Multigenerational Pedigrees Research Articles

Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p

Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Correction: Exome Sequencing of a Multigenerational Human Pedigree

The first author's name is not spelled correctly. It should be: Dale J. Hedges. The correct citation is: Hedges DJ, Burges D, Powell E, Almonte C, Huang J, et al. (2009) Exome Sequencing of a Multigenerational Human Pedigree. PLoS ONE 4(12): e8232. doi:10.1371/journal.pone.0008232

The genetic basis of recessive self-colour pattern in a wild sheep population

Bridging the genotype-phenotype gap for traits of ecological and evolutionary importance in natural populations can provide a novel insight into the origin and maintenance of variation. Here, we identify the gene and putative causal mutations underlying a recessive colour pattern phenotype ('self' or uniform colour) in a wild population of primitive Soay sheep. We targeted the agouti signalling protein (ASIP) gene, a positional candidate based on previous study that mapped the Coat pattern locus to a presumptive region on chromosome 13. We found evidence for three recessive mutations, including two functional changes in the coding sequence and a putative third cis-regulatory mutation that inactivates the promoter. These mutations define up to five haplotypes in Soays, which collectively explained the coat pattern in all but one member of a complex multi-generational pedigree containing 621 genotyped individuals. The functional mutations are in strong linkage disequilibrium in the study population, and are identical to those known to underlie the self phenotype in domestic sheep. This is indicative of a recent (and simultaneous) origin in Soay sheep, possibly as a consequence of past interbreeding with modern domestic breeds. This is only the second study in which ASIP has been linked to variation in pigmentation in a natural population. Knowledge of the genetic basis of self-colour pattern in Soay sheep, and the recognition that several mutations are segregating in the population, will aid future studies investigating the role of selection in the maintenance of the polymorphism.

Identifying heritable brain phenotypes in an extended pedigree of vervet monkeys.

The area and volume of brain structural features, as assessed by high-resolution three-dimensional magnetic resonance imaging (MRI), are among the most heritable measures relating to the human CNS. We have conducted MRI scanning of all available monkeys >2 years of age (n = 357) from the extended multigenerational pedigree of the Vervet Research Colony (VRC). Using a combination of automated and manual segmentation we have quantified several correlated but distinct brain structural phenotypes. The estimated heritabilities (h(2)) for these measures in the VRC are higher than those reported previously for such features in humans or in other nonhuman primates: total brain volume (h(2) = 0.99, SE = 0.06), cerebral volume (h(2) = 0.98, SE = 0.06), cerebellar volume (h(2) = 0.86, SE = 0.09), hippocampal volume (h(2) = 0.95, SE = 0.07) and corpus callosum cross-sectional areas (h(2) = 0.87, SE = 0.07). These findings indicate that, in the controlled environment and with the inbreeding structure of the VRC, additive genetic factors account for almost all of the observed variance in brain structure, and suggest the potential of the VRC for genetic mapping of quantitative trait loci underlying such variance.

Genetic Influences on Type 2 Diabetes and Metabolic Syndrome Related Quantitative Traits in Mauritius

Epidemiological studies report a high prevalence of type 2 diabetes and metabolic syndrome in the island nation of Mauritius. The Mauritius Family Study was initiated to examine heritable factors that contribute to these high rates of prevalence and consists of 400 individuals in 24 large extended multigenerational pedigrees. Anthropometric and biochemical measurements relating to the metabolic syndrome were undertaken in addition to family and lifestyle based information for each individual. Variance components methods were used to determine the heritability of the type 2 diabetes and metabolic syndrome related quantitative traits. The cohort was made up of 218 females (55%) and 182 males with 22% diagnosed with type 2 diabetes and a further 30% having impaired glucose tolerance or impaired fasting glucose. Notably BMI was not significantly increased in those with type 2 diabetes (P= .12), however a significant increase in waist circumference was observed in these groups (P= .02). The heritable proportion of trait variance was substantial and greater than values previously published for hip circumference, LDL and total cholesterol, diastolic and systolic blood pressure and serum creatinine. Height, weight and BMI heritabilities were all in the upper range of those previously reported. The phenotypic characteristics of the Mauritius family cohort are similar to those previously reported in the Mauritian population with a high observed prevalence rate of type 2 diabetes. A high heritability for key type 2 diabetes and metabolic syndrome related phenotypes (range 0.23 to 0.68), suggest the cohort will have utility in identifying genes that influence these quantitative traits.

EVOLUTION OF GENETIC INTEGRATION BETWEEN DISPERSAL AND COLONIZATION ABILITY IN A BIRD

Discrete behavioral strategies comprise a suite of traits closely integrated in their expression with consistent natural selection for such coexpression leading to developmental and genetic integration of their components. However, behavioral traits are often also selected to respond rapidly to changing environments, which should both favor their context-dependent expression and inhibit evolution of genetic integration with other, less flexible traits. Here we use a multigeneration pedigree and long-term data on lifetime fitness to test whether behaviors comprising distinct dispersal strategies of western bluebirds-a species in which the propensity to disperse is functionally integrated with aggressive behavior-are genetically correlated. We further investigated whether selection favors flexibility in the expression of aggression in relation to current social context. We found a significant genetic correlation between aggression and dispersal that is concordant with consistent selection for coexpression of these behaviors. To a limited extent, individuals modified their aggression to match their mate; however, we found no fitness consequences on such adjustments. These results introduce a novel way of viewing behavioral strategies, where flexibility of behavior, while often aiding an organism's fit in its current environment, may be limited and thereby enable integration with less flexible traits.

Identification of genomic regions contributing to etoposide-induced cytotoxicity

Etoposide is routinely used in combination-based chemotherapy for testicular cancer and small-cell lung cancer; however, myelosuppression, therapy-related leukemia and neurotoxicity limit its utility. To determine the genetic contribution to cellular sensitivity to etoposide, we evaluated cell growth inhibition in Centre d' Etude du Polymorphisme Humain lymphoblastoid cell lines from 24 multi-generational pedigrees (321 samples) following treatment with 0.02-2.5 microM etoposide for 72 h. Heritability analysis showed that genetic variation contributes significantly to the cytotoxic phenotypes (h (2) = 0.17-0.25, P = 4.9 x 10(-5)-7.3 x 10(-3)). Whole genome linkage scans uncovered 8 regions with peak LOD scores ranging from 1.57 to 2.55, with the most significant signals being found on chromosome 5 (LOD = 2.55) and chromosome 6 (LOD = 2.52). Linkage-directed association was performed on a subset of HapMap samples within the pedigrees to find 22 SNPs significantly associated with etoposide cytotoxicity at one or more treatment concentrations. UVRAG, a DNA repair gene, SEMA5A, SLC7A6 and PRMT7 are implicated from these unbiased studies. Our findings suggest that susceptibility to etoposide-induced cytotoxicity is heritable and using an integrated genomics approach we identified both genomic regions and SNPs associated with the cytotoxic phenotypes.

An autosomal genetic linkage map of the domestic cat, Felis silvestris catus

We report on the completion of an autosomal genetic linkage (GL) map of the domestic cat ( Felis silvestris catus). Unlike two previous linkage maps of the cat constructed with a hybrid pedigree between the domestic cat and the Asian leopard cat, this map was generated entirely with domestic cats, using a large multi-generational pedigree ( n = 256) maintained by the Nestlé Purina PetCare Company. Four hundred eighty-three simple tandem repeat (STR) loci have been assigned to linkage groups on the cat's 18 autosomes. A single linkage group spans each autosome. The length of the cat map, estimated at 4370 cM, is long relative to most reported mammalian maps. A high degree of concordance in marker order was observed between the third-generation map and the 1.5 Mb-resolution radiation hybrid (RH) map of the cat. Using the cat 1.9 × whole-genome sequence, we identified map coordinates for 85% of the loci in the cat assembly, with high concordance observed in marker order between the linkage map and the cat sequence assembly. The present version represents a marked improvement over previous cat linkage maps as it ( i) nearly doubles the number of markers that were present in the second-generation linkage map in the cat, ( ii) provides a linkage map generated in a domestic cat pedigree which will more accurately reflect recombination distances than previous maps generated in a hybrid pedigree, and ( iii) provides single linkage groups spanning each autosome. Marker order was largely consistent between this and the previous maps, though the use of a hybrid pedigree in the earlier versions appears to have contributed to some suppression of recombination. The improved linkage map will provide an added resource for the mapping of phenotypic variation in the domestic cat and the use of this species as a model system for biological research.

Pedigree reconstruction in wild cichlid fish populations

It is common practice to use microsatellites to detect parents and their offspring in wild and captive populations, in order to reconstruct a pedigree. However, correct inference is often constrained by a number of factors, including the absence of demographic data and ignorance regarding the completeness of parental sampling. Here we present a new Bayesian estimator that simultaneously estimates the pedigree and the size of the unsampled population. The method is robust to genotyping error, and can estimate pedigrees in the absence of demographic data. Using a large-scale microsatellite assay in four wild cichlid fish populations of Lake Tanganyika (1000 individuals in total), we assess the performance of the Bayesian estimator against the most popular assignment program, Cervus. We found small but significant pedigrees in each of the tested populations using the Bayesian procedure, but Cervus had very high type I error rates when the size of the unsampled population was assumed to be lower than what it was. The need of pedigree relationships to infer adaptive processes in natural populations places strong constraints on sampling design and identification of multigenerational pedigrees in natural populations.

Exact Trait‐Model‐Free Tests for Linkage Detection in Pedigrees

A number of trait-model-free tests have been proposed for linkage detection between a genomic region and a trait. These tests involve testing the dependence in segregation between a trait and marker alleles by assigning a score to every possible identity-by-descent configuration of the pedigree members without modeling the trait, and then averaging the scores over all such configurations compatible with the observed marker genotypes and genealogical relationship of the pedigree members. In this paper we propose a permutation test as an alternative to the existing exact trait-model-free tests for linkage detection. The proposed test is computationally efficient and is applicable on complex multigeneration pedigree structures. In this paper, we have compared the performance of the permutation test with two other exact trait-model-free tests for linkage detection on simulated datasets. We have demonstrated that the proposed permutation test is fully robust against mispecification of marker allele frequencies and has very good power for linkage detection. The permutation test is implemented in the program lm_ibdtests within the framework of MORGAN 2.8 (http://www.stat.washington.edu/thompson/Genepi/MORGAN/Morgan.shtml).

Quantitative trait loci analysis on Sus scrofa chromosome 7 for meat production, meat quality, and carcass traits within a Duroc purebred population

Many QTL analyses related to meat production and meat quality traits have been carried out using an F(2) resource population produced by crossing 2 genetically different breeds. This experiment was intended to investigate whether these QTL were segregating in a purebred Duroc population that had been selected for meat production and meat quality traits during 7 generations. Sus scrofa chromosome 7, for which significant QTL of intramuscular fat and many other traits have already been reported, was studied. The polymorphism of 10 microsatellite markers that were arranged at about 20-cM intervals was investigated on 1,004 pigs. In the selected population, 954 progeny were produced from mating of 99 sires and 286 dams. The QTL analysis for a full-sib family population was examined with the multigeneration pedigree structure of the population. Variance component analysis was used to detect QTL in this population and was examined for the multigeneration pedigree population. In this study, multigenerational pedigree estimated identical by descent coefficients among sibs were produced using Markov chain Monte Carlo methods. The maximum likelihood of odds score was found at the 70-cM position for the LM area, at the 0-cM position for the pork color standard, and at the 120-cM position for the number of thoracic vertebra, but no significant QTL for intramuscular fat were detected on SSC 7. These results indicate that QTL analysis via a variance component method within a purebred population was effective to determine that QTL were segregating in a population of purebred Durocs.

Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees.

OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 × 10−10). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years).CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.

Maturational costs of reproduction due to clutch size and ontogenetic conflict as revealed in the invisible fraction.

Reproduction is thought to entail costs, but assessing survival costs associated with maturation as organisms express reproductive genes for the first time is problematic because many will die prior to expressing a phenotype. We quantified selection acting on this invisible fraction by measuring selection on predicted breeding values for clutch size estimated from a multigenerational pedigree of side-blotched lizards in which clutch size was heritable (h2=0.25+/-0.04). The survival effects of predicted breeding values for clutch size during maturation, however, differed between males and females indicating ontogenetic conflict. Increased mortality during maturation was associated with lower predicted breeding values for clutch size for females, but higher predicted breeding values for males who do not produce a clutch. Genetic correlations between clutch size and male and female survival were consistent with calculated selection differentials. Experimental yolk removal did not affect progeny survival during maturation, indicating that selection on maturing progeny was not due to confounding yolk-volume maternal effects, and hormone manipulations confirmed clutch size as the target of viability selection during maturation. Such episodes of selection prior to phenotypic expression of the trait will have important consequences for the evolution of reproductive investment.

Abstract 1743: Identification of a Novel Susceptibility Locus at 9q21 for Familial Bicuspid Aortic Valve Disease

Background: Bicuspid aortic valve disease (BAV), the most common congenital cardiovascular malformation, has an incidence of 0.5–1.0% of live births. While most cases of BAV appear to be sporadic, familial inheritance patterns have been observed consistent with autosomal dominant inheritance with variable penetrance. However, little is known about specific genetic loci responsible for familial BAV. Here, we performed linkage analysis on a large multi-generational pedigree affected with BAV. Methods: We identified a large, five-generation pedigree (136 family members) with 10 individuals having BAV. Two-dimensional echocardiography was used to assign aortic valve phenotype. Genome-wide linkage analysis using 430 microsatellite markers (Marshfield Clinic) and fine mapping using 100 single nucleotide polymorphisms (Affymetrix) on chromosome 9 was performed on genomic DNA from all available family members. Logarithm of odds (LOD) scores of >2.0 were considered suggestive of linkage. Comprehensive splice site/open reading frame mutational analysis of candidate genes residing in the putative locus is underway using PCR, DHPLC, and DNA sequencing. A candidate gene, KLF9, Krüppel-like factor 9 was analyzed for mutations because of its role in cardiogenesis. Results: Multi-point genome-wide linkage analysis demonstrated a 7 cM region on chromosome 9q21 that was suggestive of linkage for familial BAV with a maximum multipoint LOD score of 2.8 flanked by the microsatellite markers GATA7D12 and D9S1834. This region contains several candidate genes with biological plausibility for BAV phenotype. KLF9- encoded Krüppel-like factor 9, localized to chromosome 9q21, was targeted as a prime candidate gene for familial BAV. However, no mutations involving the translated exons of KLF9 were detected. Further fine mapping studies and candidate gene analysis are currently underway. Conclusions: We report a novel susceptibility locus on chromosome 9q21 for BAV in a large multi-generational family. Although coding region mutations in KLF9 are not responsible for BAV in this pedigree, several candidate genes with biological plausibility for the development of congenital BAV lie within this region and warrant further scrutiny.

Four Independent Mutations in the Feline Fibroblast Growth Factor 5 Gene Determine the Long-Haired Phenotype in Domestic Cats

To determine the genetic regulation of "hair length" in the domestic cat, a whole-genome scan was performed in a multigenerational pedigree in which the "long-haired" phenotype was segregating. The 2 markers that demonstrated the greatest linkage to the long-haired trait (log of the odds > or = 6) flanked an estimated 10-Mb region on cat chromosome B1 containing the Fibroblast Growth Factor 5 (FGF5) gene, a candidate gene implicated in regulating hair follicle growth cycle in other species. Sequence analyses of FGF5 in 26 cat breeds and 2 pedigrees of nonbreed cats revealed 4 separate mutations predicted to disrupt the biological activity of the FGF5 protein. Pedigree analyses demonstrated that different combinations of paired mutant FGF5 alleles segregated with the long-haired phenotype in an autosomal recessive manner. Association analyses of more than 380 genotyped breed and nonbreed cats were consistent with mutations in the FGF5 gene causing the long-haired phenotype in an autosomal recessive manner. In combination, these genomic approaches demonstrated that FGF5 is the major genetic determinant of hair length in the domestic cat.

Direct and indirect selection of visceral lipid weight, fillet weight, and fillet percentage in a rainbow trout breeding program1

We assessed whether visceral lipid weight, fillet weight, and percentage fillet from BW, 3 traits laborious to record, could be genetically improved by indirect selection on more easily measured traits in farmed rainbow trout. Visceral lipid is discarded as waste during slaughter, influencing production efficiency and production costs. Fillet weight and fillet percentage directly influence economic returns in trout production. The study comprised 3 steps. First, we assessed the degree to which selection on percentage of visceral weight from BW indirectly changes visceral lipid weight and the size of intestines and internal organs. The phenotypic analysis of weights of viscera, intestines, visceral lipid, liver, and gonads measured from 40 fish revealed that phenotypic selection against visceral weight was most strongly directed to visceral lipid, and to a lesser degree to intestines and gonads. Because genetic relationships among these traits were not established, it is not known whether indirect selection leads to genetic responses. Second, we examined whether direct selection for the fillet traits could be replaced by indirect selection on BW, eviscerated BW, visceral weight, visceral percentage, head volume, and relative head volume (head volume relative to BW). The selection index calculations based on the quantitative genetic parameters obtained from multigenerational pedigree data showed that genetic improvement of fillet percentage through direct selection (selection accuracy, r(TI) = 0.54) was equally efficient compared with indirect selection on visceral percentage ( r(TI) = 0.54). Genetic improvement of fillet weight through direct selection (r(TI) = 0.56) was always more efficient than indirect selection, yet indirect selection for eviscerated BW ( r(TI) = 0.50) was almost as efficient as direct selection. Third, the expected genetic responses to alternative selection indices showed that improved fillet percentage was mainly a result of a moderate decrease in visceral weight rather than of a major increase in absolute fillet weight. Moreover, fillet percentage is challenging to improve, even if it exhibits moderate heritability (h(2) = 0.29). This is because fillet percentage displays low phenotypic variation. In conclusion, fillet weight and fillet percentage can be increased by indirect selection against visceral percentage and for high eviscerated BW.

Examining the effect of linkage disequilibrium between markers on the Type I error rate and power of nonparametric multipoint linkage analysis of two-generation and multigenerational pedigrees in the presence of missing genotype data.

Because most multipoint linkage analysis programs currently assume linkage equilibrium between markers when inferring parental haplotypes, ignoring linkage disequilibrium (LD) may inflate the Type I error rate. We investigated the effect of LD on the Type I error rate and power of nonparametric multipoint linkage analysis of two-generation and multigenerational multiplex families. Using genome-wide single nucleotide polymorphism (SNP) data from the Collaborative Study of the Genetics of Alcoholism, we modified the original data set into 30 total data sets in order to consider six different patterns of missing data for five different levels of SNP density. To assess power, we designed simulated traits based on existing marker genotypes. For the Type I error rate, we simulated 1,000 qualitative traits from random distributions, unlinked to any of the marker data. Overall, the different levels of SNP density examined here had only small effects on power (except sibpair data). Missing data had a substantial effect on power, with more completely genotyped pedigrees yielding the highest power (except sibpair data). Most of the missing data patterns did not cause large increases in the Type I error rate if the SNP markers were more than 0.3 cM apart. However, in a dense 0.25-cM map, removing genotypes on founders and/or founders and parents in the middle generation caused substantial inflation of the Type I error rate, which corresponded to the increasing proportion of persons with missing data. Results also showed that long high-LD blocks have severe effects on Type I error rates.

Chromosomal Translocation t(1;4) (p21;p14) Indicating Possible Susceptibility Loci for Schizophreniform Disorder and Mental Retardation

Back to table of contents Previous article Next article LETTERFull AccessChromosomal Translocation t(1;4) (p21;p14) Indicating Possible Susceptibility Loci for Schizophreniform Disorder and Mental RetardationQuirino Cordeiro M.D., Ph.D.Stevin Zung M.D., Ph.D.Eduardo Vilodres Campanha M.D.Homero Vallada M.D., Ph.D.,Quirino Cordeiro M.D., Ph.D.Search for more papers by this authorStevin Zung M.D., Ph.D.Search for more papers by this authorEduardo Vilodres Campanha M.D.Search for more papers by this authorHomero Vallada M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Family, twin, and adoption studies have provided evidence that genetic factors play an important role in the predisposition to mental disorders. However, it has proved difficult to identify the genes involved in this susceptibility. As some cases of mental disorders may be related to chromosomal abnormalities, 1 these situations are valuable resources for helping to find the genes involved in their etiopathogenesis. 2 It is unrealistic to perform cytogenetic analysis on all psychiatric patients. However, there are some groups of patients for whom screening for cytogenetic abnormality should be considered, particularly those with a) strong family histories of psychiatric disorders, b) mental retardation or a strong family history of such a condition, or c) the presence of physical dysmorphisms (indicators of disturbed prenatal development of the ectoderm, which is the embryological structure responsible for the constitution of the skin and its annexes, and CNS). 2 This letter presents the case of a patient with mild mental retardation, schizophrenia, and physical dysmorphisms, with the aim to discuss chromosomal abnormalities as a condition to indicate loci “hot spots” to be investigated. Case ReportAn 18-year-old male patient with history of mild mental retardation and physical anomalies, such as clinodactyly and epicanthal fold, started to present with delusions, hallucinations, aggressive behavior, disorganized speech, affective flattening, avolition, and social isolation (features indicative of schizophrenia). Because of the diagnosis of mental retardation and the physical abnormalities, the patient was submitted to a cytogenetic study which identified a balanced translocation t(1;4) (p21;p14) without loss of material. His parents did not show chromosomal abnormalities.Comment Cytogenetic abnormalities may provide a valuable clue to the identification of target loci. One such success story was the discovery of the genes DISC1 and DISC2 (disrupted in schizophrenia) on chromosome 1 where an inherited reciprocal translocation between chromosomes 1 and 11 was segregated with schizophrenia and other psychiatric disorders in a large multigenerational pedigree from Scotland. 3 When a chromosomal abnormality is detected in someone with a psychiatric illness, it may be considered noncoincidental and related to the disorder if some criteria are met, one of them being the existence of independent reports of the association of such abnormalities with the psychiatric disorder. The chromosomal breakpoints observed in our case report (1p22 and 4p14) are located extremely close to regions described previously by two other reports. Gordon et al. 4 described a case of a reciprocal translocation t 1 (p22;q21.3) in a patient with childhood onset schizophrenia, autism and mental retardation. Palmour et al. 5 reported a case of a schizophrenic patient with inversion on chromosome 1 (p15.2q21.3) and the proband’s mother who had the same inversion and schizotypic traits. Thus, the loci 1p22 and 4p14 may be interesting regions for genetic investigations on schizophreniform disorders and mental retardation. Department of Psychiatry, School of Medicine, University of São Paulo, BrazilReferences1 . Akanuma N, Saitoh O, Yoshikawa T, et al: Interictal schizophrenia-like psychosis in a patient with double cortex syndrome. J Neuropsychiatry Clin Neurosci 2002; 14:210–213Google Scholar2 . MacIntyre DJ, Blackwood DHR, Porteous BS, et al: Chromosomal abnormalities and mental illness. Mol Psychiatry 2003; 8:275–287Google Scholar3 . Blackwood DH, Fordyce A, Walker MT, et al: Schizophrenia and affective disorders: cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69:428–433Google Scholar4 . Gordon CT, Krasnewich D, White B, et al: Brief report: translocation involving chromosomes 1 and 7 in a boy with childhood-onset schizophrenia. J Autism Dev Disor 1994;24:537:545Google Scholar5 . Palmour RM, Miller S, Fielding A, et al: A contribution to the differential diagnosis of the “group of schizophrenias”: structuralabnormality of chromosome 4. J Psychiatry Neurosci 1994; 19:270–277Google Scholar FiguresReferencesCited byDetailsCited byNone Volume 19Issue 3 Summer, 2007Pages 339-339 Metrics PDF download History Published online 1 July 2007 Published in print 1 July 2007

Chromosomal Translocation t(1;4) (p21;p14) Indicating Possible Susceptibility Loci for Schizophreniform Disorder and Mental Retardation

Back to table of contents Previous article Next article LETTERFull AccessChromosomal Translocation t(1;4) (p21;p14) Indicating Possible Susceptibility Loci for Schizophreniform Disorder and Mental RetardationQuirino Cordeiro M.D., Ph.D.Stevin Zung M.D., Ph.D.Eduardo Vilodres Campanha M.D.Homero Vallada M.D., Ph.D.,Quirino Cordeiro M.D., Ph.D.Search for more papers by this authorStevin Zung M.D., Ph.D.Search for more papers by this authorEduardo Vilodres Campanha M.D.Search for more papers by this authorHomero Vallada M.D., Ph.D.Search for more papers by this author,Published Online:1 Jul 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Family, twin, and adoption studies have provided evidence that genetic factors play an important role in the predisposition to mental disorders. However, it has proved difficult to identify the genes involved in this susceptibility. As some cases of mental disorders may be related to chromosomal abnormalities, 1 these situations are valuable resources for helping to find the genes involved in their etiopathogenesis. 2 It is unrealistic to perform cytogenetic analysis on all psychiatric patients. However, there are some groups of patients for whom screening for cytogenetic abnormality should be considered, particularly those with a) strong family histories of psychiatric disorders, b) mental retardation or a strong family history of such a condition, or c) the presence of physical dysmorphisms (indicators of disturbed prenatal development of the ectoderm, which is the embryological structure responsible for the constitution of the skin and its annexes, and CNS). 2 This letter presents the case of a patient with mild mental retardation, schizophrenia, and physical dysmorphisms, with the aim to discuss chromosomal abnormalities as a condition to indicate loci “hot spots” to be investigated. Case ReportAn 18-year-old male patient with history of mild mental retardation and physical anomalies, such as clinodactyly and epicanthal fold, started to present with delusions, hallucinations, aggressive behavior, disorganized speech, affective flattening, avolition, and social isolation (features indicative of schizophrenia). Because of the diagnosis of mental retardation and the physical abnormalities, the patient was submitted to a cytogenetic study which identified a balanced translocation t(1;4) (p21;p14) without loss of material. His parents did not show chromosomal abnormalities.Comment Cytogenetic abnormalities may provide a valuable clue to the identification of target loci. One such success story was the discovery of the genes DISC1 and DISC2 (disrupted in schizophrenia) on chromosome 1 where an inherited reciprocal translocation between chromosomes 1 and 11 was segregated with schizophrenia and other psychiatric disorders in a large multigenerational pedigree from Scotland. 3 When a chromosomal abnormality is detected in someone with a psychiatric illness, it may be considered noncoincidental and related to the disorder if some criteria are met, one of them being the existence of independent reports of the association of such abnormalities with the psychiatric disorder. The chromosomal breakpoints observed in our case report (1p22 and 4p14) are located extremely close to regions described previously by two other reports. Gordon et al. 4 described a case of a reciprocal translocation t 1 (p22;q21.3) in a patient with childhood onset schizophrenia, autism and mental retardation. Palmour et al. 5 reported a case of a schizophrenic patient with inversion on chromosome 1 (p15.2q21.3) and the proband’s mother who had the same inversion and schizotypic traits. Thus, the loci 1p22 and 4p14 may be interesting regions for genetic investigations on schizophreniform disorders and mental retardation. Department of Psychiatry, School of Medicine, University of São Paulo, BrazilReferences1 . Akanuma N, Saitoh O, Yoshikawa T, et al: Interictal schizophrenia-like psychosis in a patient with double cortex syndrome. J Neuropsychiatry Clin Neurosci 2002; 14:210–213Google Scholar2 . MacIntyre DJ, Blackwood DHR, Porteous BS, et al: Chromosomal abnormalities and mental illness. Mol Psychiatry 2003; 8:275–287Google Scholar3 . Blackwood DH, Fordyce A, Walker MT, et al: Schizophrenia and affective disorders: cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet 2001; 69:428–433Google Scholar4 . Gordon CT, Krasnewich D, White B, et al: Brief report: translocation involving chromosomes 1 and 7 in a boy with childhood-onset schizophrenia. J Autism Dev Disor 1994;24:537:545Google Scholar5 . Palmour RM, Miller S, Fielding A, et al: A contribution to the differential diagnosis of the “group of schizophrenias”: structuralabnormality of chromosome 4. J Psychiatry Neurosci 1994; 19:270–277Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 19Issue 3 Summer, 2007Pages 339-339 Metrics PDF download History Published online 1 July 2007 Published in print 1 July 2007

Limited Family Structure and BRCA Gene Mutation Status in Single Cases of Breast Cancer

An autosomal dominant pattern of hereditary breast cancer may be masked by small family size or transmission through males given sex-limited expression. To determine if BRCA gene mutations are more prevalent among single cases of early onset breast cancer in families with limited vs adequate family structure than would be predicted by currently available probability models. A total of 1543 women seen at US high-risk clinics for genetic cancer risk assessment and BRCA gene testing were enrolled in a prospective registry study between April 1997 and February 2007. Three hundred six of these women had breast cancer before age 50 years and no first- or second-degree relatives with breast or ovarian cancers. The main outcome measure was whether family structure, assessed from multigenerational pedigrees, predicts BRCA gene mutation status. Limited family structure was defined as fewer than 2 first- or second-degree female relatives surviving beyond age 45 years in either lineage. Family structure effect and mutation probability by the Couch, Myriad, and BRCAPRO models were assessed with stepwise multiple logistic regression. Model sensitivity and specificity were determined and receiver operating characteristic curves were generated. Family structure was limited in 153 cases (50%). BRCA gene mutations were detected in 13.7% of participants with limited vs 5.2% with adequate family structure. Family structure was a significant predictor of mutation status (odds ratio, 2.8; 95% confidence interval, 1.19-6.73; P = .02). Although none of the models performed well, receiver operating characteristic analysis indicated that modification of BRCAPRO output by a corrective probability index accounting for family structure was the most accurate BRCA gene mutation status predictor (area under the curve, 0.72; 95% confidence interval, 0.63-0.81; P<.001) for single cases of breast cancer. Family structure can affect the accuracy of mutation probability models. Genetic testing guidelines may need to be more inclusive for single cases of breast cancer when the family structure is limited and probability models need to be recreated using limited family history as an actual variable.