Maximum Two-point LOD Score Research Articles

Evidence for a Novel Autosomal Dominant Retinitis Pigmentosa Linked to Chromosome 1p22.1-q12 in a Chinese Family

Purpose: To identify the causative genetic locus in a Chinese autosomal dominant retinitis pigmentosa (adRP) family that contained seven affected members in three generations.Methods: After clinical diagnosis and exclusion of all mapped genes and loci, the SLINK program was used to simulate the maximum logarithm of the likelihood ratio (LOD) score for a linkage study in this small family. A genome-wide scan was performed using microsatellite markers at 10 cM intervals. Two-point and multipoint LOD scores were calculated, and haplotypes were constructed.Results: The H11 family clinical presentation included an early onset of night blindness, a progressive loss of the peripheral visual field, typical retinitis pigmentosa (RP) fundus changes, and a cataract complication. A maximum two-point LOD score of 2.54 (θ = 0) was found at markers D1S2739, D1S457, D1S187, D1S189, and D1S305, and multipoint linkage analysis yielded a maximum LOD score of 2.54 for marker D1S187. These LOD scores were the closest to the maximum simulated LOD score. Haplotype analysis revealed that this form of adRP segregates with a 38.25 cM region that spanned 50 Mb on chromosome 1p22.1-q12.Conclusions: Although this locus overlaps the RP19 locus caused by mutations in ABCA4 and the RP32 locus, both are inherited in an autosomal recessive mode rather than the autosomal dominant mode of inheritance found in the H11 family. The identification of this potential new locus for adRP further confirms the high level of heterogeneity for RP.

Identification of Missense Mutation (I12T) in the BSND Gene and Bioinformatics Analysis

Nonsyndromic hearing loss is a paradigm of genetic heterogeneity with 85 loci and 39 nuclear disease genes reported so far. Mutations of BSND have been shown to cause Bartter syndrome type IV, characterized by significant renal abnormalities and deafness and nonsyndromic nearing loss. We studied a Pakistani consanguineous family. Clinical examinations of affected individuals did not reveal the presence of any associated signs, which are hallmarks of the Bartter syndrome type IV. Linkage analysis identified an area of 18.36 Mb shared by all affected individuals between markers D1S2706 and D1S1596. A maximum two-point LOD score of 2.55 with markers D1S2700 and multipoint LOD score of 3.42 with marker D1S1661 were obtained. BSND mutation, that is, p.I12T, cosegregated in all extant members of our pedigree. BSND mutations can cause nonsyndromic hearing loss, and it is a second report for this mutation. The respected protein, that is, BSND, was first modeled, and then, the identified mutation was further analyzed by using different bioinformatics tools; finally, this protein and its mutant was docked with CLCNKB and REN, interactions of BSND, respectively.

A novel locus for disseminated superficial actinic porokeratosis maps to chromosome 16q24.1-24.3

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant keratinization disorder with genetic heterogeneity characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, there have been three susceptible loci determined for DSAP and one locus for disseminated superficial porokeratosis (DSP), i.e. 12q23.2-24.1, 15q25.1-26.1, 1p31.3-p31.1 and 18p11.3. Moreover, the locus for porokeratosis palmaris plantaris et disseminata (PPPD) was mapped to 12q24.1-24.2, which overlapped with the first DSAP locus. Following the exclusion of these known loci in a four-generation Chinese DSAP family, we performed a genome-wide linkage analysis and identified a new locus on chromosome 16q24.1-24.3. The maximum two-point LOD score of 3.73 was obtained with the marker D16S3074 at a recombination fraction θ of 0.00. Haplotype analysis defined the critical 17.4-cM region for DSAP between D16S3091 and D16S413. This is regarded to be the forth locus for DSAP (DSAP4). ATP2C1 was sequenced as a candidate gene, however, no mutation was found. Further investigation for the genetic basis of DSAP is under way.

A frameshift mutation in SANS results in atypical Usher syndrome

A frameshift mutation in <i>SANS</i> results in atypical Usher syndrome

Identification of an autosomal recessive stuttering locus on chromosome 3q13.2–3q13.33

Stuttering is a common speech disorder with substantial genetic contributions. To better understand the genetic factors involved in stuttering, we performed a genome-wide linkage study in a newly-ascertained consanguineous stuttering family from Pakistan. A linkage scan in this family using parametric linkage analysis revealed significant linkage only on chromosome 3q13.2-3q13.33, with a maximum two-point LOD score of 4.23 under an autosomal recessive model of inheritance.

Genetic mapping of a novel hypotrichosis locus to chromosome 7p21.3–p22.3 in a Pakistani family and screening of the candidate genes

Hereditary hypotrichosis is a heterogeneous group of inherited hair loss disorders characterized by diffused or localized thinning or absence of hair affecting scalp, eyebrows and eyelashes, and other body parts. Over the past few years, at least four autosomal dominant and six autosomal recessive forms of hypotrichosis have been described. All these ten forms of hypotrichosis have been mapped on different human chromosomes and the corresponding genes have been identified in most of these cases. In the present study, we have described a six-generation Pakistani consanguineous family with an autosomal recessive transmission of hereditary hypotrichosis. All the five affected individuals of the family showed complete absence of scalp hair and sparse eyebrows and eyelashes. They were born with complete absence of scalp hairs. Facial hair of beard and mustaches were present in all the affected adult male individuals. Papules were observed only on scalp of the affected individuals. A scalp biopsy from an affected individual showed markedly reduced number of hair follicles. Human genome scan using polymorphic microsatellite markers mapped the disease locus on chromosome 7p21.3-p22.3, flanked by markers D7S1532 and D7S3047. A maximum two-point LOD score of 4.74 (theta = 0.00) was obtained at marker D7S481. The linkage interval spans 15.69 cM, which corresponds to 6.59 Mb according to the sequence-based physical map (Build 36.2). Mutation analysis of five potential candidate genes (GNA12, FOXK1, DAGLB, ZNF12, ACTB), located in the linkage interval, did not reveal any functional sequence variant.

Mapping of a novel locus for an autosomal recessive form of palmoplantar keratoderma on chromosome 3q27.2-q29

Palmoplantar keratodermas (PPKs) are a group of highly heterogeneous diseases causing hyperkeratosis of the palms and soles. They can be inherited in an autosomal recessive, dominant, mitochondrial or possibly X-linked recessive fashion. The present study describes clinical and molecular genetic analysis of a consanguineous Pakistani family showing a severe form of PPK inherited in an autosomal recessive manner. To map the gene responsible for an autosomal recessive form of PPK. Human genome scan using polymorphic microsatellite markers was performed to localize the disease gene. Eleven candidate genes, located in the linkage interval, were screened to identify the potential sequence variants. All five affected members of the family showed severe bilateral involvement of palms and soles with minor nail involvement, severe fissuring with bleeding, painful walking, and problems in grasping. Linkage analysis in the family mapped a novel locus for the disease on chromosome 3q27.2-q29. The candidate region flanked by markers D3S1530 and D3S1272 spans 28·22 cM, which corresponds to a physical distance of 11·63 Mb. The maximum two-point LOD score of 3·13 at θ = 0·00 was obtained with marker D3S2748 along the disease locus. DNA sequence analysis of 11 candidate genes, located in the linkage interval, failed to detect functional sequence variants. A novel locus for an autosomal recessive form of PPK was mapped on chromosome 3q27.2-q29 in a consanguineous Pakistani family. Failure to detect pathogenic sequence variants in the 11 candidate genes suggests either that the variants are located in the regulatory regions of the genes or that another unknown gene, responsible for the disease, is present in the region.

A locus for juvenile myoclonic epilepsy maps to 2q33–q36

We performed a whole genome linkage analysis in a three-generation south Indian family with multiple members affected with juvenile myoclonic epilepsy (JME). The maximum two-point LOD score obtained was 3.32 at recombination fraction (theta) = 0 for D2S2248. The highest multipoint score of 3.59 was observed for the genomic interval between D2S2322 and D2S2228 at the chromosomal region 2q33-q36. Proximal and distal boundaries of the critical genetic interval were defined by D2S116 and D2S2390, respectively. A 24-Mb haplotype was found to co-segregate with JME in the family. While any potentially causative variant in the functional candidate genes, SLC4A3, SLC23A3, SLC11A1 and KCNE4, was not detected, we propose to examine brain-expressed NRP2, MAP2, PAX3, GPR1, TNS1 and DNPEP, and other such positional candidate genes to identify the disease-causing gene for the disorder.

Paroxysmal kinesigenic choreoathetosis: evidence of linkage to the pericentromeric region of chromosome 16 in four Chinese families

Paroxysmal kinesigenic choreoathetosis (PKC) is an autosomal dominant condition characterized by abnormal involuntary movements precipitated by sudden movement. The pericentromeric region of chromosome 16 has been linked to PKC by several reports. This study was to localize and identify PKC gene in four Chinese PKC families. Genetic linkage mapping with eight markers spanning chromosome 16p12-q13 was performed in 43 family members. Genome-wide single nucleotide polymorphism (SNP) scans were performed on four individuals in Family 1 in which infantile convulsion (IC) was co-inherited with PKC. Individuals in Family 1 presented with both IC and paroxysmal choreoathetosis (ICCA), and Families 2, 3, and 4 presented only with PKC. Evidence for linkage was found with a maximum two-point LOD score of 4.89 for D16S690 (theta = 0.0) and a maximum multipoint LOD score was 5.34 between D16S3080 and D16S3136. Haplotype analysis showed the disease locus was between D16S3093 and D16S3057. A total of 84 SNPs spanned on 16q12.1-q13 was not segregated with the PKC phenotype, which defined an unlinked region from rs9933187 to rs8044753. Thus, the critical region of the PKC gene is across the pericentromeric region of chromosome 16, and most likely maps to a region of 20.5 Mb (6.2 cM) between D16S3093 and rs9933187 (16p11.2-q12.1). The assignment of the locus for PKC to the pericentromeric region of chromosome 16 is confirmed and putatively narrowed in the present study.

A Major Determinant for Binding and Aminoacylation of tRNA Ala in Cytoplasmic Alanyl-tRNA Synthetase Is Mutated in Dominant Axonal Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease (CMT) is the most common cause of inherited peripheral neuropathy, with an estimated frequency of 1/2500. We studied a large family with 17 patients affected by the axonal form of CMT (CMT2). Analysis of the 15 genes or loci known to date was negative. Genome-wide genotyping identified a CMT2 locus in 16q21-q23 between D16S3050 and D16S3106. The maximum two-point LOD score was 4.77 at theta = 0 for marker D16S3050. Sequencing of candidate genes identified a unique mutation, c.986G>A (p.Arg329His), affecting a totally conserved amino acid in the helical domain of cytoplasmic alanyl-tRNA synthetase (AlaRS). A second family with the same mutation and a different founder was then identified in a cohort of 91 CMT2 families. Although mislocation of mutant Arg329His-AlaRS in axons remains to be evaluated, experimental data point mostly to a quantitative reduction in tRNA(Ala) aminoacylation. Aminoacylation and editing functions closely cooperate in AlaRS, and Arg329His mutation could also lead to qualitative errors participating in neurodegeneration. Our report documents in 18 patients the deleterious impact of a mutation in human cytoplasmic AlaRS and broadens the spectrum of defects found in tRNA synthetases. Patients present with sensory-motor distal degeneration secondary to predominant axonal neuropathy, slight demyelination, and no atypical or additional CNS features.

Linkage of a Mild Late-Onset Phenotype of Fuchs Corneal Dystrophy to a Novel Locus at 5q33.1-q35.2

To identify the disease locus associated with autosomal dominant Fuchs corneal dystrophy (FCD) in a large family and to compare the progression of severity in families mapped to the FCD1 and FCD2 loci. Seventeen individuals in a large family were examined by slit lamp biomicroscopy. Blood samples were collected, DNA was extracted, and a genome-wide scan was performed with a microarray SNP chip. After initial generation of a genome-wide, two-point LOD score, linkage was confirmed and the critical interval was established by genotyping of short tandem repeat (STR) microsatellite markers. A genome-wide linkage scan localized the disease interval to the long arm of chromosome 5, with a maximum two-point parametric LOD score of 3.41. Haplotype analyses refined the critical interval to 5q33.1-q35.2, spanning a 27-Mb (29-cM) region. Clinical examination of affected individuals in this family revealed an early onset of FCD at approximately age 40, after which progression of the disease was significantly attenuated compared to the FCD1- and FCD2-linked families. Late-onset FCD is linked to a novel locus on 5q33.1-q35.2 and is associated with a milder severity in age at onset and rate of progression than the FCD1 and FCD2 loci. Correlation of individual genotypes with unique rates of disease progression will provide important tools for disease management, as well as for identifying the underlying genetic lesion, offer insight into the pathomechanism of FCD.

Gain-of-Function Mutation of KIT Ligand on Melanin Synthesis Causes Familial Progressive Hyperpigmentation

Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age. The genetic basis for FPH remains unknown. In this study, a six-generation Chinese family with FPH was subjected to a genome-wide scan for linkage analysis. Two-point linkage analysis mapped the locus for FPH at chromosome 12q21.31-q23.1, with a maximum two-point LOD score of 4.35 (Ø = 0.00) at D12S81. Haplotype analysis confined the locus within an interval of 9.09 cM, flanked by the markers D12S1667 and D12S2081. Mutation profiling of positional candidate genes detected a heterozygous transversion (c. 107A-->G) in exon 2 of the KIT ligand (KITLG) gene, predicted to result in the substitution of a serine residue for an asparagine residue at codon 36 (p.N-->S). This mutant "G" allele cosegregated perfectly with affected, but not with unaffected, members of the FPH family. Function analysis of the soluble form of sKITLG revealed that mutant sKITLGN36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells. Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLGN36S compared to wild-type control. To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLGN36S mutation, which has a gain-of-function effect on the melanin synthesis and opens a new avenue for exploration of the genetic mechanism of FPH.

Ectodermal dysplasia-cutaneous syndactyly syndrome maps to chromosome 7p21.1-p14.3

Ectodermal dysplasia syndromes are genetically heterogeneous group of disorders involving one or more of the classical ectodermal appendages (hair, nail, teeth, sweat glands) in association with anomalies of other organs or systems. In the present study a novel form of ectodermal dysplasia syndrome, ectodermal dysplasia cutaneous syndactyly (EDCS), segregating in an autosomal recessive pattern in a Pakistani family was investigated. The clinical features of the affected individuals included large prominent ear pinnae, tooth enamel hypoplasia, hypoplastic nails, bilateral partial cutaneous syndactyly, hypotrichosis, palmoplantar keratoderma and hyperhidrosis. Through genetic linkage study, EDCS syndrome was mapped on human chromosome 7p21.1-p14.3 flanked by markers D7S488 and D7S817. A maximum two-point LOD score of 2.94 (theta = 0.00) was obtained at marker D7S2496 while a maximum multipoint LOD score of 3.07 was obtained with several markers along the disease-interval. This interval spans 19.80-cM, which corresponds to 13.74-Mbp according to the sequence-based physical map (Build 36.1). Sequence analysis of 27 candidate genes, located in the candidate interval, did not reveal any functional sequence variant.

Mutations in STIL, Encoding a Pericentriolar and Centrosomal Protein, Cause Primary Microcephaly

Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterized by smaller-than-normal brain size and mental retardation. MCPH is genetically heterogeneous with six known loci: MCPH1-MCPH6. We report mapping of a novel locus, MCPH7, to chromosome 1p32.3-p33 between markers D1S2797 and D1S417, corresponding to a physical distance of 8.39 Mb. Heterogeneity analysis of 24 families previously excluded from linkage to the six known MCPH loci suggested linkage of five families (20.83%) to the MCPH7 locus. In addition, four families were excluded from linkage to the MCPH7 locus as well as all of the six previously known loci, whereas the remaining 15 families could not be conclusively excluded or included. The combined maximum two-point LOD score for the linked families was 5.96 at marker D1S386 at theta = 0.0. The combined multipoint LOD score was 6.97 between markers D1S2797 and D1S417. Previously, mutations in four genes, MCPH1, CDK5RAP2, ASPM, and CENPJ, that code for centrosomal proteins have been shown to cause this disorder. Three different homozygous mutations in STIL, which codes for a pericentriolar and centrosomal protein, were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the STIL protein. Further, another recently ascertained family was homozygous for the same mutation as one of the original families. There was no evidence for a common haplotype. These results suggest that the centrosome and its associated structures are important in the control of neurogenesis in the developing human brain.

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.

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.

Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9

BackgroundFrontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND.MethodsClinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing.ResultsNeuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree.ConclusionOur reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.

Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer

Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500-2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron-exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in alpha-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of alpha-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.

Identification of a genetic locus for autosomal dominant disseminated superficial actinic porokeratosis on chromosome 1p31.3–p31.1

Disseminated superficial actinic porokeratosis (DSAP) is a chronic autosomal dominant cutaneous disorder with high genetic heterogeneity. Two genetic loci for DSAP were identified, but no specific genes were reported to date. The pathogenic mechanism of this disorder remains to be elucidated. In this study, a large, five-generation Chinese family with DSAP was genetically characterized. Two known DSAP loci, DSAP1 and DSAP2, two DSAP candidate genes (SART3 and SSH1), one DSP-linked locus and one PPPD-linked locus were first excluded in the family. The family was then characterized by genome-wide linkage analysis and a new DSAP locus was identified on chromosome 1p31.3-p31.1 with a maximum two-point LOD score of 5.09 with marker D1S2897 (theta = 0). Fine mapping showed that the disease gene was located within an 8.2 cM or 11.9 Mb region between markers D1S438 and D1S464. This is the third locus identified for DSAP (DSAP3). Eight candidate genes including GNG12, IL12RB2, ITGB3BP, DNAJ6, PIN1L, GADD45A, RPE65 and NEGR1 were sequenced, but found to be negative for functional sequence variants. Further mutational analysis of the candidate genes in the region will identify the specific gene for DSAP, which will provide insights into the pathogenesis of DSAP.

A Genome-wide Scan Maps a Novel High Myopia Locus to 5p15

This study was conducted to investigate the genetic component of three Chinese pedigrees originating from Hong Kong with autosomal dominant high myopia. A whole-genome scan was performed by using microsatellite markers spanning the whole genome with an average spacing of 10 cM. Regions containing markers that yielded LOD scores >1.0 were further analyzed by fine mapping with additional microsatellite markers. Fine-scale mapping of the linkage region was performed by genotyping a set of gene-based SNP markers on a cohort of 94 high myopia cases and 94 control subjects. Two-point LOD scores >1 were observed at markers D5S630, D5S416, D7S510, D11S908, and D17S944. Additional microsatellite markers flanking D5S630 revealed a maximum two-point LOD score of 4.81 at D5S2505 at theta = 0.00. Haplotype analysis narrowed the linkage region to 5p15.33-p15.2 with a 17.45-cM interval. The coding sequences of five genes located within this region, IRX2, IRX1, POLS, CCT5, and CTNND2, were screened. No segregation of polymorphism with high myopia was found. Genotyping of 41 SNPs within this region in a Chinese cohort of 94 high myopia cases and 94 control subjects showed that the allele and genotype distributions of one SNP, rs370010, was different between cases and controls (genotype P = 0.01176, allele P = 0.00271 and trend P = 0.00375), but such association did not remain significant after false discovery rate (FDR) correction. This SNP is located within a hypothetical gene LOC442129. A novel autosomal dominant high myopia locus was mapped on chromosome 5p15.33-p15.2 with an interval of 17.45 cM.