, hormonal rhythms, etc.), response to sleep deprivation, P300 event-related potentials, behavioral responses to psychostimulants and other medications, response to cholinergics, increase in white matter hyperintensities (WHIs), and biochemical observations in peripheral mononuclear cells. Targeting circadian rhythm abnormalities may be a particularly useful strategy because circadian cycles appear to be an inherent evolutionarily conserved function in all organisms and have been implicated in the pathophysiology of bipolar disorder. Furthermore, lithium has been shown to regulate circadian cycles in diverse species, including humans, possibly through inhibition of glycogen synthase kinase 3-beta (GSK-3beta), a known target of lithium.

Genomic screen and follow-up analysis for autistic disorder

Abstract: Autistic disorder (AutD) is a neurodevelopmental disorder characterized by significant impairment in social, communicative, and behavioral functioning. A genetic basis for AutD is well established with as many as 10 genes postulated to contribute to its underlying etiology. We have completed a genomic screen and follow-up analysis to identify potential AutD susceptibility loci. In stage one of the genome screen, 52 multiplex families (two or more AutD affected individuals/family) were genotyped with 352 genetic markers to yield an approximately 10 centimorgan (cM) grid, inclusive of the X chromosome. The selection criterion for follow-up of interesting regions was a maximum heterogeneity lod score (MLOD) or a maximum nonparametric sib pair lod score (MLS) of at least 1.0. Eight promising regions were identified on chromosomes 2, 3, 7, 15, 18, 19, and X. In the stage two follow-up study we analyzed an additional 47 multiplex families (total=99 families). Regions on chromosomes 2, 3, 7, 15, 19, and X remained interesting (MLOD> or =1.0) in stage two analysis. The peak lod score regions on chromosomes 2, 7, 15, 19, and X overlap previously reported peak linkage areas. The region on chromosome 3 is unique.

DRD4 and novelty seeking: results of meta-analyses.

Abstract: Studies of the association between polymorphisms within and near the dopamine D4 receptor (DRD4) gene and novelty seeking (NS) have produced inconsistent results, raising questions about the strength of the relationship and the methodological conditions under which the relationship holds. We conducted three meta-analyses of existing studies to provide formal statistical measures of the strength of the DRD4-NS relationship. Results provided no support for a relationship between NS and the presence of the 7-repeat allele of the VNTR polymorphism. A small positive effect, however, was found for long repeats of the same polymorphism. The most promising findings were obtained for the relationship with the -521 C/T promoter polymorphism, for which the analysis showed an effect size of 0.32. The positive findings are consistent with a polygenic model of influence on fundamental personality dimensions.

Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands.

Abstract: The goal of this study was to identify chromosomal regions likely to contain susceptibility alleles for early-onset obsessive-compulsive disorder (OCD). A genome scan was done in 56 individuals from seven families ascertained through pediatric OCD probands; 27 of the 56 subjects had a lifetime diagnosis of definite OCD. Denser mapping of regions on chromosomes 2, 9, and 16 was subsequently done with those subjects and ten additional subjects from the largest family in the study. Direct interviews were completed with 65 of the 66 genotyped individuals. Relatives were interviewed blind to proband status. Of the 65 interviewed individuals, 32 had a lifetime diagnosis of definite OCD. Three of the seven probands had a history of Tourette disorder. Two of the 25 relatives with OCD had a tic history, whereas none of the 33 relatives without OCD had tics. The genome scan consisted of 349 microsatellite markers with an average between-marker distance of 11.3 centiMorgan (cM). Fine mapping was done with 24 additional markers at an average spacing of 1.6 cM. Parametric and nonparametric linkage analyses were conducted using GENEHUNTER(+). The maximum multipoint LOD score with a dominant model was 2.25 on 9p. However, with fine mapping and additional subjects, that LOD score decreased to 1.97. The maximum multipoint nonparametric LOD* score was 1.73 on 19q. The maximum multipoint LOD score with a recessive model was 1.40 on 6p. The results provide suggestive evidence for linkage on 9p and identify regions requiring further study with much larger samples.

Motor immaturity and specific speech and language impairment: Evidence for a common genetic basis

Abstract: Previous studies have found an association between motor immaturity and specific language impairment in children. Data from two twin studies were used to address the question of whether these linked deficits have a common etiology. Study 1 involved 57 MZ and 22 DZ pairs where one or both twins had specific speech/language impairment. A control group of 173 single-born children was also tested. Motor skill was assessed using a tapping task, which was carried out with left and right hands. Tapping scores were converted to scaled scores adjusted for age and sex. Unaffected twins and single-born controls did not differ in motor skill, but twins with speech and/or language impairments obtained significantly poorer tapping scores than controls. Bivariate DeFries-Fulker analysis pointed to shared genetic influence on tapping speed and a measure of speech production accuracy. In study 2, 37 twin pairs from study 1 were retested 2-3 years later and combined with 100 twin pairs from a general population sample. A timed peg-moving task was used to assess motor skill. Children with combined speech and language impairments obtained poorer peg-moving scores than unaffected children. Bivariate DeFries-Fulker analysis found significant shared genetic variance for impairments on peg-moving and on a test of nonword repetition. It is concluded that genes that put the child at risk for communicative problems also affect motor development, with the association being most evident when speech production is affected.

Limb malformations and the human HOX genes.

Abstract: HOX genes encode a family of transcription factors of fundamental importance for body patterning during embryonic development. Humans, like most vertebrates, have 39 HOX genes organized into four clusters, with major roles in the development of the central nervous system, axial skeleton, gastrointestinal and urogenital tracts, external genitalia, and limbs. The first two limb malformations shown to be caused by mutations in the human HOX genes were synpolydactyly and hand-foot-genital syndrome, which result from mutations in HOXD13 and HOXA13, respectively. This review describes a variety of limb malformations now known to be caused by specific different mutations in these two genes, including polyalanine tract expansions, nonsense mutations, and missense mutations, many with phenotypic consequences that could not have been predicted from previous knowledge of mouse models or HOX protein function. Limb malformations may also result from chromosomal deletions involving the HOXD and HOXA clusters, and from regulatory mutations affecting single or multiple HOX genes.

Full genome screen for Alzheimer disease: Stage II analysis*

Abstract: We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1).

Complex relationship between Parkin mutations and Parkinson disease.

Abstract: Mutations in the Parkin gene cause juvenile and early onset Parkinsonism While Parkin-related disease is presumed to be an autosomal-recessive disorder, cases have been reported where only a single Parkin allele is mutated and raise the possibility of a dominant effect In this report, we re-evaluate twenty heterozygous cases and extend the mutation screening to include the promoter and intron/exon boundaries Novel deletion, point and intronic splice site mutations are described, along with promoter variation These data, coupled with a complete review of published Parkin mutations, confirms that not only is recessive loss of Parkin a risk factor for juvenile and early onset Parkinsonism but that Parkin haplo-insufficiency may be sufficient for disease in some cases

All in the family: Evaluation of the process and content of sisters' communication about BRCA1 and BRCA2 genetic test results

Abstract: Despite the potential importance of family communication, little is known about the process and content of communicating BRCA1/2 test results to relatives. The objectives of this observational study were to describe the process and content of communicating BRCA1/2 test results to sisters, and to evaluate whether the proband's carrier status influenced communication outcomes. Participants were 43 women who were the first family member to have genetic testing (probands). Probands reported on communication outcomes for 81 sisters. Process and content variables were evaluated 1-month after receipt of BRCA1/2 test results using the Family Communication Questionnaire (FCQ). Overall, BRCA1/2 test results were communicated to 85% of sisters, and carriers communicated their results to significantly more sisters compared to uninformative (96% vs. 76%, FET = 0.02). The most important reason for communicating results was to provide genetic risk information; however, compared to uninformatives, carriers communicated their results to significantly more sisters to obtain emotional support (74%) and to get advice about medical decisions (42%) (FET = 0.001). Carriers also discussed the possibility of discrimination and recommendations for cancer management with significantly more sisters. Among sisters to whom BRCA1/2 test results were not communicated, the most important reason for not sharing test results was because of emotionally distant relationships. The results of this study suggest that probands are likely to quickly communicate their BRCA1/2 test results to relatives and that although needs for social support may motivate family communication, emotionally distant relationships may be a barrier to communication with relatives.

International nosology and classification of constitutional disorders of bone (2001).

Abstract: The last International Classification of Constitutional Disorders of Bone was published in 1998. Since then rapid advances have been made in identifying the molecular changes responsible for defined conditions and new disorders are constantly being delineated. For these reasons a further update on the classification is appropriate. It has been expended to not only the osteochondrodysplasias (33 groups) but also genetically determined dysostoses (3 groups).

FGFs, their receptors, and human limb malformations: clinical and molecular correlations.

Abstract: Fibroblast growth factors (FGFs) comprise a family of 22 distinct proteins with pleiotropic signaling functions in development and homeostasis. These functions are mediated principally by four fibroblast growth factor receptors (FGFRs), members of the receptor tyrosine kinase family, with heparin glycosaminoglycan as an important cofactor. Developmental studies in chick and mouse highlight the critical role of FGF-receptor signaling in multiple phases of limb development, including the positioning of the limb buds, the maintenance of limb bud outgrowth, the detailed patterning of the limb elements, and the growth of the long bones. Corroborating these important roles, mutations of two members of the FGFR family (FGFR1 and FGFR2) are associated with human disorders of limb patterning; in addition, mutations of FGFR3 and FGF23 affect growth of the limb bones. Analysis of FGFR2 mutations in particular reveals a complex pattern of genotype/phenotype correlation, which will be reviewed in detail. Circumstantial evidence suggests that the more severe patterning abnormalities are mediated by illegitimate paracrine signaling in the mesoderm, mediated by FGF10 or by a related FGF, and this is beginning to gain some experimental support. A further test of this hypothesis is provided by a unique family segregating two FGFR2 mutations in cis (S252L; A315S), in which severe syndactyly occurs in the absence of the craniosynostosis that typically accompanies FGFR2 mutations.

MTRR and MTHFR polymorphism: link to Down syndrome?

Abstract: Polymorphisms in genes encoding the folate metabolizing enzymes methylenetetrahydrofolate reductase (MTHFR C677T) and methionine synthase reductase (MTRR A66G) have been linked to the etiology of Down syndrome. We examined the prevalence of these variant genotypes in mothers who had given birth to a child with Down syndrome (n = 48) and in control mothers (n = 192), and investigated the biochemical factors influenced by the presence of MTRR A66G and MTHFR C677T. The frequency of the MTRR variant genotypes (AG, GG) was significantly higher in mothers of children with Down syndrome compared to controls (P = 0.0028). MTHFR C677T genotype frequencies were not significantly altered in mothers of children with Down syndrome (P = 0.74). However, mothers who had a MTHFR CT or TT genotype and a MTRR GG genotype had a 2.98-fold increased risk of having a child with Down syndrome (P = 0.02). The MTRR polymorphism did not increase plasma homocysteine. Higher homocysteine was found with the presence of the MTHFR T allele. In conclusion, MTRR A66G is significantly more common in mothers of children with Down syndrome but does not appear to increase the risk for Down syndrome by changing homocysteine metabolism. Women who have both the MTRR and MTHFR variant genotypes are also at increased risk of producing offspring with Down syndrome.

Behavioral phenotypic variation in autism multiplex families: Evidence for a continuous severity gradient

Abstract: Recent genetic investigations of autism have studied multiplex families, typically including families with multiple siblings who meet criteria for a diagnosis of autism. However, little is known about the specific behavioral characteristics of siblings with autism in these multiplex families. We investigated the behavioral phenotypic variability and similarity of 351 siblings with autism in 171 multiplex families using cluster analysis and correlations. The results of cluster analyses showed that the individuals with autism could be characterized on a severity gradient: a continuum based on severity of symptoms and impairment as measured by Autism Diagnostic Interview-Revised (ADI-R) scores, verbal-nonverbal status, and nonverbal IQ scores. Clusters based on scores from the ADI-R for the autism diagnostic criteria of the DSM-IV and nonverbal IQ scores still represented a severity gradient when the effects of verbal-nonverbal status were removed. The severity gradient was shown to be heritable, with a sib correlation of 30% or a heritability of 60%. In summary, in a sample of 171 autism multiplex families, there was no evidence of discrete behaviorally defined subgroups of affected individuals or families characterized by distinct patterns of behavioral symptoms. Rather, the clusters could be characterized along a single, heritable, continuous severity dimension.

Teratogenesis of holoprosencephaly.

Abstract: Teratogenic causes of holoprosencephaly are critically assessed. A brief general review of holoprosencephaly is followed by four tables summarizing etiologic factors. Subjects evaluated here include: 1) maternal diabetes; 2) ethyl alcohol; 3) retinoic acid; 4) mutated genes and teratogens involving the sonic hedgehog signaling network and cholesterol biosynthesis; and 5) cholesterol trafficking, sterol adducts, target tissue response, and sterol sensing domain.

Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A

Abstract: The importance of hyperhomocysteinemia, birth defects, and vascular diseases has been the subject of intense investigations. The polymorphic MTHFR mutations (C677T and A1298C) cause mild hyperhomocysteinemia, especially in homozygotes for C677T, but also in compound heterozygotes for C677T/A1298C. The subject of this report is the frequency of the polymorphic mutations in the MTHFR gene C677T, C1298A, and newly discovered mutation G1793A, as well as the association with MTRR polymorphic site A66G in different ethnic groups. Four ethnic groups were studied: African-Americans, Caucasians, Hispanics, and Ashkenazi Jews. There are statistically significant differences in the frequency of these alleles in the different populations studied, which impacts compound heterozygosity for such alleles in these populations. DNA samples obtained from the blood of healthy individuals of African-Americans, Hispanics, and Caucasians from south Texas were analyzed and compared to those obtained from Ashkenazi Jewish individuals. The polymorphic site, the G1793A allele, is least frequent among Ashkenazi individuals, 1.3%, compared to 6.9% among Caucasians (P = 0.001), 5.8% among Hispanics (P = 0.012), and 3.1% among African-Americans. The MTRR polymorphic site shows the lowest allele frequency among Hispanics, 28.6%, compared to 34% among African-Americans, 43.1% among Ashkenazi Jews (P = 0.002), and 54.4% among Caucasians (P < 0.0001). Statistically significant differences in allele frequencies of C677T and C1298A polymorphisms were also observed in these populations. Compound heterozygosity for multiple polymorphic alleles may play a role in birth defects and vascular diseases.

Genotype–phenotype correlation in cystic fibrosis: The role of modifier genes

Abstract: More than 1,000 mutations have been identified in the cystic fibrosis (CF) transmembrane regulator (CFTR) disease gene. The impact of these mutations on the protein and the wide spectrum of CF phenotypes prompted a series of Genotype-Phenotype correlation studies. The CFTR genotype is invariably correlated with pancreatic status-in about 85% of cases with pancreatic insufficiency and in about 15% of cases with pancreatic sufficiency. The correlations between the CFTR genotype and pulmonary, liver, and gastrointestinal expression are debatable. The heterogeneous phenotype in CF patients bearing the same genotype or homozygotes for nonsense mutations implicated environmental and/or genetic factors in the disease. However, the discordant phenotype observed in CF siblings argued against a major role of environmental factors and suggested that genes other than CFTR modulate the CF phenotype. A locus that modulates gastrointestinal expression was identified in mice and subsequently in humans. By analyzing nine CF patients discordant for meconium ileus we were able to show that this locus had a dominant effect. Moreover, in a collaborative study we found a higher rate of polymorphisms in beta-defensin genes 1 and 2 in CF patients and in controls. In another multicenter study mutations in alpha-1 antitrypsin (A1AT) and mannose binding lectin genes were found to be independent risk factors for liver disease in CF patients. The body of evidence available suggests that the variegated CF phenotype results from complex interactions between numerous gene products.

Genetic risk assessment in carrier testing for spinal muscular atrophy.

Abstract: As evidenced by the complete absence of a functionally critical sequence in exon 7, approximately 94% of individuals with clinically typical spinal muscular atrophy (SMA) lack both copies of the SMN1 gene at 5q13. Hence most carriers have only one copy of SMN1. Combining linkage and dosage analyses for SMN1, we observed unaffected individuals who have two copies of SMN1 on one chromosome 5 and zero copies of SMN1 on the other chromosome 5. By dosage analysis alone, such individuals, as well as carriers of non-deletion disease alleles, are indistinguishable from non-carrier individuals. We report that approximately 7% of unaffected individuals without a family history of SMA have three or four copies of SMN1, implying a higher frequency of chromosomes with two copies of SMN1 than previously reported. We present updated calculations for disease and non-disease allele frequencies and we describe how these frequencies can be used for genetic risk assessment in carrier testing for SMA.

Problem behavior in boys with fragile X syndrome.

Abstract: This study examines problem behavior over time in 59 boys with fragile X syndrome (FXS), aged 4-12 years, using the Child Behavior Checklist (CBCL). Approximately 49% of the boys scored within the borderline or clinical range on total problem behavior, while 56-57% scored in the borderline or clinical range on the attention and thought problems subscales, and 26% scored in this range on the social problems subscale. With a mean of 2.5 assessments per child, behavior problems were stable during the 3-year period of study. Total problem behavior was higher for children who displayed autistic behavior, were rated as low in adaptability, had mothers with higher maternal education levels, and were on medication. Mothers with more education also rated their children as having more attention, thought, and total problems. Children taking medication differed from boys who were not taking medication on social problems, but not on attention and thought problems. Low adaptability and more autistic characteristics predicted thought problems.

Apparent genotype–phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome

Abstract: Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by severe immunologic defects, reduced pigmentation, bleeding tendency, and progressive neurological dysfunction. Most patients present in early childhood and die unless treated by bone marrow transplantation. About 10-15% of patients exhibit a much milder clinical phenotype and survive to adulthood, but develop progressive and often fatal neurological dysfunction. Very rare patients exhibit an intermediate adolescent CHS phenotype, presenting with severe infections in early childhood, but a milder course by adolescence, with no accelerated phase. Here, we describe the organization and genomic DNA sequence of the CHS1 gene and mutation analysis of 21 unrelated patients with the childhood, adolescent, and adult forms of CHS. In patients with severe childhood CHS, we found only functionally null mutant CHS1 alleles, whereas in patients with the adolescent and adult forms of CHS we also found missense mutant alleles that likely encode CHS1 polypeptides with partial function. Together, these results suggest an allelic genotype-phenotype relationship among the various clinical forms of CHS.

Genes and translocations involved in POF.

Abstract: Changes at a single autosomal locus and many X-linked loci have been implicated in women with gonadal dysgenesis [premature ovarian failure (POF) with deficits in ovarian follicles]. For the chromosome 3 locus, a forkhead transcription factor gene (FOXL2) has been identified, in which lesions result in decreased follicles by haploinsufficiency. In contrast, sporadic X; autosomal translocations are distributed at many points on the X, but concentrate in a critical region on Xq. The association of the breakpoints with genes involved in ovarian function is thus far weak (in four analyzed cases) and has not been related to pathology in other POF patients. While many more translocations can be analyzed in detail as the human genome sequence is refined, it remains possible that translocations like X monosomy (Turner syndrome) lead to POF not by interrupting specific genes important in ovarian development, but by causing aberrations in pairing or X-inactivation during folliculogenesis. It is noted that the critical region has unusual features, neighboring the X-inactivation center and including an 18 Mb region of very low recombination. These suggest that chromosome dynamics in the region may be sensitive to structural changes, and when modified by translocations might provoke apoptosis at meiotic checkpoints. Choices among models for the etiology of POF should be feasible based on studies of ovarian follicle development and attrition in mouse models. Studies would prominently include gene expression profiling of developmental-specific pathways in nascent ovaries with controlled levels of Foxl2 and interacting proteins, or with defined changes in the X chromosome.

Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism

Abstract: A functional polymorphism in the regulatory region of the serotonin transporter gene (5-HTTLPR) is considered to be a plausible candidate gene for anxiety-related personality traits and for alcoholism. Empirical support for the association between 5-HTTLPR and psychological traits has been somewhat inconsistent; however, observations of the functional dominance of the low-activity s-allele over the l-allele have been more consistent. When studying the influence of particular genes on psychological traits, it seems useful also to assess more biological intermediate traits that may mediate the effects of those genes on the traits of interest. The present study examined relationships between 5-HTTLPR genotype, whole blood serotonin (5-HT) level, and platelet 5-HT binding in 150 Caucasian subjects from 50 biological families. Individuals with the s-allele had lower average platelet 5-HT binding availability than those with the l/l genotype (P < 0.025). Whole blood 5-HT level was not associated with 5-HTTLPR genotype. In adult men, those with the s-allele had higher mean scores on the NEO-FFI personality trait of openness than did those with the l/l genotype (P = 0.002). The effect was not statistically significant in women (P = 0.42), although it was in the same direction. Our findings do not support an association of 5-HTTLPR genotype with alcoholism diagnosis, alcoholism subtype, or the personality trait of neuroticism. The results of this pilot study suggest that further work should examine the mediation of the genetic effects on personality traits by biochemical measures and their moderation by gender. © 2002 Wiley-Liss, Inc.

Five additional Costello syndrome patients with rhabdomyosarcoma: Proposal for a tumor screening protocol

Abstract: We report five new cases of rhabdomyosarcoma (RMS) in Costello syndrome. These cases, combined with those previously reported, increase the number of solid tumors to 17 (10 RMSs, 3 neuroblastomas, 2 bladder carcinomas, 1 vestibular schwannoma, 1 epithelioma), in at least 100 known Costello syndrome patients. Despite possible ascertainment bias, and the incomplete identification of all Costello syndrome patients, the tumor frequency could be as high as 17%. This is comparable to the 7-21% frequency of solid tumors in Beckwith-Wiedemann syndrome (BWS), and may justify tumor screening. Based on the recommendations for screening BWS patients, we propose a screening protocol consisting of ultrasound examination of the abdomen and pelvis every 3-6 months until age 8-10 years for RMS and abdominal neuroblastoma; urine catecholamine metabolite analysis every 6-12 months until age 5 years for neuroblastoma; and urinalysis for hematuria annually for bladder carcinoma after age 10 years. These recommendations may need to be modified, as new information becomes available. Potential criticism of the tumor screening protocol concerns the lack of evidence for improved outcome, and possible overestimation of the tumor risk. The ability of RMSs to occur at various sites complicates tumor screening, but 8 of the 10 RMSs in Costello syndrome patients originated from the abdomen, pelvis and urogenital area. Prior diagnosis of Costello syndrome is a prerequisite for the implementation of any screening protocol. The diagnosis of Costello syndrome should also be considered in individuals with RMS and physical findings suggestive of Costello syndrome.

Craniofacial phenotypes in segmentally trisomic mouse models for Down syndrome

Abstract: Trisomy for chromosome 21 (Chr 21) has profound effects on development that result in a constellation of phenotypes known as Down syndrome (DS). Distinctive craniofacial manifestations are among the few features common to all individuals with DS. The characteristic face of a person with DS results primarily from maldevelopment of the underlying craniofacial skeleton. The Ts65Dn mouse, which has segmental trisomy 16, producing dosage imbalance for about half the genes found on human Chr 21, exhibits specific skeletal malformations corresponding directly to the craniofacial dysmorphogenesis in DS. Here we demonstrate that Ts1Cje mice, which are at dosage imbalance for about 3/4 of the genes triplicated in Ts65Dn, demonstrate a very similar pattern of anomalies in the craniofacial skeleton. However, one characteristic of Ts65Dn mice, a broadening of the cranial vault contributing to brachycephaly, is not seen in Ts1Cje mice. These observations independently confirm that a dosage imbalance for mouse genes orthologous to those on human Chr 21 has corresponding effects in both species. The subtle differences in the craniofacial phenotypes of Ts1Cje and Ts65Dn mice have implications for elucidation of the mechanisms by which this aneuploidy disrupts development.

Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations.

Abstract: We examined 26 individuals with clinical and electron microscopic signs of late infantile neuronal ceroid lipofuscinosis (LINCL). In 22 cases, we found both pathogenic alleles. Sixteen patients exclusively carried either one or a combination of the two common mutations R208X and IVS5-1G > C. In the remaining cases, four missense mutations could be detected, of which R127Q, N286S, and T353P represent novel, previously not described alleles. A clinical performance score was developed by rating motor, visual, and verbal functions and the incidence of cerebral seizures in 3-month intervals during the course of the disease. A Total Disability Score was derived by summing up the single scores for motor, visual, and verbal functions. The 16 individuals with the two common mutations were grouped together (referred to as standard patients), and the 5th, 50th, and 95th centiles were calculated and graphically depicted over time. The scores for motor function and language ability dropped earliest and progressed very similarly in the standard patients. The performance curves of two children with the N286S mutation slightly diverged from the 95th centile. However, the performance curves of one patient with atypical LINCL carrying the R127Q mutation fell far beyond the 95th centile. The presented performance rating clearly and quantitatively delineates the disease course of the LINCL patients and hence offers a useful tool for clinical evaluation of future therapeutic interventions. In addition, the described performance score system can be applied to other types of neuronal ceroid lipofuscinoses and could be adapted to various other neurodegenerative diseases of childhood.

Subtelomeric rearrangements detected in patients with idiopathic mental retardation

Abstract: A screening for submicroscopic rearrangements was performed in 111 patients with idiopathic mental retardation (MR) using fluorescence in situ hybridization (FISH) probes from the subtelomeric regions of all chromosome arms. Ten cryptic rearrangements were found (9%): five de novo deletions; one unbalanced de novo translocation; three unbalanced inherited translocations; and one unbalanced recombinant chromosome, inherited from a parent with a pericentric inversion. In addition, 50 of the patients were screened for interstitial rearrangements with spectral karyotyping (SKY), but no aberrations were found. However, SKY detected the subtelomeric rearrangement in three of the four unbalanced translocations. Dysmorphic features were present in all patients with detected subtelomeric rearrangements.