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1.  1031-1034delTAAC (Leu125Stop): a novel familial UBE3A mutation causing Angelman syndrome in two siblings showing distinct phenotypes 
BMC Medical Genetics  2012;13:124.
Background
More than 50 mutations in the UBE3A gene (E6-AP ubiquitin protein ligase gene) have been found in Angelman syndrome patients with no deletion, no uniparental disomy, and no imprinting defect.
Case Presentation
We here describe a novel UBE3A frameshift mutation in two siblings who have inherited it from their asymptomatic mother. Despite carrying the same UBE3A mutation, the proband shows a more severe phenotype whereas his sister shows a milder phenotype presenting the typical AS features.
Conclusions
We hypothesized that the mutation Leu125Stop causes both severe and milder phenotypes. Potential mechanisms include: i) maybe the proband has an additional problem (genetic or environmental) besides the UBE3A mutation; ii) since the two siblings have different fathers, the UBE3A mutation is interacting with a different genetic variant in the proband that, by itself, does not cause problems but in combination with the UBE3A mutation causes the severe phenotype; iii) this UBE3A mutation alone can cause either typical AS or the severe clinical picture seen in the proband.
doi:10.1186/1471-2350-13-124
PMCID: PMC3543165  PMID: 23256887
Angelman syndrome; UBE3A gene; Imprinting; Novel mutation; Distinct phenotypes; HRM
2.  Genome-wide sequencing for the identification of rearrangements associated with Tourette syndrome and obsessive-compulsive disorder 
BMC Medical Genetics  2012;13:123.
Background
Tourette Syndrome (TS) is a neuropsychiatric disorder in children characterized by motor and verbal tics. Although several genes have been suggested in the etiology of TS, the genetic mechanisms remain poorly understood.
Methods
Using cytogenetics and FISH analysis, we identified an apparently balanced t(6,22)(q16.2;p13) in a male patient with TS and obsessive-compulsive disorder (OCD). In order to map the breakpoints and to identify additional submicroscopic rearrangements, we performed whole genome mate-pair sequencing and CGH-array analysis on DNA from the proband.
Results
Sequence and CGH array analysis revealed a 400 kb deletion located 1.3 Mb telomeric of the chromosome 6q breakpoint, which has not been reported in controls. The deletion affects three genes (GPR63, NDUFA4 and KLHL32) and overlaps a region previously found deleted in a girl with autistic features and speech delay. The proband’s mother, also a carrier of the translocation, was diagnosed with OCD and shares the deletion. We also describe a further potentially related rearrangement which, while unmapped in Homo sapiens, was consistent with the chimpanzee genome.
Conclusions
We conclude that genome-wide sequencing at relatively low resolution can be used for the identification of submicroscopic rearrangements. We also show that large rearrangements may escape detection using standard analysis of whole genome sequencing data. Our findings further provide a candidate region for TS and OCD on chromosome 6q16.
doi:10.1186/1471-2350-13-123
PMCID: PMC3556158  PMID: 23253088
Tourette syndrome; Paired end sequencing; Chromosomal translocation; Structural variations
3.  Genotype-phenotype correlation in 22q11.2 deletion syndrome 
BMC Medical Genetics  2012;13:122.
Background
The 22q11.2 deletion syndrome (22q11.2DS) is caused by hemizygous microdeletions on chromosome 22q11.2 with highly variable physical and neuropsychiatric manifestations. We explored the genotype-phenotype relationship in a relatively large 22q11.2DS cohort treated and monitored in our clinic using comprehensive clinical evaluation and detailed molecular characterization of the deletion.
Methods
Molecular analyses in 142 subjects with 22q11.2DS features were performed by FISH and MLPA methods. Participants underwent clinical assessment of physical symptoms and structured psychiatric and cognitive evaluation.
Results
Deletions were found in 110 individuals including one with an atypical nested distal deletion which was missed by the FISH test. Most subjects (88.2%) carried the 3Mb typically deleted region and 11.8% carried 4 types of deletions differing in size and location. No statistically significant genotype-phenotype correlations were found between deletion type and clinical data although some differences in hypocalcemia and cardiovascular anomalies were noted.
Analysis of the patient with the distal nested deletion suggested a redundancy of genes causing the physical and neuropsychiatric phenotype in 22q11.2DS and indicating that the psychiatric and cognitive trajectories may be governed by different genes.
Conclusions
MLPA is a useful and affordable molecular method combining accurate diagnosis and detailed deletion characterization. Variations in deletion type and clinical manifestations impede the detection of significant differences in samples of moderate size, but analysis of individuals with unique deletions may provide insight into the underlying biological mechanisms.
Future genotype-phenotype studies should involve large multicenter collaborations employing uniform clinical standards and high-resolution molecular methods.
doi:10.1186/1471-2350-13-122
PMCID: PMC3548696  PMID: 23245648
Velocardiofacial syndrome (VCFS); Multiplex ligation probe amplification (MLPA); Copy number variation (CNV); Molecular diagnosis; Neuropsychiatric disorders
4.  Novel missense mutation in the RSPO4 gene in congenital hyponychia and evidence for a polymorphic initiation codon (p.M1I) 
BMC Medical Genetics  2012;13:120.
Background
Anonychia/hyponychia congenita is a rare autosomal recessive developmental disorder characterized by the absence (anonychia) or hypoplasia (hyponuchia) of finger- and/or toenails frequently caused by mutations in the R-spondin 4 (RSPO4) gene.
Methods
Three hypo/anonychia consanguineous Pakistani families were ascertained and genotyped using microsatellite markers spanning the RSPO4 locus on chromosome 20p13. Mutation screening of the RSPO4 gene was carried out by direct sequencing of the entire coding region and all intron-exon boundaries.
Results
Mutations in the RSPO4 gene were identified in all families including a novel missense mutation c.178C>T (p.R60W) and two recurrent variants c.353G>A (p.C118Y) and c.3G>A (p.M1I). The c.3G>A variant was identified in unaffected family members and a control sample in a homozygous state.
Conclusions
This study raises to 17 the number of known RSPO4 mutations and further expands the molecular repertoire causing hypo/anonychia. The c.353G>A emerges as a recurrent change with a possible founder effect in the Pakistani population. Our findings suggest that c.3G>A is not sufficient to cause the disorder and could be considered a polymorphism.
doi:10.1186/1471-2350-13-120
PMCID: PMC3532313  PMID: 23234511
Anonychia; Hyponychia; Mutation; RSPO4 gene; Polymorphism
5.  Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: A retrospective case control study 
BMC Medical Genetics  2012;13:121.
Background
Recurrent miscarriage affects approximately 1% of all couples. There is a known relation between hypothyroidism and recurrent miscarriage. Phosphodiesterase 8B (PDE8B) is a regulator of cyclic adenosine monophosphate (cAMP) with important influence on human thyroid metabolism. Single nucleotide polymorphism (SNP) rs 4704397 in the PDE8B gene has been shown to be associated with variations in serum Thyroid Stimulating Hormone (TSH) and thyroxine (T4) levels. The aim of this study was to investigate whether there is an association between the SNP rs 4704397 in the PDE8B gene and recurrent miscarriage.
Methods
The study was designed as a retrospective case control study. 188 cases with recurrent miscarriage were included and compared with 391 controls who had delivered at least once and with no history of miscarriage or assisted reproduction.
Results
No difference between cases and controls concerning age was found. Bivariate associations between homozygous A/A (OR 1.57, 95% CI 0.98-2.52) as well as G/G carriers (OR 1.52, 95% CI 1.02-2.25) of SNP rs 4704397 in PDE8B and recurrent miscarriage were verified (test for trend across all 3 genotypes, p = 0.059). After adjustment for known confounders such as age, BMI and smoking the association between homozygous A/A (AOR 1.63, 95% CI 1.01 - 2.64, p = 0.045) and G/G (AOR 1.52, 95% CI 1.02 - 2.27, p = 0.039) carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage remained.
Conclusions
Our findings suggest that there is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage.
doi:10.1186/1471-2350-13-121
PMCID: PMC3556309  PMID: 23237535
Phosphodiesterase 8B; Recurrent miscarriage; Single nucleotide polymorphism; Thyroid
6.  Evaluation of single nucleotide polymorphisms in microRNAs (hsa-miR-196a2 rs11614913 C/T) from Brazilian women with breast cancer 
BMC Medical Genetics  2012;13:119.
Background
Emerging evidence has shown that miRNAs are involved in human carcinogenesis as tumor suppressors or oncogenes. Single nucleotide polymorphisms (SNPs) located in pre-miRNAs may affect the processing and therefore, influence the expression of mature miRNAs. Previous studies generated conflicting results when reporting association between the hsa-miR-196a2 rs11614913 common polymorphism and breast cancer.
Methods
This study evaluated the hsa-miR-196a2 rs11614913 SNP in 388 breast cancer cases and 388 controls in Brazilian women. Polymorphism was determined by real-time PCR; control and experimental groups were compared through statistical analysis using the X2 or Fisher’s exact tests.
Results
The analysis of the SNPs frequencies showed a significant difference between the groups (BC and CT) in regards to genotype distribution (χ2: p = 0.024); the homozygous variant (CC) was more frequent in the CT than in the BC group (p = 0.009). The presence of the hsa-miR-196a2 rs11614913 C/T polymorphism was not associated with histological grades (p = 0.522), axillary lymph node positive status (p = 0.805), or clinical stage (p = 0.670) among the breast cancer patients.
Conclusions
The results of this study indicated that the CC polymorphic genotype is associated with a decreased risk of BC and the presence of the T allele was significantly associated with an increased risk of BC.
doi:10.1186/1471-2350-13-119
PMCID: PMC3563578  PMID: 23228090
Breast; Cancer; Polymorphisms; MicroRNAs
7.  Prediction of lung cancer risk in a Chinese population using a multifactorial genetic model 
BMC Medical Genetics  2012;13:118.
Background
Lung cancer is a complex polygenic disease. Although recent genome-wide association (GWA) studies have identified multiple susceptibility loci for lung cancer, most of these variants have not been validated in a Chinese population. In this study, we investigated whether a genetic risk score combining multiple.
Methods
Five single-nucleotide polymorphisms (SNPs) identified in previous GWA or large cohort studies were genotyped in 5068 Chinese case–control subjects. The genetic risk score (GRS) based on these SNPs was estimated by two approaches: a simple risk alleles count (cGRS) and a weighted (wGRS) method. The area under the receiver operating characteristic (ROC) curve (AUC) in combination with the bootstrap resampling method was used to assess the predictive performance of the genetic risk score for lung cancer.
Results
Four independent SNPs (rs2736100, rs402710, rs4488809 and rs4083914), were found to be associated with a risk of lung cancer. The wGRS based on these four SNPs was a better predictor than cGRS. Using a liability threshold model, we estimated that these four SNPs accounted for only 4.02% of genetic variance in lung cancer. Smoking history contributed significantly to lung cancer (P < 0.001) risk [AUC = 0.619 (0.603-0.634)], and incorporated with wGRS gave an AUC value of 0.639 (0.621-0.652) after adjustment for over-fitting. This model shows promise for assessing lung cancer risk in a Chinese population.
Conclusion
Our results indicate that although genetic variants related to lung cancer only added moderate discriminatory accuracy, it still improved the predictive ability of the assessment model in Chinese population.
doi:10.1186/1471-2350-13-118
PMCID: PMC3573944  PMID: 23228068
Chinese; Cumulative risk; Genetic risk score; Lung cancer; Risk assessment
8.  In-vitro characterization of novel and functional regulatory SNPs in the promoter region of IL2 and IL2R alpha in a Gabonese population 
BMC Medical Genetics  2012;13:117.
Background
The selection pressure imposed by the parasite has a functional consequence on the immune genes, leading to altered immune function in which regulatory T cells (Tregs) induced by parasites during infectious challenges modulate or thwart T effector cell mechanism.
Methods
We identified and investigated regulatory polymorphisms in the immune gene IL2 and its receptor IL2R alpha (also known as CD25) in Gabonese individuals exposed to plentiful parasitic infections.
Results
We identified two reported variants each for IL2 and its receptor IL2R alpha gene loci. Also identified were two novel variants, -83 /-84 CT deletions (ss410961576) for IL2 and -409C/T (ss410961577) for IL2R alpha. We further validated all identified promoter variants for their allelic gene expression using transient transfection assays. Three promoter variants of the IL2 locus revealed no significant expression of the reporter gene. The identified novel variant (ss410961577C/T) of the IL2R alpha revealed a significant higher expression of the reporter gene in comparison to the major allele (P<0.05). In addition, the rs12722616C/T variant of the IL2R alpha locus altered the transcription factor binding site TBP (TATA box binding protein) and C/EBP beta (CCAAT/enhancer binding protein beta) that are believed to regulate the Treg function.
Conclusions
The identification and validation of such regulatory polymorphisms in the immune genes may provide a basis for future studies on parasite susceptibility in a population where T cell functions are compromised.
doi:10.1186/1471-2350-13-117
PMCID: PMC3564939  PMID: 23217119
IL2; IL2R alpha; CD25; Polymorphism; Transfection; Regulatory T cells
9.  Thymic stromal lymphopoietin gene promoter polymorphisms and expression levels in Graves’ disease and Graves’ ophthalmopathy 
BMC Medical Genetics  2012;13:116.
Background
Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation.
Methods
In this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined.
Results
Haplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10−14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients.
Conclusions
These results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.
doi:10.1186/1471-2350-13-116
PMCID: PMC3582428  PMID: 23194010
Graves’ disease; Graves’ ophthalmopathy; Thymic stromal lymphopoietin; Th17
10.  Association of SELE genotypes/haplotypes with sE-selectin levels in Taiwanese individuals: interactive effect of MMP9 level 
BMC Medical Genetics  2012;13:115.
Background
E-selectin is implicated in various inflammatory processes and related disorders. We aimed to investigate the role of SELE-gene genotypes/haplotypes on plasma levels of MMP9 and sE-selectin in Taiwanese individuals.
Methods
Five hundred twenty individuals were enrolled. Seven tagging SELE single nucleotide polymorphisms were analyzed.
Results
SELE genotypes were found associated with MMP9 and sE-selectin levels. Multivariate analysis identified that the most significant genetic polymorphism (rs5368 genotype) was independently associated with MMP9 levels (P < 0.001). One haplotype (GGAGAGT) was marginally associated with MMP9 levels (P = 0.0490). One SELE SNP, (rs3917406, P = 0.031) was associated with sE-selectin levels after adjusting for MMP9 and sICAM1 levels. Subgroup and interaction analysis revealed association of SELE SNP rs10800469 with sE-selectin levels only in the highest quartile of MMP9 level (P = 0.002, interaction P = 0.023). Haplotype analysis showed one haplotype (AAAAAGC) borderline associated with sE-selectin level (P = 0.0511).
Conclusion
SELE genotypes/haplotypes are independently associated with MMP9 and E-selectin levels in Taiwanese individuals. The associations of SELE genotypes/haplotypes with sE-selectin levels are affected by MMP9 levels.
doi:10.1186/1471-2350-13-115
PMCID: PMC3532335  PMID: 23190470
E-selectin; Genetic association study; Polymorphism; Matrix metalloproteinase 9; Haplotype; Interaction
11.  Cross-pollination of research findings, although uncommon, may accelerate discovery of human disease genes 
BMC Medical Genetics  2012;13:114.
Background
Technological leaps in genome sequencing have resulted in a surge in discovery of human disease genes. These discoveries have led to increased clarity on the molecular pathology of disease and have also demonstrated considerable overlap in the genetic roots of human diseases. In light of this large genetic overlap, we tested whether cross-disease research approaches lead to faster, more impactful discoveries.
Methods
We leveraged several gene-disease association databases to calculate a Mutual Citation Score (MCS) for 10,853 pairs of genetically related diseases to measure the frequency of cross-citation between research fields. To assess the importance of cooperative research, we computed an Individual Disease Cooperation Score (ICS) and the average publication rate for each disease.
Results
For all disease pairs with one gene in common, we found that the degree of genetic overlap was a poor predictor of cooperation (r2=0.3198) and that the vast majority of disease pairs (89.56%) never cited previous discoveries of the same gene in a different disease, irrespective of the level of genetic similarity between the diseases. A fraction (0.25%) of the pairs demonstrated cross-citation in greater than 5% of their published genetic discoveries and 0.037% cross-referenced discoveries more than 10% of the time. We found strong positive correlations between ICS and publication rate (r2=0.7931), and an even stronger correlation between the publication rate and the number of cross-referenced diseases (r2=0.8585). These results suggested that cross-disease research may have the potential to yield novel discoveries at a faster pace than singular disease research.
Conclusions
Our findings suggest that the frequency of cross-disease study is low despite the high level of genetic similarity among many human diseases, and that collaborative methods may accelerate and increase the impact of new genetic discoveries. Until we have a better understanding of the taxonomy of human diseases, cross-disease research approaches should become the rule rather than the exception.
doi:10.1186/1471-2350-13-114
PMCID: PMC3532152  PMID: 23190421
12.  Genetic variant I148M in PNPLA3 is associated with the ultrasonography-determined steatosis degree in a Chinese population 
BMC Medical Genetics  2012;13:113.
Background
Nonalcoholic fatty liver disease (NAFLD) is an escalating medical problem worldwide. A nonsynonymous single nucleotide polymorphism rs738409 (I148M) in patatin-like phospholipase domain-containing protein 3 (PNPLA3) predisposes susceptibility to NAFLD; however, its association with steatosis grade is inconsistent in the literature. In particular, there was no significant association found between I148M and steatosis grade in two East Asian-based studies. In this study we aim to investigate whether I148M is associated with the ultrasonography-determined steatosis degree in Chinese adults.
Methods
203 NAFLD cases and 202 matched controls were recruited. Cases were classified into mild, moderate and severe fatty liver by ultrasonography. Association between I148M and the ultrasonography-determined steatosis degree as well as other clinical parameters was evaluated.
Results
The I148M variant was associated with the ultrasonography-determined steatosis degree with the M allele frequencies being 0.32, 0.54, and 0.87 in mild (n=105), moderate (n=83), and severe (n=15) cases, respectively (P–value = 7.6×10-8). We also confirmed the interaction between I148M variation and body mass index towards elevated plasma alanine aminotransferase levels in cases (P–value = 4.4×10-4).
Conclusion
The PNPLA3 I148M variant is associated with the ultrasonography-determined steatosis degree in Chinese population.
doi:10.1186/1471-2350-13-113
PMCID: PMC3523076  PMID: 23176674
PNPLA3; NAFLD; Ultrasonography; Steatosis grade
13.  PXR and CAR single nucleotide polymorphisms influence plasma efavirenz levels in South African HIV/AIDS patients 
BMC Medical Genetics  2012;13:112.
Background
This study investigated variation in NR1I2 and NR1I3 and its effect on plasma efavirenz levels in HIV/AIDS patients. Variability in plasma drug levels has largely led research on identifying causative variants in drug metabolising enzyme (DME) genes, with little focus on the nuclear receptor genes NR1I2 and NR1I3, coding for PXR and CAR, respectively, that are involved in regulating DMEs.
Methods
464 Bantu-speaking South Africans comprising of HIV/AIDS patients on efavirenz-based treatment (n=301) and 163 healthy subjects were genotyped for 6 SNPs in NR1I2 and NR1I3. 32 of the 301 patients had their DNA binding domains (DBDs) in NR1I2 and NR1I3 sequenced.
Results
Significantly decreased efavirenz plasma concentrations were observed in patients carrying the NR1I3 rs3003596C/C and T/C genotypes (P=0.015 and P=0.010, respectively). Sequencing resulted in the discovery of a further 13 SNPs, 3 of which are novel variants in the DBD of NR1I2. There were significant differences in the distribution of NR1I2 and NR1I3 SNPs between South Africans when compared to Caucasian, Asian and Yoruba population groups.
Conclusion
For the realisation of personalised medicine, PXR and CAR genetic variation should be taken into consideration because of their involvement in the regulation of DMEs.
doi:10.1186/1471-2350-13-112
PMCID: PMC3523080  PMID: 23173844
CAR; Efavirenz; HIV/AIDS; PXR; Pharmacogenetics; South Africa
14.  Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype 
BMC Medical Genetics  2012;13:111.
Background
Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2.
Methods
We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature.
Results
The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood.
Conclusions
This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.
doi:10.1186/1471-2350-13-111
PMCID: PMC3523052  PMID: 23171239
Albinism; Exome sequencing; G6PC3 protein; Inflammatory bowel disease; Oculocutaneous albinism type 4 (OCA4); Neutropenia; Severe congenital neutropenia type 4 (SCN4); SLC45A2 protein
15.  The CAG repeat polymorphism in the Androgen receptor gene modifies the risk for hypospadias in Caucasians 
BMC Medical Genetics  2012;13:109.
Background
Hypospadias is a birth defect of the urethra in males, and a milder form of 46,XY disorder of sexual development (DSD). The disease is characterized by a ventrally placed urinary opening due to a premature fetal arrest of the urethra development. Moreover, the Androgen receptor (AR) gene has an essential role in the hormone-dependent stage of sexual development. In addition, longer AR polyglutamine repeat lengths encoded by CAG repeats are associated with lower transcriptional activity in vitro. In the present study, we aimed at investigating the role of the CAG repeat length in the AR gene in hypospadias cases as compared to the controls. Our study included 211 hypospadias and 208 controls of Caucasian origin.
Methods
We amplified the CAG repeat region with PCR, and calculated the difference in the mean CAG repeat length between the hypospadias and control group using the T-test for independent groups.
Results
We detected a significant increase of the CAG repeat length in the hypospadias cases when compared to the controls (contrast estimate: 2.29, 95% Confidence Interval (1.73-2.84); p-value: 0.001). In addition, the odds ratios between the hypospadias and controls revealed that the hypospadias cases are two to 3 times as likely to have longer CAG repeats than a shorter length for each repeat length investigated.
Conclusions
We have investigated the largest number of hypospadias cases with regards to the CAG repeat length, and we provide evidence that a higher number of the CAG repeat sequence in the AR gene have a clear effect on the risk of hypospadias in Caucasians.
doi:10.1186/1471-2350-13-109
PMCID: PMC3560208  PMID: 23167717
Hypospadias; Androgen receptor gene; CAG repeats
16.  Leukotriene B4 receptor locus gene characterisation and association studies in asthma 
BMC Medical Genetics  2012;13:110.
Background
Polymorphisms spanning genes involved in the production of leukotriene B4 (LTB4) e.g. ALOX5AP and LTA4H are associated with asthma susceptibility, suggesting a role for LTB4 in disease. The contribution of LTB4receptor polymorphism is currently unknown. The aim of this study was to characterise the genes for the two pivotal LTB4 receptors, LTB4R1 and LTB4R2 in lung tissue and determine if polymorphisms spanning these genes are associated with asthma and disease severity.
Methods
Rapid amplification of cDNA ends (RACE) was used to characterise the LTB4R1 and LTB4R2 gene structure in lung. The LTB4R1/2 locus on chromosome 14q11.2 was screened for polymorphic variation. Six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in 370 Caucasian asthma families and 299 Adult Asthma Individuals (n=1877 total) and were evaluated for association with asthma and severity (BTS) outcome measures using Family Based Association Test, linear regression and chi square.
Results
LTB4R1 has complex mRNA arrangement including multiple 5′-untranslated exons, suggesting additional levels of regulation. Three potential promoter regions across the LTB4R1/2 locus were identified with some airway cell specificity. 22 SNPs (MAF>0.01) were validated across the LTB4R locus in the Caucasian population. LTB4R1 and LTB4R2 SNPs were not associated with asthma susceptibility, FEV1 or severity.
Conclusions
LTB4R1 and LTB4R2 shows splice variation in the 5′-untranslated region and multiple promoter regions. The functional significance of this is yet to be determined. Both receptor genes were shown to be polymorphic. LTB4R polymorphisms do not appear to be susceptibility markers for the development of asthma in Caucasian subjects.
doi:10.1186/1471-2350-13-110
PMCID: PMC3607986  PMID: 23167751
Association; Asthma; Family based association test; Leukotriene; Leukotriene B4 receptor; RACE; Severity
17.  SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype 
BMC Medical Genetics  2012;13:108.
Background
The presence of the Y-chromosome or Y chromosome-derived material is seen in 4-60% of Turner syndrome patients (Chromosomal Disorders of Sex Development (DSD)). DSD patients with specific Y-chromosomal material in their karyotype, the GonadoBlastoma on the Y-chromosome (GBY) region, have an increased risk of developing type II germ cell tumors/cancer (GCC), most likely related to TSPY. The Sex determining Region on the Y gene (SRY) is located on the short arm of the Y-chromosome and is the crucial switch that initiates testis determination and subsequent male development. Mutations in this gene are responsible for sex reversal in approximately 10-15% of 46,XY pure gonadal dysgenesis (46,XY DSD) cases. The majority of the mutations described are located in the central HMG domain, which is involved in the binding and bending of the DNA and harbors two nuclear localization signals. SRY mutations have also been found in a small number of patients with a 45,X/46,XY karyotype and might play a role in the maldevelopment of the gonads.
Methods
To thoroughly investigate the presence of possible SRY gene mutations in mosaic DSD patients, we performed next generation (deep) sequencing on the genomic DNA of fourteen independent patients (twelve 45,X/46,XY, one 45,X/46,XX/46,XY, and one 46,XX/46,XY).
Results and conclusions
The results demonstrate that aberrations in SRY are rare in mosaic DSD patients and therefore do not play a significant role in the etiology of the disease.
doi:10.1186/1471-2350-13-108
PMCID: PMC3538515  PMID: 23157850
Disorders of Sex Development (DSD); Chromosomal-DSD; SRY; Next generation (deep) sequencing; Mutation
18.  Association of IL-18 polymorphisms with rheumatoid arthritis and systemic lupus erythematosus in Asian populations: a meta-analysis 
BMC Medical Genetics  2012;13:107.
Background
Interleukin (IL)-18, an important proinflammatory cytokine, plays a potential pathological role in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Studies on the relationship of IL-18 gene promoter rs1946518 (−607A/C) polymorphism, rs187238 (−137G/C) polymorphism with RA and SLE are inconclusive. The aim of this study was to get a more precise estimation of the relationship in Asian populations.
Methods
Meta-analysis was conducted on the associations between the IL-18 (−607A/C and -137G/C) polymorphisms and RA and SLE, using; (1) allele contrast, (2) dominant, and (3) recessive models. A total of 11 studies were included in this study.
Results
For the relationship of IL-18 rs1946518 polymorphism with RA (additive model: OR=0.752, 95%CI=0.562-1.006; dominant model: OR=0.730, 95%CI =0.479-1.113; recessive model: OR=0.537, 95%CI=0.271-1.064) and SLE (additive model: OR=0.684, 95%CI=0.455-1.028; dominant model: OR=0.645, 95%CI=0.368-1.130; recessive model: OR=0.672, 95%CI =0.447-1.010), no significant association with RA and SLE risk can be found under all genetic models in Asian populations. However, significant associations were observed in Chinese population for both RA ((OR=0.688, 95%CI =0.532-0.889) and SLE (OR=0.606, 95%CI =0.396-0.930) under additive model. For the relationship between IL-18 rs187238 polymorphism and RA or SLE, there was no significant association detected in all genetic models, even in Chinese population.
Conclusions
This meta-analysis indicates that the IL-18-607A/C polymorphism may confer susceptibility to RA and SLE in Chinese population, but not all Asians.
doi:10.1186/1471-2350-13-107
PMCID: PMC3523015  PMID: 23153245
19.  APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family 
BMC Medical Genetics  2012;13:106.
Background
Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family.
Methods
We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives.
Results
A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls.
Conclusion
The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.
doi:10.1186/1471-2350-13-106
PMCID: PMC3523038  PMID: 23151256
Hypertriglyceridemia; Genetic; Chylomicronemia; Mutation; Homozygosity mapping; APOA5
20.  A human MYBPC3 mutation appearing about 10 centuries ago results in a hypertrophic cardiomyopathy with delayed onset, moderate evolution but with a risk of sudden death 
BMC Medical Genetics  2012;13:105.
Background
Hypertrophic Cardiomyopathy (HCM) is a genetically heterogeneous disease. One specific mutation in the MYBPC3 gene is highly prevalent in center east of France giving an opportunity to define the clinical profile of this specific mutation.
Methods
HCM probands were screened for mutation in the MYH7, MYBPC3, TNNT2 and TNNI3 genes. Carriers of the MYBPC3 IVS20-2A>G mutation were genotyped with 8 microsatellites flanking this gene. The age of this MYBPC3 mutation was inferred with the software ESTIAGE. The age at first symptom, diagnosis, first complication, first severe complication and the rate of sudden death were compared between carriers of the IVS20-2 mutation (group A) and carriers of all other mutations (group B) using time to event curves and log rank test.
Results
Out of 107 HCM probands, 45 had a single heterozygous mutation in one of the 4 tested sarcomeric genes including 9 patients with the MYBPC3 IVS20-2A>G mutation. The IVS20-2 mutation in these 9 patients and their 25 mutation carrier relatives was embedded in a common haplotype defined after genotyping 4 polymorphic markers on each side of the MYBPC3 gene. This result supports the hypothesis of a common ancestor. Furthermore, we evaluated that the mutation occurred about 47 generations ago, approximately at the 10th century.
We then compared the clinical profile of the IVS20-2 mutation carriers (group A) and the carriers of all other mutations (group B). Age at onset of symptoms was similar in the 34 group A cases and the 73 group B cases but group A cases were diagnosed on average 15 years later (log rank test p = 0.022). Age of first complication and first severe complication was delayed in group A vs group B cases but the prevalence of sudden death and age at death was similar in both groups.
Conclusion
A founder mutation arising at about the 10th century in the MYBPC3 gene accounts for 8.4% of all HCM in center east France and results in a cardiomyopathy starting late and evolving slowly but with an apparent risk of sudden death similar to other sarcomeric mutations.
doi:10.1186/1471-2350-13-105
PMCID: PMC3549277  PMID: 23140321
Hypertrophic cardiomyopathy; MYBPC3; Mutation; Founder effect
21.  Frank-ter Haar syndrome associated with sagittal craniosynostosis and raised intracranial pressure 
BMC Medical Genetics  2012;13:104.
Background
Frank-ter Haar syndrome is a rare disorder associated with skeletal, cardiac, ocular and craniofacial features including hypertelorism and brachycephaly. The most common underlying genetic defect in Frank-ter Haar syndrome appears to be a mutation in the SH3PXD2B gene on chromosome 5q35.1. Craniosynostosis, or premature fusion of the calvarial sutures, has not previously been described in Frank-ter Haar syndrome.
Case presentation
We present a family of three affected siblings born to consanguineous parents with clinical features in keeping with a diagnosis of Frank-ter Haar syndrome. All three siblings have a novel mutation caused by the deletion of exon 13 of the SH3PXD2B gene. Two of the three siblings also have non-scaphocephalic sagittal synostosis associated with raised intracranial pressure.
Conclusion
The clinical features of craniosynostosis and raised intracranial pressure in this family with a confirmed diagnosis of Frank-ter Haar syndrome expand the clinical spectrum of the disease. The abnormal cranial proportions in a mouse model of the disease suggests that the association is not coincidental. The possibility of craniosynostosis should be considered in individuals with a suspected diagnosis of Frank-ter Haar syndrome.
doi:10.1186/1471-2350-13-104
PMCID: PMC3532175  PMID: 23140272
Frank-ter Haar syndrome; Craniosynostosis; Sagittal synostosis; Intracranial pressure
22.  Association of soluble endothelial protein C receptor plasma levels and PROCR rs867186 with cardiovascular risk factors and cardiovascular events in coronary artery disease patients: The Athero Gene Study 
BMC Medical Genetics  2012;13:103.
Background
Blood coagulation is an essential determinant of coronary artery disease (CAD). Soluble Endothelial Protein C Receptor (sEPCR) may be a biomarker of a hypercoagulable state. We prospectively investigated the relationship between plasma sEPCR levels and the risk of cardiovascular events (CVE).
Methods
We measured baseline sEPCR levels in 1673 individuals with CAD (521 with acute coronary syndrome [ACS] and 1152 with stable angina pectoris [SAP]) from the AtheroGene cohort. During a median follow up of 3.7 years, 136 individuals had a CVE. In addition, 891 of these CAD patients were genotyped for the PROCR rs867186 (Ser219Gly) variant.
Results
At baseline, sEPCR levels were similar in individuals with ACS and SAP (median: 111 vs. 115 ng/mL respectively; p=0.20). Increased sEPCR levels were found to be associated with several cardiovascular risk factors including gender (p=0.006), soluble Tissue Factor levels (p=0.0001), diabetes (p=0.0005), and factors reflecting impaired renal function such as creatinine and cystatin C (p<0.0001). sEPCR levels were not significantly associated with the risk of CVE (median: 110 and 114 ng/mL in individuals with and without future CVE respectively; p=0.68). The rs867186 variant was found to explain 59% of sEPCR levels variability (p<10-200) but did not associate with CVE risk.
Conclusion
Our findings show that in patients with CAD, circulating sEPCR levels are related to classical cardiovascular risk factors and renal impairment but are not related to long-term incidence of CVE.
doi:10.1186/1471-2350-13-103
PMCID: PMC3523004  PMID: 23136988
\; Haemostasis; Protein C; Endothelial protein C receptor; Coronary artery disease
23.  Low prevalence of connexin-40 gene variants in atrial tissues and blood from atrial fibrillation subjects 
BMC Medical Genetics  2012;13:102.
Background
The atrial gap junction protein connexin-40 (Cx40) has been implicated to play an important role in atrial conduction and development of atrial fibrillation (AF). However, the frequency of Cx40 mutations in AF populations and their impact on Cx40 expression remains unclear. In this study, we sought to identify polymorphisms in the Cx40 gene GJA5, investigate the potential functional role of these polymorphisms, and determine their allelic frequencies. The prevalence of nonsynonymous Cx40 mutations in blood and atrial tissue was also compared to mutation frequencies reported in prior studies.
Methods
We conducted direct sequencing of the GJA5 coding and 3′ UTR regions in blood samples from 91 lone AF subjects and 67 atrial tissue-derived samples from a lone cohort, a mixed AF cohort, and several transplant donors. Reporter gene transfection and tissue allelic expression imbalance assays were used to assess the effects of a common insertion/deletion polymorphism on Cx40 mRNA stability and expression.
Results
We identified one novel synonymous SNP in blood-derived DNA from a lone AF subject. In atrial tissue-derived DNA from lone and mixed AF subjects, we observed one novel nonsynonymous SNP, one rare previously reported synonymous SNP, and one novel 3′ UTR SNP. A previously noted 25 bp insertion/deletion polymorphism in the 3′ UTR was found to be common (minor allele frequency = 0.45) but had no effect on Cx40 mRNA stability and expression. The observed prevalence of nonsynonymous Cx40 mutations in atrial tissues derived from lone AF subjects differed significantly (p = 0.03) from a prior atrial tissue study reporting a high mutation frequency in a group of highly selected young lone AF subjects.
Conclusions
Our results suggest that Cx40 coding SNPs are uncommon in AF populations, although rare mutations in this gene may certainly lead to AF pathogenesis. Furthermore, a common insertion/deletion polymorphism in the Cx40 3′ UTR does not appear to play a role in modulating Cx40 mRNA levels.
doi:10.1186/1471-2350-13-102
PMCID: PMC3507864  PMID: 23134779
Atrial fibrillation; Connexins; Ion channels; Genetics; Allelic expression imbalance
24.  The contribution of FTO and UCP-1 SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals 
BMC Medical Genetics  2012;13:101.
Background
Obesity has become a common human disorder associated with significant morbidity and mortality and adverse effects on quality of life. Sequence variants in two candidate genes, FTO and UCP-1, have been reported to be overrepresented in obese Caucasian population. The association of these genes polymorphisms with the obesity phenotype in a multiethnic group such as the Brazilian population has not been previously reported.
Methods
To assess the putative contribution of both FTO and UCP-1 to body mass index (BMI) and cardiovascular risk we genotyped SNPs rs9939609 (FTO) and rs6536991, rs22705565 and rs12502572 (UCP-1) from 126 morbidly obese subjects (BMI 42.9 ± 5.6 kg/m2, mean ± SE) and 113 normal-weight ethnically matched controls (BMI 22.6 ± 3.5 kg/m2, mean ± SE). Waist circumference, blood pressure, glucose and serum lipids were also measured. Each sample was also genotyped for 40 biallelic short insertion/deletion polymorphism (indels) for ethnic assignment and to estimate the proportion of European, African and Amerindian biogeographical ancestry in the Brazilian population.
Results
Cases did not differ from controls in the proportions of genomic ancestry. The FTO SNP rs9939609 and UCP-1 SNP rs6536991 were significantly associated with BMI (p= 0.04 and p<0.0001 respectively). An allele dose dependent tendency was observed for BMI for rs6536991 sample of controls. No other significant associations between any SNP and hypertension, hyperlipidemia and diabetes were noted after correction for BMI and no significant synergistic effect between FTO and UCP-1 SNPs with obesity were noted. There was not an association between rs9939609 (FTO) and rs6536991 (UCP-1) in with maximum weight loss after 1 year in 94 obese patients who underwent bariatric surgery.
Conclusion
Our data are consistent with FTO rs9939609 and UCP-1 rs6536991 common variants as contributors to obesity in the Brazilian population.
doi:10.1186/1471-2350-13-101
PMCID: PMC3526455  PMID: 23134754
FTO; UCP-1; Morbid obesity; Brazilian population; Multiethnic sample
25.  MAOA promoter methylation and susceptibility to carotid atherosclerosis: role of familial factors in a monozygotic twin sample 
BMC Medical Genetics  2012;13:100.
Background
Atherosclerosis is a complex process involving both genetic and epigenetic factors. The monoamine oxidase A (MAOA) gene regulates the metabolism of key neurotransmitters and has been associated with cardiovascular risk factors. This study investigates whether MAOA promoter methylation is associated with atherosclerosis, and whether this association is confounded by familial factors in a monozygotic (MZ) twin sample.
Methods
We studied 84 monozygotic (MZ) twin pairs drawn from the Vietnam Era Twin Registry. Carotid intima-media thickness (IMT) was measured by ultrasound. DNA methylation in the MAOA promoter region was quantified by bisulfite pyrosequencing using genomic DNA isolated from peripheral blood leukocytes. The association between DNA methylation and IMT was first examined by generalized estimating equation, followed by matched pair analyses to determine whether the association was confounded by familial factors.
Results
When twins were analyzed as individuals, increased methylation level was associated with decreased IMT at four of the seven studied CpG sites. However, this association substantially reduced in the matched pair analyses. Further adjustment for MAOA genotype also considerably attenuated this association.
Conclusions
The association between MAOA promoter methylation and carotid IMT is largely explained by familial factors shared by the twins. Because twins reared together share early life experience, which may leave a long-lasting epigenetic mark, aberrant MAOA methylation may represent an early biomarker for unhealthy familial environment. Clarification of familial factors associated with DNA methylation and early atherosclerosis will provide important information to uncover clinical correlates of disease.
doi:10.1186/1471-2350-13-100
PMCID: PMC3532355  PMID: 23116433
DNA methylation; MAOA; Carotid atherosclerosis; Monozygotic twins; Familial factors

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