BACKGROUND:Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS:We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS:Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION:In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING:This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.

To evaluate the relationship of genetic polymorphisms of ERCC2 and ERCC4 genes, both involved in nucleotide excision repair (NER), and the risk of breast cancer, a hospital-based case-control study was conducted in Korea. Histologically confirmed breast cancer cases (n = 574) and controls (n = 502) with no present or previous history of cancer were recruited from three teaching hospitals in Seoul during 1995-2001. Information on selected characteristics was collected by interviewed questionnaire. ERCC2 Asp(312)Asn (G>A) was genotyped by single-base extension assay and ERCC4 Ser(835)Ser (T>C) by dynamic allele-specific hybridization system. Although no significant association was observed between the genetic polymorphisms and the risk of breast cancer, women with both ERCC2 A allele- and ERCC4 C allele-containing genotypes showed a 2.6-fold risk (95% CI: 1.02-6.48) of breast cancer compared to women concurrently carrying the ERCC2 GG and ERCC4 TT genotypes. The breast cancer risk increased as the number of at risk genotypes increased with a borderline significance (P for trend = 0.07). Interactive effect was also observed between ERCC4 genotype and body mass idnex (BMI) for the breast cancer risk; the ERCC4 C allele containing genotypes posed a 1.7-fold (95% CI: 0.96-2.93) breast cancer risk in obese women (BMI>25 kg/m(2)) with a borderline significance. Our finding suggests that the combined effect of ERCC2 Asp(312)Asn and ERCC4 Ser(835)Ser genotypes might be associated with breast cancer risk in Korean women.

We evaluated the association between the XPD exon 10 Asp(312)Asn and exon 23 Lys(751)Gln polymorphisms and the risk of pancreatic cancer in a hospital-based study of 344 patients and 386 controls frequency matched by age, gender, and race. Stratified analyses showed ever smokers carrying the Asn(312)Asn genotype had a significantly reduced risk when compared with those carrying the (312)Asp allele (OR=0.46, 95% confidence interval 0.24-0.88) (P for interaction=0.03). The (312)Asp-(751)Gln was identified as the putative at risk haplotype. Our study shows that the XPD gene polymorphism could be a genetic risk modifier for smoking-related pancreatic cancer.

The purpose of this study was to evaluate the role of polymorphisms in DNA repair genes as genetic indicators of susceptibility to familial and sporadic breast cancer. We analysed DNA samples from 285 breast cancer patients and 442 control subjects, for XRCC1 Arg399Gln, XPD Lys751Gln, RAD51 G135C and XRCC3 Thr241Met polymorphisms using PCR-RFLP. We observed that women carriers of XRCC1 399Gln genotypes and without family history of breast cancer have a protective effect concerning this disease (OR = 0.54 95% CI 0.35-0.84; p = 0.006). Furthermore, we found that carriers of XRCC3 241Met genotypes without FH have an increased susceptibility of breast cancer (OR = 2.21 95% CI 1.42-3.44; p < 0.001). Additionally, we verified an increased risk of breast cancer in women with FH and carrying RAD51 135C genotypes (OR = 2.17 95% CI 1.19-3.98; p = 0.012). Our results suggest XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair polymorphisms as important biomarkers to sporadic breast cancer susceptibility, as well as, RAD51 G135C polymorphism as a real risk modifier in familial breast cancer cases.

Excision repair cross-complementing group 1 (ERCC1) and group 2 (ERCC2) proteins play important roles in the repair of DNA damage and adducts. Single nucleotide polymorphisms (SNPs) of DNA repair genes are suspected to influence the risk of lung cancer. This study aimed to investigate the association between the ERCC2 751, 312 and ERCC1 118 polymorphisms and the risk of lung adenocarcinoma in Chinese non-smoking females.

We evaluated the association between the XPD exon 10 Asp(312)Asn and exon 23 Lys(751)Gln polymorphisms and the risk of pancreatic cancer in a hospital-based study of 344 patients and 386 controls frequency matched by age, gender, and race. Stratified analyses showed ever smokers carrying the Asn(312)Asn genotype had a significantly reduced risk when compared with those carrying the (312)Asp allele (OR=0.46, 95% confidence interval 0.24-0.88) (P for interaction=0.03). The (312)Asp-(751)Gln was identified as the putative at risk haplotype. Our study shows that the XPD gene polymorphism could be a genetic risk modifier for smoking-related pancreatic cancer.

Oral contraceptives (OCs) affect the risk of several cancers in women, but have been virtually unstudied for squamous cell carcinoma (SCC). We examined the hypothesis that OCs influence SCC risk in a case-control study among women and also examined whether polymorphisms in the DNA repair gene, Xeroderma pigmentosum group D (XPD), modified the risk. Incident cases of SCC were identified by a network of dermatologists and pathology laboratories. Population-based controls were frequency matched to cases by age and gender (n=261 SCC cases, 298 controls). Overall, OC use was associated with a 60% higher risk of SCC (odds ratio (OR), 1.6; 95% confidence interval (95% CI): 1.0-2.5). ORs for SCC were higher among those who last used OCs > or =25 years before diagnosis (OR: 2.1; 95% CI: 1.2-3.7), and among these women, SCC risk increased with duration of use (OR for < or =2 years, 1.7; 95% CI: 0.9-3.5; OR for 3-6 years, 2.6; 95% CI: 1.0-6.5; OR for > or =7 years, 2.7; 95% CI: 0.9-8.5, P(trend)=0.01). Furthermore, the XPD Lys751Gln polymorphism was a significant modifier of the OC-SCC association (P(interaction)=0.03). These findings lead us to hypothesize a potential relationship between OCs and SCC risk, and that this could involve DNA repair pathways.