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To reveal the clinical and genetic features of 54 Chinese pedigrees with syndromic or nonsyndromic retinal dystrophies related to CEP290 and to explore the genotype-phenotype correlation.Retrospective cohort study.Patients diagnosed with nonsyndromic inherited retinal dystrophy (IRD) or syndromic ciliopathy (SCP) were enrolled. We identified 61 patients from 54 families carrying biallelic pathogenic CEP290 variants using next-generation sequencing, Sanger sequencing, and co-segregation validation. Genotype-phenotype correlation was evaluated.This study included 37 IRD patients from 32 families and 24 patients with SCP from 22 pedigrees. Four retinal dystrophy phenotypes were confirmed: Leber congenital amaurosis (LCA, 46/61), early-onset severe retinal dystrophy (EOSRD, 4/61), retinitis pigmentosa (RP, 10/61), and cone-rod dystrophy (CORD, 1/61). The SCP phenotypes included Joubert syndrome (JS) (23/24) and Bardet-Biedl syndrome (BBS) (1/24). We detected 73 different CEP290 variants, of which 33 (45.2%) were not previously reported. Two novel copy number variations (CNVs) and one novel pathogenic synonymous change were identified. The most recurrent alterations in the IRD and SCP were p.Q123* (6/64, 9.4%) and p.I556Ffs*17 (10/44, 22.7%), respectively. IRD patients carried more stop-gain alleles (25/64, 39.1%), whereas SCP patients carried more frameshift alleles (23/44, 52.3%).LCA was the most common retinal dystrophy phenotype, and JS was the most prevalent syndrome in CEP290 patients; RP/CORD and BBS may be present in early adulthood. The hot spot variants and distribution of genotypes were distinct between IRD and SCP. Our study expands the CEP290 variant spectrum and enhances the current knowledge of CEP290 heterogeneity.

Hereditary hearing loss is genetically heterogeneous, with diverse clinical manifestations. Here we performed targeted genome sequencing of 227 hearing loss related genes in 1027 patients with bilateral hearing loss and 520 healthy volunteers with normal hearing to comprehensively identify the molecular etiology of hereditary hearing loss in a large cohort from China. We obtained a diagnostic rate of 57.25% (588/1027) for the patients, while 4.67% (48/1027) of the patients were identified with uncertain diagnoses. Of the implicated 35 hearing loss genes, three common genes, including SLC26A4(278/588), GJB2(207/588), MT-RNR1(19/588), accounted for 85.54% (503/588) of the diagnosed cases, while 32 uncommon hearing loss genes, including MYO15A, MITF, OTOF, POU3F4, PTPN11, etc. accounted for the remaining diagnostic rate of 14.46% (85/588). Apart from Pendred syndrome, other eight types of syndromic hearing loss were also identified. Of the 64 uncertain significant variants and 244 pathogenic/likely pathogenic variants identified in the patients, 129 novel variants were also detected. Thus, the molecular etiology presented with high heterogeneity with the leading causes to be SLC26A4 and GJB2 genes in the Chinese hearing loss population. It’s urgent to develop a database of the ethnicity-matched healthy population as well as to perform functional studies for further classification of uncertain significant variants.

Background Phenylketonuria (PKU) is an autosomal recessive congenital metabolic disorder caused by PAH variants. Previously, approximately 5% of PKU patients remained undiagnosed after Sanger sequencing and multiplex ligation-dependent probe amplification. To date, increasing numbers of pathogenic deep intronic variants have been reported in more than 100 disease-associated genes. Methods In this study, we performed full-length sequencing of PAH to investigate the deep intronic variants in PAH of PKU patients without definite genetic diagnosis. Results We identified five deep intronic variants (c.1199+502A>T, c.1065+241C>A, c.706+368T>C, c.706+531>C, and c.706+608A>C). Of these, the c.1199+502A>T variant was found at high frequency and may be a hotspot PAH variant in Chinese PKU. c.706+531T>C and c.706+608A>C are two novel variants that extend the deep intronic variant spectrum of PAH. Conclusion Deep intronic variant pathogenicity analysis can further improve the genetic diagnosis of PKU patients. In silico prediction and minigene analysis are powerful approaches for studying the functions and effects of deep intronic variants. Targeted sequencing after full-length gene amplification is an economical and effective tool for the detection of deep intron variation in genes with small fragments.

Background Phenylketonuria (PKU) is a common, congenital, autosomal recessive, metabolic disorder caused by Phenylalanine hydroxylase (PAH) variants. Methods 967 PKU patients from Gansu, China were genotyped by Sanger sequencing, multiplex ligation-dependent probe amplification, and whole exome sequencing. We analyzed the variants of PAH exons, their flanking sequences, and introns. Results The detection of deep intronic variants in PAH gene can significantly improve the genetic diagnostic rate of PKU. The distribution of PAH variants among PKU subtypes may be related to the unique genetic background in Gansu, China. Conclusion The identification of PAH hotspot variants will aid the development of large-scale neonatal genetic screening for PKU. The five new PAH variants found in this study further expand the spectrum of PAH variants. Genotype–phenotype correlation analysis may help predict the prognosis of PKU patients and enable precise treatment regimens to be developed.

Background KIAA0586, also known as Talpid3, plays critical roles in primary cilia formation and hedgehog signaling in humans. Variants in KIAA0586 could cause some different ciliopathies, including Joubert syndrome (JBTS), which is a clinically and genetically heterogeneous group of autosomal recessive neurological disorders. Methods and Results A 9-month-old girl was diagnosed as JBTS by the “molar tooth sign” of the mid-brain and global developmental delay. By whole-exome sequencing, we identified a single nucleotide variant c.3303G > A and a 1.38-kb deletion in KIAA0586 in the proband. These two variants of KIAA0586 were consistent with the mode of autosomal recessive inheritance in the family, which was verified using Sanger sequencing. Conclusions This finding of a compound heterozygote with a 1.38-kb deletion and c.3303G > A gave a precise genetic diagnosis for the patient, and the novel 1.38-kb deletion also expanded the pathogenic variation spectrum of JBTS caused by KIAA0586.

To explore the genetic basis for a child with mental retardation.Whole exome sequencing was carried out for the child. Candidate variant was screened based on his clinical features and verified by Sanger sequencing.The child was found to harbor a c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant in the SYNGAP1 gene. Bioinformatic analysis suggested it to be pathogenic. The same variant was not detected in either parent.The c.995_1002delAGACAAAA(p.Asp332AlafsTer84) frameshift variant of the SYNGAP1 gene probably underlay the mental retardation in this child. Above finding has expanded the spectrum of SYNGAP1 gene variants and provided a basis for the diagnosis and treatment for this child.

MYOC mutations are the leading genetic causes of primary open-angle glaucoma (POAG). We previously identified a recurrent Gly367Arg mutant myocilin (MYOC/p.G367R) associated with juvenile open-angle glaucoma (JOAG) in a large Chinese family, but the pathogenic mechanism remains unclear. The MYOC/p.G367R carrier presented a high intraocular pressure and typic POAG phenotype, including an open anterior angle, a thinning retina nerve fiber layer, and a tubular visual field. Trabecular meshwork (TM) cell lines (iHTMCs) and primary TM cells (pHTMCs) expressing wild-type or mutant (G367R) myocilin were constructed to further verify the disease-causing roles of MYOC/p.G367R mutation in the TM. The G367R mutant had no effect on cytoskeletal arrangement or fibronectin production. Consistently, the combination of G367R-myocilin with the chaperones Grp94 and CRYAB impaired the intracellular degradation mechanism and caused aggregation of myocilin in the ER. The excessive accumulation of mutated myocilin in the ER resulted in chronic ER stress, and apoptosis. Moreover, autophagy plays an essential role in regulating the pathogenesis of MYOC mutations. Rapamycin activated autophagy and decreased intracellular myocilin accumulation. Chloroquine inhibited autophagy and promoted intracellular myocilin retention, exacerbating ER stress and oxidative stress in TM cells. Meanwhile, the retinal cell line 661W was used to study the effect of MYOC/p.G367R mutation in retinal cells. Similar to TM cells, the autophagic activity of 661W cells expressing G367R-myocilin was inhibited. In addition, MYOC/p.G367R mutation induced mitochondrial dysfunction and promoted superoxide onion generation in 661W cells. Together, our findings suggest that G367R mutant myocilin induces cell dysfunction of the TM and retina through excessive intracellular accumulation of mutant myocilin caused by impairment of protein clearance mechanisms. Furthermore, autophagy may serve as a therapeutic target to promote the degradation of mutant myocilin and alleviate cell dysfunction.

To carry out genetic analysis for 3 children from two Chinese families affected with maple syrup urine disease (MSUD).Target capture - next-generation sequencing and Sanger sequencing were used to detect pathogenic variants associated with MSUD.The proband from family 1 was found to harbor homozygous c.560GT (p.Gly187Val) variant of the BCKDHB gene (NM_000056), whilst the two patients from family 2 were found to harbor compound heterozygous variants c.197-2AG (splicing)/c.218delT (p.F74Sfs*4) of the BCKDHB gene. Among these, the c.560GT and c.218delT variants were unreported previously.The new variants discovered in this study have expanded the mutational spectrum of the BCKDHB gene.

Phenylketonuria (PKU) is a genetic disorder with amino acid metabolic defect, which does great harms to the development of newborns and children. Early diagnosis and treatment can effectively prevent the disease progression. Here we developed a PKU screening model using random forest classifier (RFC) to improve PKU screening performance with excellent sensitivity, false positive rate (FPR) and positive predictive value (PPV) in all the validation dataset and two testing Chinese populations. RFC represented outstanding advantages comparing several different classification models based on machine learning and the traditional logistic regression model. RFC is promising to be applied to neonatal PKU screening.

To establish a newborn screening system for Duchenne muscular dystrophy (DMD) through assessment of MM isoenzyme of creatine kinase (CK-MM) activity.The CK-MM level was detected using dry blood spot filter paper from 10 252 male newborns. The results were grouped based on their gestational age, sampling time and intervals between the experiments. The threshold value for CK-MM necessitating genetic testing was determined. Next-generation sequencing (NGS) was carried out for those with a CK-MM value over the threshold, and the result was verified by multiplex ligation-dependent probe amplification (MLPA).Based on the result of non-parametric rank sum test, the median CK-MM concentration has increased with the gestational age, and was inversely correlated with the age of the newborns among unaffected specimens. CK-MM on dry blood spot filter paper can be stable for 14 days at 2-8℃. Statistical analysis of CK-MM value of the 10 252 neonates suggested that the threshold may be set as 700 ng/mL. Exonic deletions were found in 2 confirmed cases, whose CK-MM level was greater than 2000 ng/mL.Detection of CK-MM in dry blood spot filter paper has provided an effective method for newborn screening of DMD. This simple and inexpensive method can be used for large-scale screening, which is of great value to the early intervention and treatment of the disease.

To explore the genetic basis for a child with unexplained global developmental delay (GDD), seizure, and facial deformity.Whole exome sequencing (WES) was carried out for the patient. Candidate variants were verified by Sanger sequencing of the patient and his parents.WES revealed that the patient has carried a previously unreported de novo heterozygous nonsense c.4906CT (p.Arg1636Ter) variant of the KMT2A gene, Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.4906CT variant of KMT2A gene was predicted to be pathogenic (PVS1+ PS2+ PM2+PP3).The heterozygous nonsense c.4906CT (p.Arg1636Ter) variant of the KMT2A gene probably underlay the disease in the child. Above finding has enriched the spectrum of pathogenic variants of the KMT2A gene.

Background Mucopolysaccharidosis type II (MPS II) is an X-linked multisystem disorder caused by mutations in the gene encoding iduronate 2-sulfatase (IDS). The clinical manifestations of MPS II include skeletal deformities, airway obstruction, cardiomyopathy, and neurologic deterioration. MPS II has high genetic heterogeneity disorder, and ~ 658 variants of IDS have been reported. Methods We undertook a detailed pedigree analysis of four patients within the same family by targeted next-generation sequencing and Sanger sequencing. Results We identified a novel heterozygous frameshift variant, c.1224delC(p.Pro408ProfsTer31), of IDS in three patients. We defined c.1224delC as a pathogenic variant according to the 2015 guidelines set by the American College of Medical Genetics and Genomics. Conclusion We reported the second Chinese female MPS II patient. We helped to ensure that these two families had healthy babies. Our findings have enlarged the mutational spectrum of IDS, and these findings could be useful for genetic counseling and the prenatal diagnosis of MPS II.

PPP2R5D-related neurodevelopmental disorder, which is mainly caused by de novo missense variants in the PPP2R5D gene, is a rare autosomal dominant genetic disorder with about 100 patients and a total of thirteen pathogenic variants known to exist globally so far. Here, we present a 24-month-old Chinese boy with developmental delay and other common clinical characteristics of PPP2R5D-related neurodevelopmental disorder including hypotonia, macrocephaly, intellectual disability, speech impairment, and behavioral abnormality. Trio-whole exome sequencing (WES) and Sanger sequencing were performed to identify the causal gene variant. The pathogenicity of the variant was evaluated using bioinformatics tools. We identified a novel pathogenic variant in the PPP2R5D gene (c.620G>T, p.Trp207Leu). The variant is located in the variant hotspot region of this gene and is predicted to cause PPP2R5D protein dysfunction due to an increase in local hydrophobicity and unstable three-dimensional structure. We report a novel pathogenic variant of PPP2R5D associated with PPP2R5D-related neurodevelopmental disorder from a Chinese family. Our findings expanded the phenotypic and mutational spectrum of PPP2R5D-related neurodevelopmental disorder.

Background Treacher Collins syndrome (TCS) is a rare autosomal dominant or recessive disorder, that involves unique bilateral craniofacial malformations. The phenotypes of TCS are extremely diverse. Interventional surgery can improve hearing loss and facial deformity in TCS patients. Method We recruited seven TCS families. Variant screening in probands was performed by targeted next‐generation sequencing (NGS). The variants identified were confirmed by Sanger sequencing. The pathogenicity of all the mutations was evaluated using the guidelines of the American College of Medical Genetics and Genomics (ACMG) and InterVar software. Results Three frameshift variants, two nonsense variants, one missense variant, and one splicing variant of TCOF1 were identified in the seven TCS probands. Five variants including c.1393C > T, c.4111 + 5G>C, c.1142delC, c.2285_2286delCT, and c.1719delG had not been previously reported. Furthermore, we report the c.149A > G variant for the first time in a Chinese TCS patient. We provided prenatal diagnosis for family 4. Proband 7 chose interventional surgery. Conclusion We identified five novel variants in TCOF1 in Chinese patients with TCS, which expands the mutation spectrum of TCOF1 in TCS. Bone conduction hearing rehabilitation can improve hearing for TCS patients and prenatal diagnosis can provide fertility guidance for TCS families., Figure 1. The facial features of these patients are characteristic of TCS. Figure 2. Sanger sequencing of TCOF1: P is proband, F is father, M is mother, AF is amniotic fluid. None of the parents of these seven families detected the same variation as the proband had. The Sanger sequencing of fetus for family 4 was normal

Background Silver‐Russell syndrome (SRS) is a heterogeneous imprinting disorder featuring severe intrauterine and postnatal growth retardation and dysmorphic features. Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the SLC26A4 gene characterized by sensorineural hearing loss. Methods Karyotyping analysis was performed to investigate any chromosomal abnormalities. Whole‐genome copy number variation and loss of heterozygosity were analyzed using an Affymetrix CytoScan 750 K Microarray. Variant screening was performed by targeted next‐generation sequencing on all known deafness‐causing genes. Results The proband was a patient with SRS caused by maternal uniparental disomy 7. The PDS of the proband was caused by homozygous variant c.919‐2A > G of SLC26A4; both mutated alleles were inherited from his mother. Conclusion This is the first report of uniparental disomy 7 leading to SRS and Pendred syndrome. Patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure should undergo molecular testing to reach a clinical diagnosis.

Methylmalonic acidemia (MMA)-affected patients may have developmental, hematological, neurological, metabolic, ophthalmological, and dermatological clinically abnormal findings. This study aimed to identify mutations in 13 Chinese MMA cases. We provided genetic counseling, treatment, and prenatal diagnosis for the families with MMA. Liquid chromatography-tandem mass spectrometry (LC–MS/MS) was performed and the results were confirmed by gas chromatography and mass spectrometry (GC/MS). Variant screening in probands was performed by targeted next-generation sequencing. Identified variants were confirmed by Sanger sequencing. Of these 13 MMA cases, seven were isolated MMA, and among them, six were caused by variants in MMUT and one was caused by a variant in MCEE. The other six cases were MMA with homocystinuria, which was caused by variants in MMACHC. We found six novel variants in three MMA-causing genes as follows: c.2008G>A, c.301_302insTA, c.984delC, and c.319A>T of MMUT; c.445T>C of MMACHC; and c.296T>C of MCEE. We provided prenatal diagnosis for two families with MMA at their next pregnancy, and one family had a healthy newborn. In conclusion, our findings expand the spectrum of genotypes in MMA. Effective genetic counseling is required to allow awareness of the patients’ families that MMA disease is treatable and a good prognosis can be obtained.

Numerous studies have focused on the development of novel and innovative approaches for the treatment of peripheral nerve injury using artificial nerve guide conduits. In this study, we attempted to bridge 3.5-cm defects of the sciatic nerve with a longitudinally oriented collagen conduit (LOCC) loaded with human umbilical cord mesenchymal stem cells (hUC-MSCs). The LOCC contains a bundle of longitudinally aligned collagenous fibres enclosed in a hollow collagen tube. Our previous studies showed that an LOCC combined with neurotrophic factors enhances peripheral nerve regeneration. However, it remained unknown whether an LOCC seeded with hUC-MSCs could also promote regeneration. In this study, using various histological and electrophysiological analyses, we found that an LOCC provides mechanical support to newly growing nerves and functions as a structural scaffold for cells, thereby stimulating sciatic nerve regeneration. The LOCC and hUC-MSCs synergistically promoted regeneration and improved the functional recovery in a dog model of sciatic nerve injury. Therefore, the combined use of an LOCC and hUC-MSCs might have therapeutic potential for the treatment of peripheral nerve injury.

Deltamethrin (DLT) is effective against a broad spectrum of insects. Exposure to DLT has been demonstrated to cause oxidative stress. However, the mechanism of oxidative stress induced by DLT is little known. Groups of rats were gavaged with DLT once daily for 7 days at six dosages: 0, 2, 5, 10, 20, 40 mg/kg. The intensity of neurotoxicity and liver dysfunction caused by DLT were significantly increased in a dose-dependent manner. We found that DLT caused the increase of cytosolic superoxide in tissues. Western blot analysis showed that both the expression of p66shc and Ser36 phosphorylated p66shc, which were involved in ROS generation, were increased in tissues treated with DLT. Further investigation showed that DLT treatment resulted in the increase of intracellular ROS accompanied with elevated p66shc expression in different cell lines. And treatment of cells with DLT induced p66shc phosphorylation at Ser36 and the translocation of p66shc from cytoplasm to mitochondria. Moreover, the overexpression of wildtype p66shc caused the increase of DLT-mediated ROS level in SH-SY5Y cells, but cells overexpressing p66shcSer36Ala mutant plasmid had the opposite effect. And p66shc suppression by siRNA blunted DLT-mediated ROS generation. Taken together, our findings indicated p66shc mediated DLT-induced oxidative stress, which may be partly responsible for toxic effects.

To identify the mutational spectrum of 63 northwest Chinese probands with Oculocutaneous albinism (OCA), and identify correlations between phenotype and genotype. We recruited 63 clinically diagnosed with OCA patients in Gansu Provincial Maternal and Child Health Care Hospital. Mutation screening analysis was performed by direct sequencing and NGS-target sequencing to screen the variants on genes related to OCA. PolyPhen2 and PROVEN tools were used to predict the possible functional role of the novel variants. We assessed the pathogenicity of the novel mutations according to the clinical interpretation of genetic variants by ACMG/AMP 2015 guideline. By molecular testing, 56 of the OCA probands were diagnosed as OCA 1, three were OCA 2 and one was OCA 4. The most common variants of TYR were c.929insC(33.7%), c.896 G > A(12.5%), c.832 C > T(9.6%).We found five novel variants of TYR that have not previously been reported. We make an accurate diagnosis and classification for the OCA probands. Our result enlarged the mutational spectrum of TYR and SLC45A2. These findings could be useful for genetic counseling and gene diagnosis of OCA in Northwest of China.

With the rapid development of genomic sequencing technology, the cost of obtaining personal genomic data and analyzing it effectively has been gradually reduced. The analysis and utilization of genomic data have gradually come into the public view, the privacy leakage of genomic data has aroused the attention of researchers. Genomic data has unique format and a large amount of data, but the existing genetic privacy protection schemes often fail to consider security, availability and efficiency together. In this paper, we analyzed widely used genomic data file formats and designed a hybrid encryption scheme for large genomic data files. Firstly, we designed a key agreement protocol based on RSA asymmetric cryptography. Secondly, we used AES symmetric encryption to encrypt the genomic data by optimizing the packet processing of files and multithreading encryption, and improved the usability by assisting the computing platform with key management. Software implementation indicates that the scheme can be applied to the secure transmission of genomic data in the network environment and provide an efficient encryption method for the privacy protection of genomic data.

Purpose To identify mutations in crystallin genes in Chinese families with congenital cataracts. Methods Forty-two unrelated families with non-syndromic congenital cataracts were enrolled in this study. The coding exons and adjacent intronic regions of crystallin genes, including CRYAA, CRYAB, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, CRYGC, CRYGD and CRYGS, were analyzed with Sanger sequencing. Novel variants were further evaluated in 112 ethnically matched controls. To confirm the novel mutations, short tandem repeat (STR) haplotypes were constructed to check the cosegregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools, including Sorting Intolerant From Tolerant v5.1.1 (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Human Splicing Finder. The pathogenicity of all the mutations was evaluated according to the guidelines of the American College of Medical Genetics (ACMG) and InterVar software. Results Seven previously reported mutations in crystallin genes identified in ten unrelated families were associated with the congenital nuclear cataracts. Four novel mutations in crystallin genes, including c.35G>T (p.R12L) in CRYAA, c.463C>A (p.Q155K) in CRYBB2, IVS1 c.10–1G>A in CRYGC, and c.346delT (p.F116Sfsx29) in CRYGD, were identified in four unrelated families with congenital cataracts. These mutations cosegregated with all affected individuals in each family were not observed in the unaffected family members or in the 112 unrelated controls. All four novel mutations were categorized as disease “likely pathogenic” except IVS1 c.10–1G>A in CRYGC “pathogenic” using InterVar software in accordance with the ACMG standard. Mutations in crystallin genes were responsible for 33.33% of the Chinese families with congenital cataracts in this cohort. Conclusions In this study, we identified four novel mutations in crystallin genes in Chinese families with congenital cataracts. The results expand the mutational spectrum of crystallin genes, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine.

Background Congenital cataract, a kind of cataract presenting at birth or during early childhood, is a leading cause of childhood blindness. To date, more than 30 genes on different chromosomes are known to cause this disorder. This study aimed to identify the HSF4 mutations in a cohort from Chinese families affected with congenital cataracts. Methods Forty-two unrelated non-syndromic congenital cataract families and 112 ethnically matched controls from southeast China were recruited from the southeast of China. We employed Sanger sequencing method to discover the variants. To confirm the novel mutations, STR haplotypes were constructed to check the co-segregation with congenital cataract. The pathogenic potential of the novel mutations were assessed using bioinformatics tools including SIFT, Polyphen2, and Human Splicing Finder. The pathogenicity of all the mutations was evaluated by the guidelines of American College of Medical Genetics and InterVar software. Results No previously reported HSF4 mutations were found in all the congenital cataract families. Five novel HSF4 mutations including c.187 T > C (p.Phe63Leu), c.218G > T (p.Arg73Leu), c.233A > G (p.Tyr78Cys), IVS5 c.233-1G > A and c.314G > C (p.Ser105Thr) were identified in five unrelated families with congenital cataracts, respectively. These mutations co-segregated with all affected individuals in each family were not observed in the unaffected family members or in 112 unrelated controls. All five mutations were categorized to be the disease “pathogenic” according to ACMG guidelines and using InterVar software. Mutations in the HSF4 were responsible for 11.90% Chinese families with congenital cataracts in our cohort. Conclusions In the study, we identified five novel HSF4 mutations in Chinese families with congenital cataracts. Our results expand the spectrum of HSF4 mutations causing congenital cataracts, which may be helpful for the molecular diagnosis of congenital cataracts in the era of precision medicine. Electronic supplementary material The online version of this article (10.1186/s12881-018-0636-3) contains supplementary material, which is available to authorized users.

Table S1. The PCR primers and conditions for all the tested genes. The selected hot spot exons and splice junctions of these genes were amplified by PCR from genomic DNA using the primers and conditions. (DOCX 29 kb)

We report the clinical and genetic characterization of a Chinese Leber′s hereditary optic neuropathy (LHON) family with complete penetrance and high percentage of recovery. Sequence analysis of the complete mitochondrial DNA revealed the presence of heteroplasmic ND6/T14484C mutation and 27 other variants, belonging to the East-Asian haplogroup B4b′d. Of those variants, a novel homoplasmic G10680A mutation substituted a threonine for a highly conserved alanine at ND4L amino acid 71, which was not found in unaffected family members and 100 normal controls. It indicated that G10680A may play a synergistic role with the primary mutation T14484C, leading to the complete penetrance of LHON in the presenting family. In addition, the other modifier factors including nuclear background, mitochondrial haplotypes and other environmental factors should account for the phenotypic variability of visual impairment in this family.

Arsenic usually accumulates in soil, water and airborne particles, from which it is taken up by various organisms. Exposure to arsenic through food and drinking water is a major public health problem affecting some countries. At present there are limited laboratory data on the effects of arsenic exposure on early embryonic development and the mechanisms behind its toxicity. In this study, we used zebrafish as a model system to investigate the effects of arsenite on early development. Zebrafish embryos were exposed to a range of sodium arsenite concentrations (0-10.0mM) between 4 and 120h post-fertilization (hpf). Survival and early development of the embryos were not obviously influenced by arsenite concentrations below 0.5mM. However, embryos exposed to higher concentrations (0.5-10.0mM) displayed reduced survival and abnormal development including delayed hatching, retarded growth and changed morphology. Alterations in neural development included weak tactile responses to light (2.0-5.0mM, 30hpf), malformation of the spinal cord and disordered motor axon projections (2.0mM, 48hpf). Abnormal cardiac function was observed as bradycardia (0.5-2.0mM, 60hpf) and altered ventricular shape (2.0mM, 48hpf). Furthermore, altered cell proliferation (2.0mM, 24hpf) and apoptosis status (2.0mM, 24 and 48hpf), as well as abnormal genomic DNA methylation patterning (2.0mM, 24 and 48hpf) were detected in the arsenite-treated embryos. All of these indicate a possible relationship between arsenic exposure and developmental failure in early embryogenesis. Our studies suggest that the negative effects of arsenic on vertebrate embryogenesis are substantial.