Construction of a 1-Mb restriction-mapped cosmid contig containing the candidate region for the familial mediterranean fever locus (MEFV) on chromosome 16p13.3

In this paper we describe the assembly and restriction map of a 1.05-Mb cosmid contig spanning the candidate region for familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation localized to 16p13.3. Using a combination of cosmid walking and screening for P1, PAC, BAG, and YAC clones, we have generated a contig of genomic clones spanning similar to 1050 kb that contains the FMF critical region. The map consists of 179 cosmid, 15 P1, 10 PAC, 3 BAG, and 17 YAC clones, anchored by 27 STS markers. Eight additional STSs have been developed from the similar to 700 kb immediately centromeric to this genomic region. Five of the 35 STSs are microsatellites that have not been previously reported. NotI and EcoRI mapping of the overlapping cosmids, hybridization of restriction fragments from cosmids to one another, and STS analyses have been used to validate the assembly of the contig. Our contig totally subsumes the 250-kb interval recently reported, by founder haplotype analysis, to contain the FMF gene. Thus, our high-resolution clone map provides an ideal resource for transcriptional mapping toward the eventual identification of this disease gene. (C) 1997 Academic Press.

A high-resolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups

Familial Mediterranean fever (FMF) is a recessive disorder of inflammation caused by mutations in a gene (designated MEFV) on chromosome 16p13.3, We have recently constructed a 1-Mb cosmid contig that includes the FMF critical region. Here we show genotype data for 12 markers from our physical map, including 5 newly identified microsatellites, in FMF families. Intrafamilial recombinations placed MEFV in the similar to 285 kb between D16S468/D16S3070 and D16S3376. We observed significant linkage disequilibrium in the North African Jewish population, and historical recombinants in the founder haplotype placed MEFV between D16S3082 and D16S3373 (similar to 200 kb). In smaller panels of Iraqi Jewish, Arab, and Armenian families, there were significant allelic associations only for D16S3370 and D16S2617 among the Armenians. A sizable minority of Iraqi Jewish and Armenian carrier chromosomes appeared to be derived from the North African Jewish ancestral haplotype. We observed a unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians and two other haplotypes restricted to either the Iraqi Jewish or the Armenian population. These data support the view that a few major mutations account for a large percentage of the cases of FMF and suggest that same of these mutations arose before the affected Middle Eastern populations diverged from one another. (C) 1997 Academic Press.

QTL affecting body weight in a candidate region of cattle chromosome 5

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

PCR candidate region mismatch scanning: adaptation to quantitative, high-throughput genotyping

Linkage and association analyses were performed to identify loci affecting disease susceptibility by scoring previously characterized sequence variations such as microsatellites and single nucleotide polymorphisms. Lack of markers in regions of interest, as well as difficulty in adapting various methods to high-throughput settings, often limits the effectiveness of the analyses. We have adapted the Escherichia coli mismatch detection system, employing the factors MutS, MutL and MutH, for use in PCR-based, automated, high-throughput genotyping and mutation detection of genomic DNA. Optimal sensitivity and signal-to-noise ratios were obtained in a straightforward fashion because the detection reaction proved to be principally dependent upon monovalent cation concentration and MutL concentration. Quantitative relationships of the optimal values of these parameters with length of the DNA test fragment were demonstrated, in support of the translocation model for the mechanism of action of these enzymes, rather than the molecular switch model. Thus, rapid, sequence-independent optimization was possible for each new genomic target region. Other factors potentially limiting the flexibility of mismatch scanning, such as positioning of dam recognition sites within the target fragment, have also been investigated. We developed several strategies, which can be easily adapted to automation, for limiting the analysis to intersample heteroduplexes. Thus, the principal barriers to the use of this methodology, which we have designated PCR candidate region mismatch scanning, in cost-effective, high-throughput settings have been removed.

Identification and evaluation of candidate genes for inherited retinal -degenerative diseases

Although more than 100 genes associated with inherited retinal disease have been mapped to chromosomal locations, less than half of these genes have been cloned. This text includes identification and evaluation of candidate genes for three autosomal dominant forms of inherited retinal degeneration: atypical vitelliform macular dystrophy (VMD1), cone-rod dystrophy (CORD), and retinitis pigmentosa (RP). ^ VMD1 is a disorder characterized by complete penetrance but extremely variable expressivity, and includes macular or peripheral retinal lesions and peripappilary abnormalitites. In 1984, linkage was reported between VMD1 and soluble glutamate-pyruvate transaminase GPT); however, placement of GPT to 8q24 on linkage maps had been debated, and VMD1 did not show linkage to microsatellite markers in that region. This study excluded linkage between the loci by cloning GPT, identifying the nucleotide substitution associated with the GPT sozymes, and by assaying VMD1 family samples with an RFLP designed to detect the substitution. In addition, linkage of VMD1 to the known dominant macular degeneration loci was excluded. ^ CORD is characterized by early onset of color-vision deficiency, and decreased visual acuity, However, this retinal degeneration progresses to no light perception, severe macular lesion, and “bone-spicule” accumulations in the peripheral retina. In this study, the disorder in a large Texan family was mapped to the CORD2 locus of 19q13, and a mutation in the retina/pineal-specific cone-rod homeobox gene (CRX) was identified as the disease cause. In addition, mutations in CRX were associated with significantly different retinal disease phenotypes, including retinitis pigmentosa and Leber congenital amaurosis. ^ Many of the mutations leading to inherited retinal disorders have been identified in genes like CRX, which are expressed predominantly in the retina and pineal gland. Therefore, a combination of database analysis and laboratory investigation was used to identify 26 novel retina/pineal-specific expressed sequence tag (EST) clusters as candidate genes for inherited retinal disorders. Eight of these genes were mapped into the candidate regions of inherited retinal degeneration loci. ^ Two of the eight clusters mapped into the retinitis pigmentosa RP13 candidate region of 17p13, and were both determined to represent a single gene that is highly expressed in photoreceptors. This gene, the Ah receptor-interacting like protein-1 (AIPL1), was cloned, characterized, and screened for mutations in RP13 patient DNA samples. ^

Interleukin 9: A candidate gene for asthma

Asthma is a complex heritable inflammatory disorder of the airways associated with clinical signs of atopy and bronchial hyperresponsiveness. Recent studies localized a major gene for asthma to chromosome 5q31-q33 in humans. Thus, this segment of the genome represents a candidate region for genes that determine susceptibility to bronchial hyperresponsiveness and atopy in animal models. Homologs of candidate genes on human chromosome 5q31-q33 are found in four regions in the mouse genome, two on chromosome 18, and one each on chromosomes 11 and 13. We assessed bronchial responsiveness as a quantitative trait in mice and found it linked to chromosome 13. Interleukin 9 (IL-9) is located in the linked region and was analyzed as a gene candidate. The expression of IL-9 was markedly reduced in bronchial hyporesponsive mice, and the level of expression was determined by sequences within the qualitative trait locus (QTL). These data suggest a role for IL-9 in the complex pathogenesis of bronchial hyperresponsiveness as a risk factor for asthma.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Identification of candidate genes for dyslexia susceptibility on chromosome 18

Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis. Methodology/Principal Findings: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L). Conclusions: Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

Suggestive linkage to chromosome 1q for bone mineral apparent density in Brazilian sister adolescents.

OBJECTIVE: To investigate linkage to chromosome 1q and 11q region for lumbar spine, femoral neck and total body BMD and volumetric BMD in Brazilian sister adolescents aged 10-20-year-old and 57 mothers. METHODS: We evaluated 161 sister pairs (n=329) aged 10-20 years old and 57 of their mothers in this study. Physical traits and lifestyle factors were collected as covariates for lumbar spine (LS), femoral neck (FN) and total body (TB) BMD and bone mineral apparent density (BMAD). We selected nine microsatellite markers in chromosome 1q region (spanning nearly 33cM) and eight in chromosome 11q region (spanning nearly 34cM) to perform linkage analysis. RESULTS: The highest LOD score values obtained from our data were in sister pairs LS BMAD analysis. Their values were: 1.32 (P<0.006), 2.61 (P<0.0002) and 2.44 (P<0.0004) in D1S218, D1S2640 and D1S2623 markers, respectively. No significant LOD score was found with LS and FN BMD/BMAD in chromosome 11q region. Only TB BMD showed significant linkage higher than 1.0 for chromosome 11q region in the markers D11S4191 and D11S937. DISCUSSION/CONCLUSIONS: Our results provided suggestive linkage for LS BMAD at D1S2640 marker in adolescent sister pairs and suggest a possible candidate gene (LHX4) related to adolescent LS BMAD in this region. These results reinforce chromosome 1q21-23 as a candidate region to harbor one or more bone formation/maintenance gene. In the other hand, it did not repeat for chromosome 11q12-13 in our population.

Molecular genetics of narcolepsy

1 Abstract Sleep is a vital necessity, yet its basic physiological function is still unknown, despite numerous studies both in healthy humans and animal models. The study of patients with sleep disorders may help uncover major biological pathways in sleep regulation and thus shed light on the actual function of sleep. Narcolepsy is a well defined but rare sleep disorder characterized by excessive daytime sleepiness and cataplexy, thought to be caused by a combination of genetic and environmental factors. The aim of this work was to identify genes or genetic variants, which contribute to the pathogenesis of sporadic and familial narcolepsy. Sporadic narcolepsy is the disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1 *1501-DQB1 *0602 haplotype is common in the general population (15-25%), it has been suggested that it is necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2. Further analysis revealed that the identified SNP is strongly linked to DRB1*03-DQB1*02 and DRBΠ 301-DQB1*0603. Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype. This unexpected protective HLA haplotype suggests a causal involvement of the HLA region in narcolepsy susceptibility. Familial cases of narcolepsy account for 10% of all narcolepsy cases. However, due to low number of affected family members, narcolepsy families are usually not eligible for genetic linkage studies. We identified and characterized a large Spanish family with 11 affected family members representing the largest ever reported narcolepsy family. We ran a genetic linkage analysis using DNA of 11 affected and 15 unaffected family members and hereby identified a chromosomal candidate region on chromosome 6 encompassing 163 kb with a maximum multipoint LOD score of 5.02. The coding sequences of 4 genes within this haplotype block as well as 2 neighboring genes were screened for pathogenetic mutations in 2 affected and 1 healthy family members. So far no pathogenic mutation could be identified. Further in-depth sequencing of our candidate region as well as whole genome exome sequencing are underway to identify the pathogenic mutation(s) in this family and will further improve our understanding of the genetic basis of narcolepsy. 2 Résumé Le sommeil est un processus vital, dont la fonction physiologique est encore inconnue, malgré de nombreuses études chez des sujets humains sains ainsi que dans des modèles animaux. L'étude de patients souffrant de troubles du sommeil peut permettre la découverte de voies biologiques jouant un rôle majeur dans la régulation du sommeil. L'un de ces troubles, la narcolepsie, est une maladie rare mais néanmoins bien définie, caractérisée par une somnolence diurne excessive accompagnée de cataplexies. Les connaissances actuelles suggèrent qu'une combinaison de facteurs génétiques et environnementaux en est à l'origine. Le but du présent travail était d'identifier !e(s) gène(s) ou les polymorphismes constituant des facteurs de risque dans les formes sporadique et familiale de narcolepsie. La narcolepsie sporadique est la maladie possédant la plus forte association avec le complexe majeur d'histocompatibilité humain (HLA) jamais reportée. La fréquence au sein de la population générale de l'haplotype associé HLA-DRB1*1501- DQB1*0602 (15-25%) suggère que ce dernier est nécessaire, mais pas suffisant, pour (e développement de la maladie. Nous avons voulu approfondir la recherche de facteurs génétiques augmentant le risque de la narcolepsie. A cette fin, nous avons entrepris une étude d'association à l'échelle du génome (genome-wide association study, GWAS) parmi 562 sujets narcoleptiques européens (cas) et 702 individus contrôle de même origine ethnique et nous avons trouvé une association avec un variant protecteur près du gène HLA- DQA2. Ce résultat a été répliqué indépendamment dans 370 cas et 495 contrôles, tous hétérozygotes au locus DRB1*1501-DQB1*0602. Une analyse plus fine montre que le polymorphisme identifié est fortement lié aux allèles DRB1*03-DQB1*02 et DRB1*1301-DQB1*0603. Nous notons que seul un cas était porteur d'un haplotype en trans DRB1*1301-DQBr0603. La découverte de cet allele HLA protecteur suggère que la région HLA joue un rôle causal dans la susceptibilité à la narcolepsie. Dix pourcents des cas de narcolepsie sont familiaux. Cependant, le faible nombre de membres affectés rend ces familles inéligibles pour des études de liaison génétique. Nous avons identifié et caractérisé une grande famille espagnole, dont 11 membres sont atteints par la maladie, ce qui représente la plus grande famille narcoleptique rapportée jusqu'à ce jour. A partir de l'ADN de 11 membres atteints et 15 non- atteints, nous avons identifié par étude de liaison une région candidate de 163 kîlobases (kb) sur le chromosome 6, correspondant à un LOD score multipoints de 5.02. Nous avons cherché, sans succès, des mutations pathogéniques dans la séquence codante de deux gènes situés à l'intérieur de ce segment, ainsi que 4 gènes adjacents. Un séquençage plus approfondi de la région ainsi que le séquençage des exons de tout le génome est en cours et doit s'avérer plus fructueux et révéler la ou tes mutation(s) pathogénique(s) dans cette famille, ce qui contribuerait à une meilleure compréhension des causes génétiques de la narcolepsie. 3 Résumé pour un large public Le sommeil est une nécessité vitale, dont le rôle physiologique exact reste inconnu malgré de nombreuses études sur des sujets humains sains ainsi que sur des modèles animaux. C'est pourquoi les troubles du sommeil intéressent les chercheurs, car l'élucidation des mécanismes responsables peut permettre de mieux comprendre le fonctionnement du sommeil normal. La narcolepsie est une maladie du sommeil caractérisée par une somnolence diurne excessive. Les personnes atteintes peuvent s'endormir involontairement à tout moment de la journée, et souffrent également de pertes du tonus musculaire (cataplexie) lors de fortes émotions, par exemple un fou rire. La narcolepsie est une maladie rare, apparaissant dans 1 personne sur 2000. Les connaissances actuelles suggèrent qu'une combinaison de facteurs génétiques et environnementaux en est à l'origine. Nous avons voulu identifier les facteurs génétiques influençant le déclenchement de la maladie, d'abord dans sa forme sporadique, puis dans une famille comptant de nombreux membres atteints. En comparant les variations génétiques de près de 1000 sujets narcoleptiques européens avec ceux de 1200 individus sains, nous avons trouvé chez 30% de ces derniers un variant protecteur, qui diminue de 50 fois le risque de développer la maladie, ce qui constitue le plus puissant facteur génétique protecteur décrit à ce jour. Nous avons ensuite étudié une grande famille espagnole comptant une trentaine de membres, dont 11 sont atteints de narcolepsie. De nouveau, nous avons comparé les variations génétiques des membres atteints avec ceux des membres sains. Nous avons ainsi pu identifier une région dans le génome où se trouverait le(s) gène(s) impliqué(s) dans la maladie dans cette famille, mais n'avons pas encore trouvé le(s) variant(s) exact(s). Une étude plus approfondie devrait permettre de P(les) identifier et ainsi contribuer à l'élucidation des mécanismes menant au développement de la narcolepsie.

A calcineurin inhibitory protein overexpressed in Down's syndrome interacts with the product of a ubiquitously expressed transcript

The Down's syndrome candidate region 1 (DSCR1) protein, encoded by a gene located in the human chromosome 21, interacts with calcineurin and is overexpressed in Down's syndrome patients. As an approach to clarifying a putative function for this protein, in the present study we used the yeast two-hybrid system to identify DSCR1 partners. The two-hybrid system is a method that allows the identification of protein-protein interactions through reconstitution of the activity of the yeast GAL 4 transcriptional activator. The gene DSCR1 fused to the GAL 4 binding domain (BD) was used to screen a human fetal brain cDNA library cloned in fusion with the GAL 4 activation domain (AD). Three positive clones were found and sequence analysis revealed that all the plasmids coded for the ubiquitously expressed transcript (UXT). UXT, which is encoded in human Xp11, is a 157-amino acid protein present in both cytosol and nucleus of the cells. This positive interaction of DSCR1 and UXT was confirmed in vivo by mating the yeast strain AH109 (MATa)expressing AD-UXT with the strain Y187 (MATalpha) expressing BD-DSCR1, and in vitro by co-immunoprecipitation experiments. These results may help elucidate a new function for DSCR1 and its participation in Down's syndrome pathogenesis.

Cytogenomic characterization of an unexpected 17.6 Mb 9p deletion associated to a 14.8 Mb 20p duplication in a dysmorphic patient with multiple congenital anomalies presenting a normal G-banding karyotype

We describe a female patient with developmental delay, dysmorphic features and multiple congenital anomalies who presented a normal G-banded karyotype at the 550-band resolution. Array and multiplex-ligation probe amplification (MLPA) techniques identified an unexpected large unbalanced genomic aberration: a 17.6 Mb deletion of 9p associated to a 14.8 Mb duplication of 20p. The deleted 9p genes, especially CER1 and FREM1, seem to be more relevant to the phenotype than the duplicated 20p genes. This study also shows the relevance of using molecular techniques to make an accurate diagnosis in patients with dysmorphic features and multiple anomalies suggestive of chromosome aberration, even if on G-banding their karyotype appears to be normal. Fluorescence in situ hybridization (FISH) was necessary to identify a masked balanced translocation in the patient's mother, indicating the importance of associating cytogenetic and molecular techniques in clinical genetics, given the implications for patient management and genetic counseling. (C) 2012 Elsevier B.V. All rights reserved.

Auriculo-Condylar Syndrome. Confronting a Diagnostic Challenge

Auriculo-condylar syndrome (ACS) is characterized by typical ears malformation (so-called "question mark" ears), prominent cheeks, microstomia, and abnormality of the temporomandibular joint and condyle of the mandible. In this report we describe a new simplex case and a previously unreported family with affected individuals in three generations documenting clinical variability. Linkage study for markers located in candidate region for ACS1 (1p21.1-q23.3) was excluded in our familial case, reinforcing the hypothesis of genetic heterogeneity for this condition. A review of the literature focusing diagnostic criteria and features of ACS was performed. (C) 2011 Wiley Periodicals, Inc.

Linkage mapping of ovine microphthalmia to chromosome 23, the sheep orthologue of human chromosome 18

PURPOSE: To characterize the phenotype and map the locus responsible for autosomal recessive inherited ovine microphthalmia (OMO) in sheep. METHODS: Microphthalmia-affected lambs and their available relatives were collected in a field, and experimental matings were performed to obtain affected and normal lambs for detailed necropsy and histologic examinations. The matings resulted in 18 sheep families with 48 cases of microphthalmia. A comparative candidate gene approach was used to map the disease locus within the sheep genome. Initially, 27 loci responsible for the microphthalmia-anophthalmia phenotypes in humans or mice were selected to test for comparative linkage. Fifty flanking markers that were predicted from comparative genomic analysis to be closely linked to these genes were tested for linkage to the disease locus. After observation of statistical evidence for linkage, a confirmatory fine mapping strategy was applied by further genotyping of 43 microsatellites. RESULTS: The clinical and pathologic examinations showed slightly variable expressivity of isolated bilateral microphthalmia. The anterior eye chamber was small or absent, and a white mass admixed with cystic spaces extended from the papilla to the anterior eye chamber, while no recognizable vitreous body or lens was found within the affected eyes. Significant linkage to a single candidate region was identified at sheep chromosome 23. Fine mapping and haplotype analysis assigned the candidate region to a critical interval of 12.4 cM. This ovine chromosome segment encompasses an ancestral chromosomal breakpoint corresponding to two orthologue segments of human chromosomes 18, short and long arms. For the examined animals, we excluded the complete coding region and adjacent intronic regions of ovine TGIF1 to harbor disease-causing mutations. CONCLUSIONS: This is the first genetic localization for hereditary ovine isolated microphthalmia. It seems unlikely that a mutation in the TGIF1 gene is responsible for this disorder. The studied sheep represent a valuable large animal model for similar human ocular phenotypes.

The locus for bovine dilated cardiomyopathy maps to chromosome 18

Bovine dilated cardiomyopathy (BDCMP) is a severe and terminal disease of the heart muscle observed in Holstein-Friesian cattle over the last 30 years. There is strong evidence for an autosomal recessive mode of inheritance for BDCMP. The objective of this study was to genetically map BDCMP, with the ultimate goal of identifying the causative mutation. A whole-genome scan using 199 microsatellite markers and one SNP revealed an assignment of BDCMP to BTA18. Fine-mapping on BTA18 refined the candidate region to the MSBDCMP06-BMS2785 interval. The interval containing the BDCMP locus was confirmed by multipoint linkage analysis using the software loki. The interval is about 6.7 Mb on the bovine genome sequence (Btau 3.1). The corresponding region of HSA19 is very gene-rich and contains roughly 200 genes. Although telomeric of the marker interval, TNNI3 is a possible positional and a functional candidate for BDCMP given its involvement in a human form of dilated cardiomyopathy. Sequence analysis of TNNI3 in cattle revealed no mutation in the coding sequence, but there was a G-to-A transition in intron 6 (AJ842179:c.378+315G>A). The analysis of this SNP using the study's BDCMP pedigree did not conclusively exclude TNNI3 as a candidate gene for BDCMP. Considering the high density of genes on the homologous region of HSA19, further refinement of the interval on BTA18 containing the BDCMP locus is needed.