Maximum LOD Score Research Articles

Replication of the Recessive STBMS1 Locus but with Dominant Inheritance

Strabismus is a common eye disorder with a prevalence of 1% to 4%. Comitant strabismus accounts for approximately 75% of all strabismus, yet more is known about the less common incomitant disorders. Comitant strabismus is at least partly inherited, but only one recessive genetic susceptibility locus, on chromosome 7p, has been identified in one family. The purpose of this study was to determine the frequency of STBMS1 as a cause of primary nonsyndromic comitant esotropia (PNCE). Twelve families were recruited within the UK Hospital Eye Service as children attended for treatment of PNCE. All consenting persons were clinically assessed, and DNA was sampled. Chromosome 7 microsatellite markers were genotyped in all 12 families, and LOD scores were calculated under recessive and dominant models. One family was linked to STBMS1; in three, linkage was significantly excluded; and the remainder were uninformative. Twenty-six members from three generations of the linked family were analyzed further. Five family members were defined as affected; two had esotropia with an accommodative element; and three underwent strabismus surgery and appeared to have had an infantile/early-onset esotropia. A maximum LOD score of 3.21 was obtained under a dominant mode of inheritance; a recessive model gave an LOD score of 1.2. This study confirms that PNCE can result from sequence variants in an unknown gene at the STBMS1 locus. However, this locus accounts for only a proportion of cases, and other genetic loci remain to be identified. In contrast with the previously reported family, the pedigree described in this study is consistent with dominant rather than recessive inheritance at the STBMS1 locus.

A susceptibility locus on 1p32–1p34 for congenital macrostomia in a Chinese family and identification of a novel PTCH2 mutation

Macrostomia, (horizontal facial cleft, lateral facial cleft, transversefacialcleft)isararecongenitalmalformation.Onoccasion,itcanbea sign in certain syndromes, such as Goldenhar syndrome orTreacher–Collin syndrome [McCarthy and West, 1977]. Rarely,it occurs as an isolated malformation. The cause has remainedunknown.We studied autosomal dominantly inherited macrosomia in alarge family of Chinese Han origin (Fig. 1A and Table I). Linkageandhaplotypeanalysisidentifiedthemacrostomia-associatedlocusbetween markers D1S193 and D1S2652 on 1p32–1p34; the maxi-mum LOD score at D1S2797 was 4.18 (q¼0.00, Table II). At thislocus, we identified a heterozygous mutation in exon 11(NC_000001.9) of PTCH2 (1423G!A, resulting in Val471Ile inthe 4th transmembrane domain) (NP_003729) in all patients withmacrosomia (Fig. 1B). No mutation was found in family memberswholackedmacrosomiaandwefoundnoPTCH2mutationsin520unrelated controls.Although over-expression of SMO induced GLI-dependentluciferase activity, co-expression of wild-type PTCH2 inhibitedSMO-induced activity significantly, confirming the inhibitoryfunction of PTCH2 in the SHH signaling network (Fig. 1C). Incontrast, co-expression of PTCH2 Val471Ile did not inhibit SMO-inducedluciferaseactivity.Over-expressionofPTCH2significantlyinhibited cell proliferation, but over-expression of PTCH2 Va-l471Ile did not appear to have a major effect on the cell growth rate(Fig. 1D). Western blot analysis confirmed that the expression levelof PTCH2 and PTCH2 Val471Ile is similar (Fig. 1E).The hedgehog signaling network has been reviewed extensivelyelsewhere [Cohen, 2003]. PTCH2 encodes a 1204-amino acidtransmembrane protein with about a 54% overall identity toPTCH1 [Motoyama et al., 1998; Smyth et al., 1999] and a 90%identity to Ptch2 in mice [Carpenter et al., 1998]. In the absence ofSonic Hedgehog (SHH) stimulation, PTCH2, like PTCH1, canmaintain the hedgehog signaling pathway in an inactive state byinhibiting SMO. When SHH binds to PTCH2, the inhibitory effectof PTCH2 on SMO is removed, resulting in activation of SMO,downstreamsignaling,andupregulationoftargetgenes,suchastheGLI family proteins [Hahn et al., 1996; Young et al., 2000; Chenetal., 2002;Vokesand McMahon, 2004;Hutchinetal.,2005]. SHH

The epidemiology of, and risk factors for, mortality from severe sepsis and septic shock in a tertiary-care university hospital setting

This study investigated the clinical characteristics of, and outcomes and risk factors for hospital mortality of 390 patients admitted with severe sepsis or septic shock in an intensive care unit (ICU). Prospectively collected data from patients collected between 1 July 2004 and 30 June 2006 were analysed. Overall hospital mortality was 49.7% and comorbidities were found in 40.3% of patients, the most common of which was haematological malignancy. The respiratory tract was the most common site of infection (50%). Hospital-acquired infections accounted for 55.6% of patients with Gram-negative bacteria predominant (68%). Multivariate analysis showed that acute respiratory distress syndrome, pulmonary artery catheter placement, comorbidities, hospital-acquired infection, APACHE II score and maximum LOD score, were independent risk factors for hospital mortality. In conclusion, severe sepsis and septic shock are common causes of ICU admission. Patients with risk factors for increased mortality should be carefully monitored and aggressive treatment administered.

Ein neuer Genort für eine autosomal-dominante, nichtsyndromale Schwerhörigkeit (DFNA33) liegt auf Chromosom 13q34-qter

By investigation of a German family pedigree with non-syndromic hearing impairment of early onset and autosomal-dominant mode of inheritance, linkage to known DFNA loci was excluded, and the existence of a new locus (DFNA33) was revealed. In a subsequent genomic scan the phenotype was mapped to a 6 cM interval on chromosome 13q34-qter. A maximum two-point lod score of 2.96 was obtained for the marker D13S285 with a maximum lod score in the multipoint analysis of 3.28 at 124.56 cM.

Linkage analysis between idiopathic generalized epilepsies and the GABAA receptor α5, β3 and γ3 subunit gene cluster on chromosome 15

We tested the hypothesis that genetic variants within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster on chromosome 15q11-q13 confer genetic susceptibility to common subtypes of idiopathic generalized epilepsy (IGE).Ninety-four families were selected from IGE patients with either juvenile myoclonic epilepsy (JME), juvenile (JAE) or childhood absence epilepsy (CAE). Cosegregation was tested between dinucleotide polymorphisms associated with the human GABA(A) alpha5, beta3 and gamma3 subunit gene cluster and three different IGE trait models.Evidence against linkage to the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster was found in the entire family set and subsets selected from either CAE or JAE. In 61 families of JME patients, a maximum lod score (Zmax=1.40 at Theta(max)=0.00) was obtained for a broad IGE spectrum ("idiopathic" generalized seizure or generalized spike and wave discharges in the electroencephalogram) assuming genetic heterogeneity (alpha=0.37; P=0.06) and an autosomal recessive mode of inheritance.The possible hint of linkage in families of JME patients emphasizes the need for further studies to determine whether a recessively inherited gene variant within the GABA(A) alpha5, beta3 and gamma3 subunit gene cluster contributes to the pathogenesis of "idiopathic" generalized seizures and associated EEG abnormalities in a proportion of families.

Evidence for an interaction of schizophrenia susceptibility loci on chromosome 6q23.3 and 10q24.33–q26.13 in Arab Israeli families

A genome scan for schizophrenia related loci in Arab Israeli families by Lerer et al. [Lerer et al. (2003); Mol Psychiatry 8:488-498] detected significant evidence for linkage at chromosome 6q23. Subsequent fine mapping [Levi et al. (2005); Eur J Hum Genet 13:763-771], association [Amann-Zalcenstein et al. (2006); Eur J Hum Genet 14:1111-1119] and replication studies [Ingason et al. (2007); Eur J Hum Genet 15:988-991] identified AHI1 as a putative susceptibility gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23-26 region. Genes at these two loci may act independently in the pathogenesis of the disease in our homogeneous sample of Arab Israeli families or may interact with each other and with other factors in a common biological pathway. The purpose of our current study was to test the hypothesis of genetic interaction between these two loci and to identify the type of interaction between them. The initial stage of our study focused on the 10q23-q26 region which has not been explored further in our sample. The second stage of the study included a test for possible genetic interaction between the 6q23.3 locus and the refined 10q24.33-q26.13 locus. A final candidate region of 19.9 Mb between markers D10S222 (105.3 Mb) and D10S587 (125.2 Mb) was found on chromosome 10 by non-parametric and parametric linkage analyses. These linkage findings are consistent with previous reports in the same chromosomal region. Two-locus multipoint linkage analysis under three complex disease inheritance models (heterogeneity, multiplicative, and additive models) yielded a best maximum LOD score of 7.45 under the multiplicative model suggesting overlapping function of the 6q23.3 and 10q24.33-q26.13 loci.

Autosomal‐dominant locus for restless legs syndrome in French‐Canadians on chromosome 16p12.1

We describe an autosomal-dominant locus for Restless Legs Syndrome (RLS) in a French-Canadian (FC) pedigree. Genome-wide microsatellite scan and linkage analysis were used in this study. The locus maps to chromosome 16p12.1 and spans 1.18 Mega bases. The maximum multipoint LOD scores are of 3.5 over the total of 10 markers. Evidence for the same locus was also found in a smaller FC pedigree sime095. The analysis of the sequence of 8 annotated genes within the region did not reveal any pathogenic mutations. Copy number variation and karyotype analyses did not reveal any chromosomal abnormality in the region. Further analyses of the region are necessary to find the genetic cause of RLS in this family.

Genetic effect on blood pressure is modulated by age: the Hypertension Genetic Epidemiology Network Study.

Genome-wide linkage analysis was performed for systolic and diastolic blood pressures in the Hypertension Genetic Epidemiology Network. We investigated the role of gene-age interactions using a recently developed variance components method that incorporates age variation in genetic effects. Substantially improved linkage evidence, in terms of both the number of linkage peaks and their significance levels, was observed. Twenty-six linkage peaks were identified with maximum logarithm of odds scores ranging between 3.0 and 4.6, 15 of which were cross-validated by the literature. The chromosomal region 1p36 that showed the highest logarithm of odds score in our study was found to be supported by evidence from 3 studies. The new method also led to vastly improved validation across ethnic groups. Ten of the 15 supported linkage peaks were cross-validated between 2 different ethnic groups, and 2 peaks on chromosomal region 1q31 and 16p11 were validated in 3 ethnic groups. In conclusion, this investigation demonstrates that genetic effects on blood pressure vary by age. The improved genetic linkage results presented here should help to identify the specific genetic variants that explain the observed results.

Genomewide Linkage in a Large Caucasian Family Maps a New Locus for Intracranial Aneurysms to Chromosome 13q

Familial aggregation of intracranial aneurysms (IAs) indicates a genetic role in the pathogenesis of this disease. Despite a number of reported susceptibility loci, no disease-causing gene variants have been identified. In this study, we used a parametric genomewide linkage approach to search for new IA susceptibility loci in a large Caucasian family. The affection status of family members with clinical signs of IA was confirmed with medical records or through radiological or surgical examinations. All other relatives were screened using MR angiography. Genomewide linkage analysis was performed on 35 subjects using approximately 250 000 single nucleotide polymorphic markers. Ten individuals had an IA. Linkage analysis using a dominant model showed significant linkage to a 7-cM region in 13q14.12-21.1 with a maximum logarithm of odds score of 4.56. A new IA susceptibility locus on 13q was identified, adding to the number of IA loci already reported. Given that no coding variants have been reported to date, it is possible that alternative genetic variants such as regulatory elements or copy number variation are important in IA pathogenesis. We are proceeding with attempts to identify such variants in our locus.

QTLs of factors of the metabolic syndrome and echocardiographic phenotypes: the hypertension genetic epidemiology network study.

BackgroundIn a previous study of the Hypertension Genetic Epidemiology Network (HyperGEN) we have shown that metabolic syndrome (MetS) risk factors were moderately and significantly associated with echocardiographic (ECHO) left ventricular (LV) phenotypes.MethodsThe study included 1,393 African Americans and 1,133 whites, stratified by type 2 diabetes mellitus (DM) status. Heritabilities of seven factor scores based on the analysis of 15 traits were sufficiently high to pursue QTL discovery in this follow-up study.ResultsThree of the QTLs discovered relate to combined MetS-ECHO factors of "blood pressure (BP)-LV wall thickness" on chromosome 3 at 225 cM with a 2.8 LOD score, on chromosome 20 at 2.1 cM with a 2.6 LOD score; and for "LV wall thickness" factor on chromosome 16 at 113.5 with a 2.6 LOD score in whites. The remaining QTLs include one for a "body mass index-insulin (BMI-INS)" factor with a LOD score of 3.9 on chromosome 2 located at 64.8 cM; one for the same factor on chromosome 12 at 91.4 cM with a 3.3 LOD score; one for a "BP" factor on chromosome 19 located at 67.8 cM with a 3.0 LOD score. A suggestive linkage was also found for "Lipids-INS" with a 2.7 LOD score located on chromosome 11 at 113.1 cM in African Americans. Of the above QTLs, the one on chromosome 12 for "BMI-INS" is replicated in both ethnicities, (with highest LOD scores in African Americans). In addition, the QTL for "LV wall thickness" on chromosome 16q24.2-q24.3 reached its local maximum LOD score at marker D16S402, which is positioned within the 5th intron of the cadherin 13 gene, implicated in heart and vascular remodeling.ConclusionOur previous study and this follow-up suggest gene loci for some crucial MetS and cardiac geometry risk factors that contribute to the risk of developing heart disease.

Pili annulati: refinement of the locus on chromosome 12q24.33 to a 2·9-Mb interval and candidate gene analysis

Pili annulati is an autosomal dominant hair shaft disorder characterized by alternating light and dark bands in hairs of affected individuals. Recently, a locus for pili annulati was mapped to chromosome 12q24.32-24.33 and recombination events defined a critical region of 9.2 cM (3.9 Mb). The aim of the current study was to narrow the size of the candidate region and to identify the pathogenic mutation for pili annulati by analysing the candidate genes. In three families with 90 individuals, including 40 affected subjects, linkage analysis was performed with 13 microsatellite markers in the candidate region on chromosome 12. Candidate genes were analysed for their expression in hair follicles and other tissues by reverse transcriptase-polymerase chain reaction (RT-PCR) and mutation analysis. Multipoint LOD score analysis for all three families confirmed the locus on the long arm of chromosome 12 with a maximum LOD score of 12.26 at marker D12S357. In two families, recombinations were identified which narrowed the region to 2.9 Mb containing 36 genes. We analysed the candidate genes in this region by RT-PCR and found that 24 were expressed in human hair follicles. Based on the result of the expression analysis, DNA sequencing of the coding region of the candidate genes was performed; this did not result in the discovery of a causal mutation. We reduced the critical interval of pili annulati to 2.9 Mb and excluded mutations in the coding region of all 36 possible candidate genes by sequence analysis.

Genetic Evidence That Sequence Variation at the β-Globin Locus Underlies Differences in Cell Hemoglobin Concentration and Cell Hydration in Single (Hbbs) Vs. Diffuse (Hbbd) Inbred Mouse Strains: Implications for Inherited Anemias

Erythrocyte dehydration is a distinguishing feature of hematological diseases including sickle cell anemia and hereditary spherocytosis (HS). Identification of genes influencing hydration status will increase our understanding of red cell pathologies and provide new targets for risk assessment and drug development. We mapped quantitative trait loci (QTLs) influencing red cell hydration using the cell hemoglobin concentration mean (CHCM) as a marker of hydration status. CHCM (analogous to the calculated mean cell hemoglobin content, MCHC) was obtained using an Advia 120 whole blood analyzer, which provides a direct measure of hemoglobin concentration on a cell-by-cell basis. We established seven F2 intercrosses and one backcross and phenotyped 200–500 offspring from each cross at 8–10 weeks of age. Genome-wide scans were performed to detect single loci associated with CHCM (main effect QTL) using the R/qtl software (www.rqtl.org). Significance thresholds were determined by permutation testing (1000 permutations). A highly significant locus was identified on chromosome 7 in 6 of the 8 crosses (maximum LOD score of 82) with a 95% confidence interval (CI) spanning from approximately 90–129 mega base pairs (Mb). Previously we identified two QTL for CHCM (Peters et al., Mamm. Genome 17: 2006); hence, we have designated the chromosome 7 locus Chcmq3 (CHCM quantitative locus 3). Chcmq3 has a significant impact on the baseline CHCM; it alone accounts for 48% of the variance of the trait. The 95% CI was subsequently narrowed using statistical and bioinformatic tools. First we performed combined cross analysis (Li et al., Genetics 169: 2005) where genotype data from multiple crosses in which the same QTL is detected is re-coded to a phenotype-based designation based on allele effects and re-analyzed as a single dataset to increase statistical power. This analysis reduced the CI to 7 Mb containing 289 genes. Using a dense single nucleotide polymorphism (SNP) map, including imputed SNPs (Center for Genome Dynamics, http://cgd.jax.org) and phenotypic data from 32 inbred strains, we performed interval-specific haplotype analysis and haplotype association mapping to eliminate regions identical by descent and obtain a final interval of 0.38 Mb containing 30 candidate genes. Twenty one were olfactory receptor (Olfr) genes, poor biological candidates, leaving 9 candidates including the beta-globin cluster. Two major ancestral haplotype blocks span the beta globin cluster, and the parental strains contributing the high allele in each cross (129S1/SvImJ, DBA/2J, NZW/LacJ, WSB/EiJ, MRL/MpJ, CBA/J) are of the hemoglobin-diffuse electrophoretic variant (Hbbd), while the low allele strains (C57BL/6J, SM/J) are hemoglobin-single (Hbbs) variants. Notably, examination of the Mouse Phenome Database (www.jax.org/phenome, project Peters1) reveals that Hbbd strains all have relatively high CHCM values, while Hbbs strains have lower CHCM values. Moreover, in the two crosses in which Chcmq3 was not detected, the parental strains shared the same haplotype at the beta globin locus. As a QTL can not be detected in the absence of genetic variation in the underlying gene, this observation supports beta globin as a strong candidate gene for Chcmq3. Furthermore, in preliminary quantitative PCR studies, strain 129S1/SvImJ, a diffuse variant, showed higher expression of adult beta globin, Hbb-b1, in the spleen than C57BL/6J (single variant). The data suggest that polymorphisms in beta globin itself modify hemoglobin concentration in mice and reinforce the notion that hemoglobin charge and/or structure may directly or indirectly modulate membrane ion transport and erythrocyte hydration in both mice and humans.

Novel mutation of IL1RAPL1 gene in a nonspecific X‐linked mental retardation (MRX) family

Mental retardation (MR) affects approximately 2% of the population. About 10% of all MR cases result from defects of X-linked genes. Mutations in most of more than 20 known genes causing nonspecific form of X-linked MR (MRX) are very rare and may account for less than 0.5-1% of MR. Linkage studies in extended pedigrees followed by mutational analysis of known MRX genes in the linked interval are often the only way to identify a genetic cause of the disorder. We performed linkage analysis in several MRX families, and in one family with four males with MR we mapped the disease to an interval encompassing Xp21.2-22.11 (with a maximum LOD score of 2.71). Subsequent mutation analysis of genes located in this interval allowed us to identify a partial deletion of the IL1RAPL1 gene. Different nonoverlapping deletions involving IL1RAPL1 have been reported previously, suggesting that this region could be deletion-prone. In this report, we present the results of the molecular analyses and clinical examinations of four affected family members with the deletion in IL1RAPL1. Our data further confirm the importance and usefulness of linkage studies for gene mapping in MRX families and demonstrate that IL1RAPL1 plays an important role in the etiology of MRX. With the development of new methods (aCGH, MLPA), further rearrangements in this gene (including deletions and duplications) might be discovered in the nearest future.

A novel Refsum-like disorder that maps to chromosome 20

Clinical and genetic characterization of a neurologic disorder resembling Refsum disease in a Norwegian consanguineous family. The affected individuals comprise a brother and sister and their third cousin. The family comes from a small island community and genealogic studies showed that both sets of parents are descendants of a man born in 1585. Based on the hypothesis that this is an autosomal recessive disease and that the patients were homozygous for the same mutation (identical by descent), we used homozygosity mapping to define the genetic locus of this disorder. This slowly progressive disorder starts in childhood with signs of peripheral neuropathy (pes cavus, tendoachilles contracture). Hearing loss and cataract become evident in the third decade. Subsequently, patients develop a disorder of gait due to the combination of ataxia and spasticity, and a pigment retinopathy. While the clinical picture is reminiscent of Refsum disease, affected individuals have normal phytanic and pristanic acid levels in plasma, as well as normal enzymatic activity for alpha-oxidation. We mapped the disease to a 15.96 Mb region on chromosome 20 (20p11.21-q12), containing approximately 200 genes (maximum lod score = 6.3). Sequencing of 23 candidate genes failed to demonstrate detrimental sequence variants. Our findings show that the clinical syndromes that include Refsum disease are more heterogeneous than previously recognized. We have chosen to report the clinical features and mapping of this novel disorder in the hope that this will permit identification of other families and thus proper genetic characterization.

A novel HSF4gene mutation (p.R405X) causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

BackgroundHereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667). Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene.MethodsA large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438) was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4) were sequenced. A mutation-specific restriction enzyme digest (HphI) was performed for all family members and unrelated controls.ResultsThe disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at θ = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X).ConclusionWe identified the first nonsense mutation (p.R405X) in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.

Familial dyskinesia and facial myokymia (FDFM): Follow‐up of a large family and linkage to chromosome 3p21‐3q21

We previously reported a five-generation family manifesting an autosomal dominant disorder of facial myokymia and dystonic/choreic movements (FDFM). The dyskinetic episodes are initially paroxysmal but may become constant. With increasing age they may lessen or even disappear. The previous study excluded nine candidate genes chosen for their association with myokymia or chorea and two regions containing single or clustered ion channel genes. We now report identification by whole genome linkage analysis of a broad region on chromosome 3p21-3q21 that segregates with the disease in all 10 affected members in three generations who participated in the study. GENEHUNTER-MODSCORE Version 2.0.1 provided a maximum multipoint LOD score of 3.099. No other disorders primarily characterized by myokymia, dystonia, or chorea are known to map to this region. Identification of additional families with FDFM may narrow the critical region and facilitate the choice of candidate genes for further analysis.

Genome-wide SNP-based linkage analysis of tuberculosis in Thais

Tuberculosis, a potentially fatal infectious disease, affects millions of individuals annually worldwide. Human protective immunity that contains tuberculosis after infection has not been clearly defined. To gain insight into host genetic factors, nonparametric linkage analysis was performed using high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping platform, a GeneChip array comprised 59 860 bi-allelic markers, in 93 Thai families with multiple siblings, 195 individuals affected with tuberculosis. Genotyping revealed a region on chromosome 5q showing suggestive evidence of linkage with tuberculosis (Z(lr) statistics=3.01, logarithm of odds (LOD) score=2.29, empirical P-value=0.0005), and two candidate regions on chromosomes 17p and 20p by an ordered subset analysis using minimum age at onset of tuberculosis as the covariate (maximum LOD score=2.57 and 3.33, permutation P-value=0.0187 and 0.0183, respectively). These results imply a new evidence of genetic risk factors for tuberculosis in the Asian population. The significance of these ordered subset results supports a clinicopathological concept that immunological impairment in the disease differs between young and old tuberculosis patients. The linkage information from a specific ethnicity may provide unique candidate regions for the identification of the susceptibility genes and further help elucidate the immunopathogenesis of tuberculosis.

A novel genetic locus for familial febrile seizures and epilepsy on chromosome 3q26.2–q26.33

Febrile seizures (FS) are common in children, and the incidence is 2-5% before the age of 5 years. A four-generation Chinese family with autosomal dominant febrile seizure and epilepsy was studied by genome-wide linkage analysis. Significant linkage was identified with markers on chromosome 3q26.2-26.33 with a maximum pairwise LOD score of >3.00. Fine mapping defined the new genetic locus within a 10.7-Mb region between markers D3S3656 and D3S1232. A maximum multipoint LOD score of 5.27 was detected at marker D3S1565. A previously reported CLCN2 gene for epilepsy was excluded as the disease-causing gene in the family by mutational analysis of all exons and exon-intron boundaries of CLCN2 and by haplotype analysis. Mutation analysis of KCNMB2 and KCNMB3, which were two potassium-channel genes in this linkage region, did not reveal a disease causing mutation. Our results identified another novel locus on chromosome 3q26.2-26.33, and future studies of the candidate genes at the locus will identify a new gene for combined FS and idiopathic epilepsies.

CBCL Pediatric Bipolar Disorder Profile and ADHD: Comorbidity and Quantitative Trait Loci Analysis

Objective The pediatric bipolar disorder profilme of the Child Behavior Checklist (CBCL-PBD), a parent-completed measure that avoids clinician ideological bias, has proven useful in differentiating patients with attention-deficit/hyperactivity disorder (ADHD). We used CBCL-PBD profiles to distinguish patterns of comorbidity and to search for quantitative trait loci in a genomewide scan in a sample of multiple affected ADHD sibling pairs. Method A total of 540 ADHD subjects ages 5 to 18 years were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version and CBCL. Parents were assessed with the Schedule for Affective Disorders and Schizophrenia-Lifetime version supplemented by the Schedule for Affective Disorders and Schizophrenia for School-Age Children for disruptive behavioral disorders. Patterns of psychiatric comorbidity were contrasted based on the CBCL-PBD profile. A quantitative trait loci variance component analysis was used to identify potential genomic regions that may harbor susceptibility genes for the CBCL-PBD quantitative phenotype. Results Bipolar spectrum disorders represented less than 2% of the overall sample. The CBCL-PBD classification was associated with increased generalized anxiety disorder ( p = .001), oppositional defiant disorder ( p = .008), conduct disorder ( p = .003), and parental substance abuse ( p = .005). A moderately significant linkage signal (multipoint maximum lod score = 2.5) was found on chromosome 2q. Conclusions The CBCL-PBD profile distinguishes a subset of ADHD patients with significant comorbidity. Linkage analysis of the CBCL-PBD phenotype suggests certain genomic regions that merit further investigation for genes predisposing to severe psychopathology.

Mutation in the HPGD gene encoding NAD+ dependent 15-hydroxyprostaglandin dehydrogenase underlies isolated congenital nail clubbing (ICNC)

Background:Isolated congenital nail clubbing (ICNC) is a rare autosomal recessive disorder characterised by enlargement of the terminal segments of fingers and toes with thickened nails due to proliferation of the...