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Retinitis pigmentosa (RP) is the most common and highly heterogeneous form of hereditary retinal degeneration. This study was to identify mutations in the 60 genes that were known to be associated with RP in 157 unrelated Chinese families with RP. Genomic DNA from probands was initially analyzed by whole exome sequencing. Sanger sequencing was used to confirm potential candidate variants affecting the encoded residues in the 60 genes, including heterozygous variants from genes that are related to autosomal dominant RP, homozygous or compound heterozygous variants from genes that are related to autosomal recessive RP, and hemizygous variants from genes that are related to X-linked RP. Synonymous and intronic variants were also examined to confirm whether they could affect splicing. A total of 244 candidate variants were detected by exome sequencing. Sanger sequencing confirmed 240 variants out of the 244 candidates. Informatics and segregation analyses suggested 110 potential pathogenic mutations in 28 out of the 60 genes involving 79 of the 157 (50 %) families, including 31 (39 %, 31/79) families with heterozygous mutations in autosomal dominant genes, 37 (47 %, 37/79) families with homozygous (9) or compound heterozygous (28) mutations in autosomal recessive genes, and 11 (14 %, 11/79) families with hemizygous mutations in X-linked genes. Of the 110 identified variants, 74 (67 %) were novel. The genetic defects in approximately half of the 157 studies families were detected by exome sequencing. A comprehensive analysis of the 60 known genes not only expanded the mutation spectrum and frequency of the 60 genes in Chinese patients with RP, but also provided an overview of the molecular etiology of RP in Chinese patients. The analysis of the known genes also supplied the foundation and clues for discovering novel causative RP genes.

Background: Inherited retinal dystrophies (IRDs) are a group of retinal diseases characterized by irreversible degeneration of photoreceptors. Many IRDs present significant genetic and clinical heterogeneities, which have challenged the genetic and clinical diagnosis for IRDs. This study aims to determine the genetic lesions with phenotypic correlations in patients with diverse autosomal recessive IRDs using next-generation sequencing (NGS). Methods: A cohort of 20 Chinese families affected with autosomal recessive IRDs were recruited with their detailed family history and clinical information collected. To call disease causative mutations in the patients, targeted sequence capture of IRDs-relevant genes using two in-house designed microarrays followed by NGS was applied. Bioinformatics annotation, intrafamilial cosegregation analyses, in silico prediction, and functional analyses were subsequently conducted for the variants identified by NGS. Genotype-phenotype correlations were also analyzed in the families to assist clinical diagnosis. Results: With this approach, homozygous and biallelic variants were identified in 11 out of the 20 families (55%) as very likely disease causing mutations including a total of 17 alleles, of which 11 are novel. The 17 alleles identified here include 5 missense mutations, 5 nonsense mutations, 3 frameshift mutations, and 4 splice site mutations. Noteworthy, we found biallelic RP1 mutations in a patient with cone-rod dystrophy (CRD), which was not previously correlated with RP1 mutations. Moreover, identification of biallelic mutations in FLVCR1 in a patient with complex systemic phenotypes has finalized the clinical diagnosis as posterior column ataxia with RP (PCARP). Conclusions: Targeted NGS approach could effectively detect mutations in patients with diverse autosomal recessive IRDs, significantly improve clinical diagnosis and gain better insights of genotype-phenotype correlations.

Background Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis. Methods By whole exome sequencing, we identified responsible gene of family 4794 with autosomal recessively nonsyndromic hearing loss (ARNSHL). We also used DNA from 56 Chinese familial patients with ARNSHL (autosomal recessive nonsyndromic hearing loss) and 108 ethnicity-matched negative samples to perform extended variants analysis. Results We identified MYO15A c.IVS25 + 3G > A and c.8375 T > C (p.V2792A) as the disease-causing mutations. Both mutations co-segregated with hearing loss in family 4794, but were absent in the 56 index patients and 108 ethnicity-matched controls. Conclusions Our results demonstrated that the hearing loss of family 4794 was caused by novel compound heterozygous mutations in MYO15A.

The genetic defects underlying approximately half of all retinitis pigmentosa (RP) cases are unknown. A number of genes responsible for Leber congenital amaurosis (LCA) may also cause RP when they are mutated. Our previous study revealed that variants in the most frequently mutated nine exons accounted for approximately half of the mutations detected in a cohort of patients with LCA. The aim of the present study was to detect mutations in LCA-associated genes in patients with RP using two different strategies. Sanger sequencing was used to screen mutations in the nine exons in 293 patients with RP and exome sequencing was used to detect variants in 12 LCA-associated genes in 157 of the 293 patients with RP and then to validate the variants by Sanger sequencing. Potential pathogenic mutations were identified in four patients with early onset RP, including homozygous CRB1 mutations in two patients, compound heterozygous CRB1 mutations in one patient and compound heterozygous CEP290 mutations in one patient. The present study indicated that mutations in CEP290 may also be associated with RP but not with LCA. With the exception of CEP290, the remaining 11 genes known to be associated with LCA but not with RP are unlikely to be a common cause of RP.

The genetic factors underlying the pathogenesis of chronic rhinosinusitis (CRS) remains unclear. We herein identified four related subjects with CRS and primary ciliary dyskinesia (PCD) from geographically disperse Chinese Han communities and performed exome capture and sequencing of one affected individual and unaffected parents. We found a novel mutation in DNAH5 (c. 8030G>A) in CRS and PCD which was different from those attributed to cystic fibrosis and a defect of cilia motility in a Chinese family through exome capture and sequencing. Our findings showed that c. 8030G>A of DNAH5 may be implicated as the disease-causing gene of CRS and PCD in this Chinese family, which may expand the understanding of clinicians on the pathogenesis of CRS. Moreover, the identification of this novel mutation in DNAH5 indirectly indicates that exome capture and sequencing are beneficial in the genetic research of midget consanguinity families.

We isolated human epidermis-derived mesenchymal stem cell-like pluripotent cells (hEMSCPCs) and demonstrate efficient harvesting, maintenance in vitro for at least 30 passages, reprogramming into multiple phenotypes in vivo, and integration into adult host tissues after injection into the mouse blastocyst to create chimeras. Cell phenotype was examined by karyotyping, immunostaining, immunofluorescence, and flow cytometry. A nested PCR protocol using primers specific for human SRY genes was designed to detect hEMSCPC-derived cells in female chimeric mice. FISH was used to validate the results of nested PCR. Results indicated that hEMSCPCs were derived from epidermis but were distinct from epidermal cells; they resembled mesenchymal stem cells (MSCs) morphologically and expressed the main markers of MSCs. About half of all female offspring of mice implanted with embryos injected with hEMSCPCs at the blastocyst stage harbored the human Y chromosome and tissue-specific human protein, thereby demonstrating the transdifferentiation of hEMSCPCs.

Objective: The goal of this study was to identify mutations in 25 known causative genes in 47 unrelated Chinese families with cone-rod dystrophy (CORD). Methods: Forty-seven probands from unrelated families with CORD were recruited. Genomic DNA prepared from leukocytes was analyzed by whole exome sequencing. Variants in the 25 genes were selected and then validated by Sanger sequencing. Results: Fourteen potential pathogenic mutations, including nine novel and five known, were identified in 10 of the 47 families (21.28%). Homozygous, compound heterozygous, and hemizygous mutations were detected in three, four, or three families, respectively. The 14 mutations in the 10 families were distributed among CNGB3 (three families), PDE6C (two families), ABCA4 (one family), RPGRIP1 (one family), RPGR (two families), and CACNA1F (one family). Conclusions: This study provides a brief view on mutation spectrum of the 25 genes in a Chinese cohort with CORD. Identification of novel mutations enriched our understanding of variations in these genes and their associated phenotypes. To our knowledge, this is the first systemic exome-sequencing analysis of all of the 25 CORD-associated genes.

Hereditary nonsyndromic hearing loss is highly heterogeneous and most patients with a presumed genetic etiology lack a specific diagnosis. It has been estimated that several hundred genes may be associated with this sensory deficit in humans. Here, we identified compound heterozygous mutations in the TMC1 gene as the cause of recessively inherited sensorineural hearing loss by using whole-exome sequencing in a family with two deaf siblings. Sanger sequencing confirmed that both siblings inherited a missense mutation, c.589G>A p.G197R (maternal allele), and a nonsense mutation, c.1171C>T p.Q391X (paternal allele), in TMC1. We also used DNA from 50 Chinese familial patients with ARNSHL and 208 ethnicity-matched negative samples to perform extended variants analysis. Both variants co-segregated in family 1953, which had the hearing loss phenotype, but were absent in 50 patients and 208 ethnicity-matched controls. Therefore, we concluded that the hearing loss in this family was caused by novel compound heterozygous mutations in TMC1.

Stem cells can be derived from the embryo (embryonic stem cells, ESCs), from adult tissues (adult stem cells, ASCs), and by induction of fibroblasts (induced pluripotent stem cells, iPSs). Ethical problems, immunological rejection, and difficulties in obtaining human tissues limit the use of ESCs in clinical medicine. Induced pluripotent stem cells are difficult to maintain in vitro and carry a greater risk of tumor formation. Furthermore, the complexity of maintenance and propagation is especially difficult in the clinic. Adult stem cells can be isolated from several adult tissues and present the possibility of self-transplantation for the clinical treatment of a variety of human diseases. Recently, several ASCs have been successfully isolated and cultured in vitro, including hematopoietic stem cells (HSCs) , mesenchymal stem cells (MSCs), epidermis stem cells, neural stem cells (NSCs), adipose-derived stem cells (ADSCs), islet stem cells, and germ line stem cells. Human mesenchymal stem cells originate mainly from bone marrow, cord blood, and placenta, but epidermis-derived MSCs have not yet been isolated. We isolated small spindle-shaped cells with strong proliferative potential during the culture of human epidermis cells and designed a medium to isolate and propagate these cells. They resembled MSCs morphologically and demonstrated pluripotency in vivo; thus, we defined these cells as human epidermis-derived mesenchymal stem cell-like pluripotent cells (hEMSCPCs). These hEMSCPCs present a possible new cell resource for tissue engineering and regenerative medicine.

Adult peripheral blood-derived cells are able to differentiate into a variety of cell types, including nerve cells, liver-like cells and epithelial cells. However, their differentiation into retina-like cells is controversial. In the present study, transdifferentiation potential of human adult peripheral blood mononuclear cells into retina-like cells and integration into the retina of mice were investigated. Freshly isolated adult peripheral blood mononuclear cells were divided into two groups: cells in group I were cultured in neural stem cell medium, and cells in group II were exposed to conditioned medium from rat retinal tissue culture. After 5 days, several distinct cell morphologies were observed, including standard mononuclear, neurons with one or two axons and elongated glial-like cells. Immunohistochemical analysis of neural stem cell, neuron and retina cell markers demonstrated that cells in both groups were nestin-, MAP2 (microtubule-associated protein)- and GFAP (glial fibrillary acidic protein)-positive. Flow cytometry results suggested a significant increase in nestin-, MAP2- and CD16-positive cells in group I and nestin-, GFAP-, MAP2-, vimentin- and rhodopsin-positive cells in group II. To determine survival, migration and integration in vivo, cell suspensions (containing group I or group II cells) were injected into the vitreous or the peritoneum. Tissue specimens were obtained and immunostained 4 weeks after transplantation. We found that cells delivered by intravitreal injection integrated into the retina. Labelled cells were not detected in the retina of mice receiving differentiated cells by intraperitoneal injection, but cells (groups I and II) were detected in the liver and spleen. Our findings revealed that human adult peripheral blood mononuclear cells could be induced to transdifferentiate into neural precursor cells and retinal progenitor cells in vitro, and the differentiated peripheral blood mononuclear cells can migrate and integrate into the retina in vivo.

The prediction of traffic incident duration is an important foundation of advanced incident management system and driver information system. In this paper, actual traffic incident data was used to study the prediction problem of traffic incident duration by the method of neural network. 660 sets of actual traffic incident data from a freeway management center were used to train a neural network model, and 170 sets of incident data in the same data collection, which are different from training data, were used to test the prediction effect of the model. The test result shows that the correlation of the prediction values and the actual values is 0.8535, which indicates that the prediction result of the neural network model can basically represent actual incident duration.

A freeway incident management system is an important component of an intelligent transportation system (ITS). In this paper, referring to the successful research and practical experiences at home and abroad, with the ITS framework of China as a guide, a framework of a freeway incident management system is developed according to the freeway traffic situations of China and the further development trends of the freeway network. The proposed system framework consists of the following modules: incident detection, incident influence prediction, emergency rescue, traffic control, program generation, information service, and simulation and evaluation. Each module is simply described after the framework is given. Because the system framework proposed in this paper is based on the actual situations of China, its applicability to other countries' freeway needs a further study.

This study aimed to identify the genetics underlying dominant forms of inherited retinal dystrophies using whole exome sequencing (WES) in six families extensively screened for known mutations or genes. Thirty-eight individuals were subjected to WES. Causative variants were searched among single nucleotide variants (SNVs) and insertion/deletion variants (indels) and whenever no potential candidate emerged, copy number variant (CNV) analysis was performed. Variants or regions harboring a candidate variant were prioritized and segregation of the variant with the disease was further assessed using Sanger sequencing in case of SNVs and indels, and quantitative PCR (qPCR) for CNVs. SNV and indel analysis led to the identification of a previously reported mutation in PRPH2. Two additional mutations linked to different forms of retinal dystrophies were identified in two families: a known frameshift deletion in RPGR, a gene responsible for X-linked retinitis pigmentosa and p.Ser163Arg in C1QTNF5 associated with Late-Onset Retinal Degeneration. A novel heterozygous deletion spanning the entire region of PRPF31 was also identified in the affected members of a fourth family, which was confirmed with qPCR. This study allowed the identification of the genetic cause of the retinal dystrophy and the establishment of a correct diagnosis in four families, including a large heterozygous deletion in PRPF31, typically considered one of the pitfalls of this method. Since all findings in this study are restricted to known genes, we propose that targeted sequencing using gene-panel is an optimal first approach for the genetic screening and that once known genetic causes are ruled out, WES might be used to uncover new genes involved in inherited retinal dystrophies.

Importance Inherited retinal dystrophies (IRDs) are a group of retinal degenerative diseases presenting genetic and clinical heterogeneities, which have challenged the genetic and clinical diagnoses of IRDs. Genetic evaluations of patients with IRD might result in better clinical assessments and better management of patients. Objective To determine the genetic lesions with phenotypic correlations in patients with diverse autosomal recessive IRD using next-generation sequencing. Design, Setting, and Participants A cohort of 20 Chinese families affected with autosomal recessive IRD were recruited (with data on their detailed family history and on their clinical condition). To identify disease-causing mutations in the patients, the targeted sequence capture of IRD-relevant genes using 2 in-house–designed microarrays, followed by next-generation sequencing, was performed. Bioinformatics annotation, intrafamilial cosegregation analyses, in silico analyses, and functional analyses were subsequently conducted for the variants identified by next-generation sequencing. Main Outcomes and Measures The results of detailed clinical evaluations, the identification of disease-causing mutations, and the clinical diagnosis. Results Homozygous and biallelic variants were identified in 11 of the 20 families (55%) as very likely disease-causing mutations, including a total of 17 alleles, of which 12 are novel. The 17 alleles identified here include 3 missense, 6 nonsense, 4 frameshift, and 4 splice site mutations. In addition, we found biallelic RP1 mutations in a patient with cone-rod dystrophy, which was not previously correlated with RP1 mutations. Moreover, the identification of pathogenic mutations in 3 families helped to refine their clinical diagnoses. Conclusions and Relevance In this study, to our knowledge, many mutations identified in those known loci for autosomal recessive IRD are novel. Specific RP1 mutations may correlate with cone-rod dystrophy. Genetic evaluations with targeted next-generation sequencing might result in a better clinical diagnosis and a better clinical assessment and, therefore, should be recommended for such patients.

To study the effects of Sorbaria sorbifolia extract (SSE) on DMN-induced chronic liver damage in rats.Seventy-two rats were divided into four groups, normal, model, SSE and colchicin group. Serum hyaluronic (HA) and type precollagen (PCIII) were detected by radioimmunoassay. Degrees of fibrosis and alpha-smooth muscle actin (alpha-SMA) were determined by histopathology under microscope. Hydroxyproline (Hyp) and the markers of liver function were examined also.The levels of serum ALT, AST, ALb, AKP in SSE groups were notably improved as compared with the model group. Serum HA, PCIII and Hyp of hepatic tissue in SSE groups were obviously lower than those of model group. The markers of oxidative stress( SOD, MDA, GSH-Px) were strikingly improved also in SSE groups. HE stains and alpha-SMA expression showed that the degrees of liver fibrosis in SSE groups was slighter than that of model group. There was significant difference between the model group and SSE groups (P0.05 or P0.01). The rats in SSE groups were better than those of colchinicines group.SSE is able to protect against DMN-induced chronic liver damage, which may act through oxidative stress.

This study attempts to develop a new freeway incident detection algorithm that uses the data of pulse lengths and pulse gaps from the loop detectors as parameters and apply LVQ neural network to process the data to determine if an incident occurs. This algorithm reduces greatly incident detection time, so it offers a reliable basis to rapidly process the traffic incidents. Meanwhile, the algorithm can make use of the self-learning ability of neural network to determine the different thresholds for various freeways. At last, as the simulation results shown, the new algorithm for incident detection has a lower false alarm rate(about 0.41%), a faster detection speed and a higher detection rate(about 97%). It's found to be potentially applicable in practice.

To study the constituents from Sorbaria sorbifolia and their antitumor activities.The constituents were isolated with silia gel column chromatography and identified by physicochemical properties and spectroscopic analysis. Thirty six mice were inoculated with sarcocarcinoma 180 according to the standard method, Sorbaria sorbifolia ethyl acetate etract was administrated for 10 days, tumor and body weight, the activities of NK cell and the contents of TNF-alpha, IL-2 in serum were detected.Three compounds were isolated from the ethyl acetate extract and identified as 5,2',4'-trihydroxy-6,7,5'-trimethoxyflavone(I), succinic acid(II) and p-hydroxybenzoic acid(III). The tumor of the test groups were lighter than that of control group(P0.05). There was no remarkable difference between the control and test groups in body weight (P0.05). The activity of NK cell and the contents of TNF-alpha, IL-2 in serum were higher than that of control group (P0.05).Compounds I and II were isolated from Sorbaria sorbifolia ethyl acetate extract for the first time. The ethyl acetate extract could improve immune function and strengthen antitumor effect in sarcocarcinoma 180.

Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.

The goals of wireless sensor networks WSNs are to sense and collect data and to transmit the information to a sink. Because the sensor nodes are typically battery powered, the main challenges in WSNs are to optimise the energy consumption and to prolong the network lifetime. This paper proposes a centralised clustering algorithm termed the minimum distance clustering algorithm that is based on an improved differential evolution MD-IDE. The new algorithm combines the advantages of simulated annealing and differential evolution to determine the cluster heads CHs for minimising the communication distance of the WSN. Many simulation results demonstrate that the performance of MD-IDE outperforms other well-known protocols, including the low-energy adaptive clustering hierarchy LEACH and LEACH-C algorithms, in the aspects of reducing the communication distance of the WSN for reducing energy consumption.

PURPOSE: Leber congenital amaurosis (LCA) is a genetically heterogeneous disease with, to date, 19 identified causative genes. Our aim was to evaluate the mutations in all 19 genes in Chinese families with LCA. METHODS: LCA patients from 41 unrelated Chinese families were enrolled, including 25 previously unanalyzed families and 16 families screened previously by Sanger sequencing, but with no identified mutations. Genetic variations were screened by whole-exome sequencing and then validated using Sanger sequencing. RESULTS: A total of 41 variants predicted to affect protein coding or splicing was detected by whole-exome sequencing, and 40 were confirmed by Sanger sequencing. Bioinformatic and segregation analyses revealed 22 potentially pathogenic variants (17 novel) in 15 probands, comprised of 3 of 16 previously analyzed families and 12 of 25 (48%) previously unanalyzed families. In the latter 12 families, mutations were found in CEP290 (three probands); GUCY2D (two probands); and CRB1, CRX, RPE65, IQCB1, LCA5, TULP1, and IMPDH1 (one proband each). Based on the results from 87 previously analyzed probands and 25 new cases, GUCY2D, CRB1, RPGRIP1, CEP290, and CRX were the five most frequently mutated genes, which was similar to the results from studies in Caucasian subjects. CONCLUSIONS: Whole-exome sequencing detected mutations in the 19 known LCA genes in approximately half of Chinese families with LCA. These results, together with our previous results, demonstrate the spectrum and frequency of mutations of the 19 genes responsible for LCA in Han Chinese individuals. Whole-exome sequencing is an efficient method for detecting mutations in highly heterogeneous hereditary diseases. Chinese Abstract.

Table S2. Distribution and summary of genome-wide variants. Table S3. Summary of SNP annotations. Table S4. SNP loci (30) selected for validation by Sequenom MassARRAY. Table S5. GWAS results for six traits using SNPs and SVs. Table S6. Estimation of domestication bottlenecks in peach and other crop and fruit species. Table S7. Domestication bottleneck verified using BOTTLENECK. Table S12. Genomic regions continuously selected by both domestication and improvement. Table S13. Summary of SNPs associated with SSC and fruit weight. Table S14. SNPs associated with chilling requirement. Table S19. Shared selective sweeps between western and eastern improved groups. Table S20. Eastern specific improvement sweeps. Table S21. Western group specific improvement sweeps. Table S22. Best fitting parameters for the two-population model for cultivated and wild peach groups in the demographic analysis. Table S23. Primers used in this study. (DOC 486 kb)

Table S2. Distribution and summary of genome-wide variants. Table S3. Summary of SNP annotations. Table S4. SNP loci (30) selected for validation by Sequenom MassARRAY. Table S5. GWAS results for six traits using SNPs and SVs. Table S6. Estimation of domestication bottlenecks in peach and other crop and fruit species. Table S7. Domestication bottleneck verified using BOTTLENECK. Table S12. Genomic regions continuously selected by both domestication and improvement. Table S13. Summary of SNPs associated with SSC and fruit weight. Table S14. SNPs associated with chilling requirement. Table S19. Shared selective sweeps between western and eastern improved groups. Table S20. Eastern specific improvement sweeps. Table S21. Western group specific improvement sweeps. Table S22. Best fitting parameters for the two-population model for cultivated and wild peach groups in the demographic analysis. Table S23. Primers used in this study. (DOC 486 kb)

Figure S1. Genetic diversity of the 480 peach accessions. Figure S2. Manhattan plot and QQ plot of genome-wide association studies on seven important agronomic traits. Figure S3. A candidate 70.5-kb deletion underlying fruit texture. Figure S4. Phenetic neighbor-joining tree of 480 peach accessions constructed using PHYLIP with 100 bootstrap replicates. Figure S5. Population structure of the 480 peach accessions. Figure S6. Phenotypes and nucleotide diversity changes during peach improvement and domestication. Figure S7. Genome-wide association studies (GWAS) of SSC and fruit weight. Figure S8. Regional LD decay measured by R2 at the 20.0â 30.0-Mb region of chromosome 2. Figure S9. Total organic acids in domesticated peaches and wild relatives. Figure S10. Genome-wide association study of total phenolic content for peach. Figure S11. Expression profile of a sugar transport gene, Prupe.4G037800, during fruit development in peach. Figure S12. A candidate gene for SSC associated with increase of fruit taste during domestication. Figure S13. Distribution of chilling requirement in 371 peach accessions. Figure S14. Manhattan plot (left) and QQ plot (right) of GWAS for chilling requirement (CR) by classifying accessions into low CR and non-low CR. Figure S15. Comparison of flowering times between Arabidopsis overexpressing of peach SVP gene (OE) and the wild type (WT) Arabidopsis. Figure S16. A PCR-based marker for low CR peach identification based on the results of CR GWAS. Figure S17. Comparison of improvement sweeps between eastern and western improved groups. Figure S18. Shared and private SVs among three callers. Figure S19. Distribution of genotype missing rate for 480 peach accessions. Figure S20. Demographic model for peach domestication and spread. Figure S21. Shared domestication and improvement sweeps identified by ROD and XP-CLR methods. (PDF 2514 kb)

Background Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense mutations in PRPS1 that lead to three different phenotypes: Arts Syndrome (MIM 301835), X-linked Charcot-Marie-Tooth (CMTX5, MIM 311070) or X-linked non-syndromic sensorineural deafness (DFN2, MIM 304500). All three are X-linked recessively inherited and males affected display variable degree of central and peripheral neuropathy. We applied whole exome sequencing to a three-generation family with optic atrophy followed by retinitis pigmentosa (RP) in all three cases, and ataxia, progressive peripheral neuropathy and hearing loss with variable presentation. Methods Whole exome sequencing was performed in two affecteds and one unaffected member of the family. Sanger sequencing was used to validate and segregate the 12 candidate mutations in the family and to confirm the absence of the novel variant in PRPS1 in 191 controls. The pathogenic role of the novel mutation in PRPS1 was assessed in silico and confirmed by enzymatic determination of PRS activity, mRNA expression and sequencing, and X-chromosome inactivation. Results A novel missense mutation was identified in PRPS1 in the affected females. Age of onset, presentation and severity of the phenotype are highly variable in the family: both the proband and her mother have neurological and ophthalmological symptoms, whereas the phenotype of the affected sister is milder and currently confined to the eye. Moreover, only the proband displayed a complete lack of expression of the wild type allele in leukocytes that seems to correlate with the degree of PRS deficiency and the severity of the phenotype. Interestingly, optic atrophy and RP are the only common manifestations to all three females and the only phenotype correlating with the degree of enzyme deficiency. Conclusions These results are in line with recent evidence of the existence of intermediate phenotypes in PRS-I deficiency syndromes and demonstrate that females can exhibit a disease phenotype as severe and complex as their male counterparts. Electronic supplementary material The online version of this article (doi:10.1186/s13023-014-0190-9) contains supplementary material, which is available to authorized users.