BACKGROUND:Our preliminary bioinformatics analysis showed that lncRNA TINCR may absorb miR-214-5p by serving is sponge, while miR-214-5p targets ROCK1. This study aimed to investigate the interactions among these 3 factors in hepatocellular carcinoma (HCC).METHODS:Expression of TINCR, ROCK1 and miR-214-5p in HCC and non-tumor tissues was detected by performing qPCR. The correlations among TINCR, ROCK1 and miR-214-5p in HCC tissues were analyzed by performing linear regression. Overexpression experiments were performed to analyze gene interactions. Cell proliferation was analyzed by CCK-8 assay.RESULTS:We found that TINCR and ROCK1 were upregulated, while miR-214-5p was downregulated in HCC. TINCR and ROCK1 were positively correlated, while TINCR and miR-214-5p were not significantly correlated. In HCC cells, TINCR overexpression is followed by ROCK1 overexpression, while miR-214-5p overexpression induced the downregulation of ROCK1. In addition, TINCR and miR-214-5p did not affect the expression of each other. TINCR and ROCK1 overexpression led to increased rate of cancer cell proliferation, while miR-214-5p played an opposite role and reduced the effects of TINCR overexpression. Therefore, TINCR sponges miR-214-5p to upregulate ROCK1 in HCC, thereby promoting cancer cell invasion and migration.
Background CDKN2Ahypermethylation is among the major events associated with carcinogenesis and is also observed in non-neoplastic colonic mucosa in patients with ulcerative colitis (UC). Macrophage migration inhibitory factor (MIF) plays a crucial role in promoting gastrointestinal inflammation characteristic of UC. The aim of this study is to explore associations betweenCDKN2Amethylation status andMIFpolymorphisms (rs755622 and rs5844572). Methods One hundred and fifty-nine patients diagnosed with UC were enrolled in this study. The methylation status ofp14(ARF)andp16(INK4a)was determined by MSP;MIFgenotypes were identified by PCR-SSCP. Results We found no differences with respect to mean age, gender, clinical type (chronic continuous or relapse/remitting), or extent of disease among the patients with methylated and unmethylatedp14(ARF)orp16(INK4a). Carrying the rs755622 C allele indicated a significantly higher risk forp14(ARF)methylation (odds ratio (OR), 2.16; 95% confidence interval (CI), 1.08-4.32;p = 0.030); similarly, carrying the rs5844572 7-repeat allele indicated a significantly higher risk forp16(INK4a)methylation (OR, 2.57; 95% CI, 1.26-5.24;p = 0.0094) after an adjusted regression analysis. The carriers of the rs755662 C allele or the rs5844572 7-repeat allele were both at a significantly higher risk for methylation of bothp14(ARF)andp16(INK4a)when compared to the cohort in which neither of the genes were methylated (OR, 2.70; 95% CI, 1.22-6.01;p = 0.015 and OR, 2.87; 95% CI, 1.25-6.62;p = 0.013, respectively). Additionally, carrying rs755622 C allele was significantly associated with CIHM in chronic continuous of clinical type and total colitis (OR, 25.9; 95% CI, 2.55-262.6;p = 0.0059 and OR, 4.38; 95% CI, 1.12-17.2;p = 0.034, respectively), and carrying 7-repeat allele of rs5844572 was significantly associated in chronic continuous type (OR, 14.5; 95%CI, 1.46-144.3;p = 0.022). Conclusions Taken together, our findings suggest thatMIFgenotypes associated with inflammation may also be involved in promoting carcinogenesis viaCDKN2Ahypermethylation in patients diagnosed with UC.
Background Stickler syndrome is the most common genetic cause of rhegmatogenous retinal detachment (RRD) in children, and has a high risk of blindness. Type I (STL1) is the most common subtype, caused by COL2A1 mutations. This study aims to analyze the mutation spectrum of COL2A1 and further elucidate the genotype-phenotype relationships in the East Asian populations with STL1, which is poorly studied at present. Methods By searching MEDLINE, Web of Science, CNKI, Wanfang Data, HGMD and Clinvar, all publications associated with STL1 were collected. Then, they were carefully screened to obtain all reported STL1-related variants in COL2A1 and clinical features in East Asian patients with STL1. Results There were 274 COL2A1 variants identified in 999 patients with STL1 from 466 unrelated families, and more than half of them were truncation mutations. Of the 107 STL1 patients reported in the East Asian population, it was found that patients with truncation mutations had milder systemic phenotypes, whereas patients with splicing mutations had severer phenotypes. In addition, several recurrent variants (c.3106C > T, c.1833 + 1G > A, c.2710C > T and c.1693C > T) were found. Conclusions Genotype-phenotype correlations should certainly be studied carefully, contributed to making personalized follow-up plans and predicting prognosis of this disorder. Genome editing holds great potential for treating inherited diseases caused by pathogenic mutations. In this study, several recurrent variants were found, providing potential candidate targets for genetic manipulation in the future.
Background: Familial benign chronic pemphigus, also known as Hailey-Hailey disease (HHD), is a clinically rare bullous Dermatosis. However the mechanism has not been clarified. The study aim to detect novel mutations in exons of ATP2C1 gene in HHD patients; to explore the possible mechnism of HHD pathogenesis by examining the expression profile of hSPCA1, miR-203, p63, Notch1 and HKⅡ proteins in the skin lesions of HHD patients. Methods: Genomic DNA was extracted from peripheral blood of HHD patients. All exons of ATP2C1 gene in HHD patients were amplified by PCR and the products were purified and sequenced. All related signaling proteins of interest were stained by using skin lesion tissues from HHD patients and miR-203 levels were also determined. Results: One synonymous mutation c.G2598A (in exon 26), one nonsense mutation c.C635A and two missense mutations c.C1286A (p.A429D) and c. A1931G (p. D644G) were identified. The nonsense mutation changed codon UCG to stop codon UAG, causing a premature polypeptide chain of the functional region A. The two missense mutations were located in the region P (phosphorylation region) and the Mn binding site of hSPCA1. The level of hSPCA1 was significantly decreased in HHD patients compared to the normal human controls, accompanied by an increase of miR-203 level and a decrease of p63 and HKⅡ levels. Conclusion: In our study, we found four mutations in HHD. Meanwhile we found increase of miR-203 level and a decrease of p63 and HKⅡ levels. In addition, Notch1, which was negatively regulated p63, is downregulated. These factors may be involved in the signaling pathways of HHD pathogenesis. Our data showed that both p63 and miR-203 may have significant regulatory effects on Notch1 in the skin.
Background The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. Case presentation The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). Conclusions This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.
Background Alström syndrome is a rare recessively inherited disorder caused by variants in the ALMS1 gene. It is characterized by multiple organ dysfunction, including cone-rod retinal dystrophy, dilated cardiomyopathy, hearing loss, obesity, insulin resistance, hyperinsulinemia, type 2 diabetes mellitus and systemic fibrosis. Heterogeneity and age-dependent development of clinical manifestations make it difficult to obtain a clear diagnosis, especially in pediatric patients. Case presentation Here we report the case of a girl with Alström syndrome. Genetic examination was proposed at age 22 months when suspected macular degeneration was the only major finding. Next generation sequencing of a panel of genes linked to eye-related pathologies revealed two compound heterozygous variants in the ALMS1 gene. Frameshift variants c.1196_1202del, p.(Thr399Lysfs*11), rs761292021 and c.11310_11313del, (p.Glu3771Trpfs*18), rs747272625 were detected in exons 5 and 16, respectively. Both variants cause frameshifts and generation of a premature stop-codon that probably leads to mRNA nonsense-mediated decay. Validation and segregation of ALMS1 variants were confirmed by Sanger sequencing. Conclusions Genetic testing makes it possible, even in childhood, to increase the number of correct diagnoses of patients who have ambiguous phenotypes caused by rare genetic variants. The development of high-throughput sequencing technologies offers an exceptionally valuable screening tool for clear genetic diagnoses and ensures early multidisciplinary management and treatment of the emerging symptoms.
Background Dihidropyrimidinase (DHP) deficiency is an inherited inborn error of pyrimidine metabolism with a variable clinical presentation and even asymptomatic subjects. Dihydropyrimidinase is encoded by theDPYSgene, thus pathogenic mutations in this gene can cause DHP deficiency. To date, several variations in theDPYSgene have been reported but only 23 of them have been confirmed to be pathogenic. Therefore, the biochemical, clinical and genetic aspects of this disease are still unclear. Case presentation Here, we report a 22-year-old woman with DHP deficiency. To identify the genetic cause of DHP deficiency in this patient, Whole Exome Sequencing (WES) was performed, which revealed a novel homozygote stop gain mutation (NM_001385: Exon 9, c.1501 A > T, p.K501X) in theDPYSgene. Sanger sequencing was carried out on proband and other family members in order to confirm the identified mutation. According to the homozygote genotype of the patient and heterozygote genotype of her parents, the autosomal recessive pattern of inheritance was confirmed. In addition, bioinformatics analysis of the identified variant using Mutation Taster and T-Coffee Multiple Sequence Alignment showed the pathogenicity of mutation. Moreover, mRNA expression level ofDPYSgene in the proband's liver biopsy showed about 6-fold reduction compared to control, which strongly suggested the pathogenicity of the identified mutation. Conclusions This study identified a novel pathogenic stop gain mutation inDPYSgene in a DHP deficient patient. Our findings can improve the knowledge about the genetic basis of the disease and also provide information for accurate genetic counseling for the families at risk of these types of disorders.
Background Investigations in genetics have provided valuable information about the correlation between gene variants and tendinopathy. Single Nucleotide Polymorphisms of COL5A1 gene are reported to be involved in Achilles tendinopathy, chronic degenerative tendon changes at the elbow, and other tendinopathies. The influence of Single Nucleotide Polymorphisms of COL5A1 was previously analyzed in rotator cuff disease with confounding results. Moreover, the rs12722 polymorphism in COL5A1 gene has been implicated in the aetiology of musculoskeletal soft tissue injuries in several association studies. This study aims to analyse the possible influence of rs12722 polymorphism in COL5A1 in the outcomes of rotator cuff repair. Methods Seventy-nine patients were included in the study. DNA was extracted from 1.2 ml of venous blood and genotyped for COL5A1 SNPs rs12722. Rotator cuff muscle strength and range of motion (ROM) in anterior elevation, external and internal rotation of the shoulder were evaluated. Results Patients presenting COL5A1 SNP rs12722 CC showed a ROM of passive external rotation statistically significantly higher compared to patients with CT genotype and TT genotype. Conclusions COL5A1 SNP rs12722 may influence the functional outcomes of RCRs, even though further studies are required to confirm these preliminary results.
Background: Maternal cytomegalovirus (CMV) infection and/or reactivation in pregnancy is associated with a myriad of adverse infant outcomes. However, the role of host genetic polymorphisms in modulating maternal CMV status is inconclusive. This study investigated the possible association of single nucleotide polymorphisms in toll like receptor (TLR) and cytokine genes with maternal plasma CMV DNA status in black Zimbabweans. Methods: In a cross-sectional study, 110 women in late gestation who included 36 CMV infected cases and 74 CMV uninfected, age and HIV status matched controls were enrolled. Twenty single nucleotide polymorphisms in 10 genes which code for proteins involved in immunity against CMV were genotyped using Iplex GOLD SNP genotyping protocol on the Agena MassARRAY® system. Statistical analyses were performed using Stata SE and the ‘Genetics’ and ‘SNPassoc’ packages of the statistical package R. Results: The TLR7 rs179008A>T (p<0.001) polymorphism was associated while the TLR9 rs352139T>C (p=0.049) polymorphism was on the borderline for association with CMV positive (CMV+) status. In contrast, the interleukin ( IL)-6 rs10499563T>C (p<0.001) and TLR2 rs1816702C>T (p=0.001) polymorphisms were associated with CMV negative (CMV-) status. Furthermore, allele frequencies of SNPs in TLR2, TLR4, TLR9, TLR7 , IL - 6 , IL-10 , IL-28B , IL-1A and interferon AR1 ( IFNAR1 ) genes are being reported here for the first time in a Zimbabwean population. The allele frequencies in the Zimbabwean population re generally comparable to other African populations but different when compared to European and Asian populations. Conclusions: Toll like receptor and interleukin genetic polymorphisms influence CMV status in late gestation among black Zimbabweans. This is attributable to possible modulation of immune responses to CMV reactivation in a population previously exposed to CMV infection.
Background Spontaneous coronary artery dissection (SCAD) is frequently reported as a disorder that primarily affects women without risk factors for cardiovascular disease. Although it has been recognized as one of the genetically mediated vascular disorders, the genetic pathogenesis of SCAD remains obscure to date. Case presentation In this report, we presented a rare case of pregnancy-associated SCAD in a young woman that occurred in multiple coronary arteries within a short period. The initial conservative management and then intravascular ultrasound-guided primary percutaneous coronary intervention (PCI) were adopted to achieve optimal results of revascularization in affected coronary arteries and avoid potential risks for PCI-associated complications. We further performed the whole-exome sequencing and Sanger sequencing and, for the first time, reported a novel heterozygous missense variant, c.4574 C > T (p.Arg1438Cys), in the NOTCH1 gene. This variant has never been documented in the medical literature and was predicted as being potentially damaging or disease-causing variant. Conclusions We described a rare case of recurrent SCAD in a young woman after baby delivery. The initial conservative management and PCI with multiple stent implantations were successfully implemented to achieve optimal results of revascularization in coronary arteries. We, for the first time, identified a novel missense variant in the NOTCH1 gene, which appears to be a potential predisposing factor for artery fragility.
Background Coagulation factor XIII (FXIII) plays an essential role in maintaining hemostasis by crosslinking fibrin. Deficiency in FXIII affects clot stability and increases the risk of severe bleeding. Congenital FXIII deficiency is a rare disease. Recently, we identified a Chinese family with FXIII deficiency and investigated the pathogenesis of congenital FXIII deficiency, contributing non-coding pathogenic variants. Methods We performed common tests, coding sequencing by targeted next-generation sequencing (NGS), whole-genome sequencing and splice-sites prediction algorithms. The pathogenesis was investigated via minigene and nonsense-mediated mRNA decay (NMD) by experiments in vitro. Results The proband is homozygote for a novel deep intronic c.799-12G > A mutation in the F13A1 gene. Through direct sequencing of the minigenes mRNA, we found 10 bases of intron 6 insert in the mRNA of mutant minigenes mRNA. The relative expression of EGFP-F13A1 was higher by suppression of NMD in vitro. Furthermore, we found the proband with enhanced thrombin generation (TG). Conclusion We reported a novel deep intronic c.799-12G > A mutation of F13A1 which produced a new acceptor site and frame shifting during translation introducing a premature termination codon. Our results support the premature termination codon triggered NMD. We need to pay attention to the position of potential alterable splicing sites while counselling and genetic test. The finding of enhanced TG indicated that we should be aware of the risk of thrombosis in patients with FXIII deficiency during replacement therapy.
Background Epigenetics could facilitate greater understanding of disparities in the emergence of childhood obesity. While blood is a common tissue used in human epigenetic studies, saliva is a promising tissue. Our prior findings in non-obese preschool-aged Hispanic children identified 17 CpG dinucleotides for which differential methylation in saliva at baseline was associated with maternal obesity status. The current study investigated to what extent baseline DNA methylation in salivary samples in these 3–5-year-old Hispanic children predicted the incidence of childhood obesity in a 3-year prospective cohort. Methods We examined a subsample ( n = 92) of Growing Right Onto Wellness (GROW) trial participants who were randomly selected at baseline, prior to randomization, based on maternal phenotype (obese or non-obese). Baseline saliva samples were collected using the Oragene DNA saliva kit. Objective data were collected on child height and weight at baseline and 36 months later. Methylation arrays were processed using standard protocol. Associations between child obesity at 36 months and baseline salivary methylation at the previously identified 17 CpG dinucleotides were evaluated using multivariable logistic regression models. Results Among the n = 75 children eligible for analysis, baseline methylation of Cg1307483 ( NRF 1) was significantly associated with emerging childhood obesity at 36-month follow-up (OR = 2.98, p = 0.04), after adjusting for child age, gender, child baseline BMI-Z, and adult baseline BMI. This translates to a model-estimated 48% chance of child obesity at 36-month follow-up for a child at the 75th percentile of NRF1 baseline methylation versus only a 30% chance of obesity for a similar child at the 25th percentile. Consistent with other studies, a higher baseline child BMI-Z during the preschool period was associated with the emergence of obesity 3 years later, but baseline methylation of NRF1 was associated with later obesity even after adjusting for child baseline BMI-Z. Conclusions Saliva offers a non-invasive means of DNA collection and epigenetic analysis. Our proof of principle study provides sound empirical evidence supporting DNA methylation in salivary tissue as a potential predictor of subsequent childhood obesity for Hispanic children. NFR1 could be a target for further exploration of obesity in this population.
The DENND1A gene is one of the most important sites associated with polycystic ovary syndrome (PCOS). We attempted to analyze the correlation between five single nucleotide polymorphisms (SNPs) in the DENND1A gene and the development of PCOS. A total of 346 PCOS patients and 225 normal ovulatory women were involved in the case-control study. Clinical variables and hormones were recorded. According to the Hap Map database, five tagging SNPs (rs2479106, rs2768819, rs2670139, rs2536951 and rs2479102) in the DENND1A gene were identified. The TaqMan probe and the PCR–RFLP (restriction fragment length polymorphism) methods were used for revealing these genotypes. TaqMan Genotype Software was used to analyze the alleles of the five SNPs. Linkage disequilibrium and the gene frequency analysis demonstrated that the CCGGG haplotype might increase the risk of PCOS (P = 0.038, OR = 1.89, 95% CI = 1.027–3.481). Significant differences were found in genotypic and allelic distributions at the rs2536951 and rs2479102 loci between PCOS women and controls (P < 0.001). The LH levels and LH/FSH ratios were higher in PCOS patients than in the control group. A detailed analysis revealed that for the rs2479106 locus, these two values were significantly different in the control subjects who had AA, AG and GG genotypes (P = 0.013 and P = 0.007, respectively), and for the rs2468819 locus, these two values were significantly different among the PCOS patients with AA, AG and GG genotypes (P = 0.013 and 0.002, respectively). The tagging SNPs rs2479106 and rs2468819 in the DENND1A gene are associated with PCOS in the Chinese population, whereas rs2670139, rs2536951 and rs2479102 are not correlated with PCOS in the same population.
Background Hypertension is one of the risk factors for obesity-related cardiovascular diseases. We investigated whether genetic variations in serotonin 2A receptor ( HTR2A ) were associated with hypertension. Methods We carried out a cross-sectional study in cohorts A (Ansan-Ansung cohort, N = 6039) and B (Wonju-Pyengchang cohort, N = 7524). Several genetic variants in HTR2A including rs7330636, rs9590999, rs2183057, and rs4942595 were selected and genotyped. Results In hypertensive participants in cohort A, the baseline systolic blood pressure and body mass index were 141.80 ± 17.20 mg/dL and 24.48 ± 4.75 kg/m 2 , respectively, which were higher than in those without hypertension ( p < 0.001). rs4942595TC genotype was associated with hypertension in cohort A (OR = 0.739), after adjusting for variables. Subjects with rs4942578AA genotype had a decreased risk of hypertension after adjusting for clinical factor (OR = 0.735) in cohort B, and an elevated risk of hypertension in cohort A (OR = 1.562). The logistic regression analysis showed that participants with rs4941573TC genotype were 1.327 times more likely to have a higher blood pressure than those with TT genotype (95% CI 1.101–1.599) in cohort B. Whereas, the OR for developing hypertension in subjects with rs17069883CC genotype compared to those with AA genotype was 1.447 (95% CI 1.018–2.056; p for trend = 0.040) in cohort A. Conclusions HTR2A genetic variations were associated with hypertension risk in our study.
Background Intellectual disability (ID) constitutes the most common group of neurodevelopmental disorders. Exome sequencing has enabled the discovery of genetic mutations responsible for a wide range of ID disorders. Case presentation In this study, we reported on two male siblings, aged 4 and 2 years, with motor and mental developmental delays and mild dysmorphic facial features. To identify the genetic causes of these symptoms, we employed trio-whole exome sequencing for the proband. We found a novel hemizygous missense variant in the PAK3 gene (c.1112G > A, p.Cys371Tyr), which encodes the p21-activated kinase 3, in the proband, which inherited from mother. The younger brother also has the hemizygous variant, which was confirmed by Sanger sequencing. The variant is located in the kinase domain and was regarded as a likely pathogenic variant in this family. Conclusion We diagnosed two male siblings with developmental delays as having a PAK3 likely pathogenic variant. This finding expands the list of PAK3 gene mutations associated with neurodevelopmental disorders and provides further details on its clinical features.
Background Propionic acidemia (PA)(OMIM#606054) is an inborn error of branched-chain amino acid metabolism, caused by defects in the propionyl-CoA carboxylase (PCC) enzyme which encoded by thePCCAandPCCBgenes. Case presentation Here we report a Chinese neonate diagnosed with suspected PA based on the clinical symptoms, gas chromatography-mass spectrometry (GC/MS), and brain imaging tests. Targeted next-generation sequencing (NGS) was performed on the proband. We detected only one heterozygous recurrent nonsense variant (c.937C > T, p.Arg313Ter) in thePCCAgene. When we manually checked the binary alignment map (BAM) diagram ofPCCAgene, we found a heterozygous deletion chr13:100915039-100915132delinsAA (c.773_819 + 47delinsAA) (GRCh37.p13) inside the exon 10 in thePCCAgene. The results were validated by Sanger sequencing and qPCR method in the family: the variant (c.937C > T, p.Arg313Ter) was in the maternal allele, and the delins was in the paternal allele. When the mother was pregnant again, prenatal diagnosis was carried out through amniocentesis at 18 weeks gestation, the fetus carried neither of the two mutations. After birth, newborn screening was undertaken, the result was negative. Conclusions We identified a recurrent c.937C > T and a novel c.773_819 + 47delinsAA mutations in thePCCAgene, which may be the genetic cause of the phenotype of this patient. Our findings expanded the spectrum of causative genotype-phenotype of thePCCAgene. For the cases, the NGS results revealed only a heterozygous mutation in autosomal recessive disease when the gene is associated with phenotypes, it is necessary to manually check the BAM diagram to improve the detection rate. Targeted NGS is an effective technique to detect the various genetic lesions responsible for the PA in one step. Genetic testing is essential for genetic counselling and prenatal diagnosis in the family to avoid birth defects.
Background MYH14 gene mutations have been suggested to be associated with nonsyndromic/syndromic sensorineural hearing loss. It has been reported that mutations in MYH14 can result in autosomal dominant nonsyndromic deafness-4A (DFNA4). Methods In this study, we examined a four-generation Han Chinese family with nonsyndromic hearing loss. Targeted next-generation sequencing of deafness genes was employed to identify the pathogenic variant. Sanger sequencing and PCR-RFLP analysis were performed in affected members of this family and 200 normal controls to further confirm the mutation. Results Four members of this family were diagnosed as nonsyndromic bilateral sensorineural hearing loss with postlingual onset and progressive impairment. A novel missense variant, c.5417C > A (p.A1806D), in MYH14 in the tail domain of NMH II C was successfully identified as the pathogenic cause in three affected individuals. The family member II-5 was suggested to have noise-induced deafness. Conclusion In this study, a novel missense mutation, c.5417C > A (p.A1806D), in MYH14 that led to postlingual nonsyndromic autosomal dominant SNHL were identified. The findings broadened the phenotype spectrum of MYH14 and highlighted the combined application of gene capture and Sanger sequencing is an efficient approach to screen pathogenic variants associated with genetic diseases.
Background More than 95% of individuals with RTT have mutations in methyl-CpG-binding protein 2 (MECP2), whose protein product modulates gene transcription. The disorder is caused by mutations in a single gene and the disease severity in affected individuals can be quite variable. Specific MECP2 mutations may lead phenotypic variability and different degrees of disease severity. It is known that low bone mass is a frequent and early complication of subjects with Rett syndrome. As a consequence of the low bone mass Rett girls are at an increased risk of fragility fractures. This study aimed to investigate if specific MECP2 mutations may affects the degree of involvement of the bone status in Rett subjects. Methods In 232 women with Rett syndrome (mean age 13.8 ± 8.3 yrs) we measured bone mineral density at whole body and at femur (BMD-FN and BMD-TH) by using a DXA machine (Hologic QDR 4500). QUS parameters were assessed at phalanxes by Bone Profiler-IGEA (amplitude dependent speed of sound: AD-SoS and bone transmission time: BTT). Moreover, ambulation capacity (independent or assisted), fracture history and presence of scoliosis were assessed. We divided the subjects with the most common point mutations in two group based on genotype-phenotype severity; in particular, there has been consensus in recognising that the mutations R106T, R168X, R255X, R270X are considered more severe. Results As aspect, BMD-WB, BMD-FN and BMD-TH were lower in subjects with Rett syndrome that present the most severe mutations with respect to subjects with Rett syndrome with less severe mutations, but the difference was statistically significant only for BMD-FN and BMD-TH ( p < 0.05). Also both AD-SoS and BTT values were lower in subjects that present the most severe mutations with respect to less severe mutations but the difference was not statistically significant. Moreover, subjects with Rett syndrome with more severe mutations present a higher prevalence of scoliosis ( p < 0.05) and of inability to walk ( p < 0.05). Conclusion This study confirms that MECP2 mutation type is a strong predictor of disease severity in subjects with Rett syndrome. In particular, the subjects with more severe mutation present a greater deterioration of bone status, and a higher prevalence of scoliosis and inability to walk.
Background: Loss of function mutations in the spermine synthase gene (SMS) have been reported to cause a rare X-linked intellectual disability known as Snyder-Robinson Syndrome (SRS). Besides intellectual disability, SRS is also characterized by reduced bone density, osteoporosis and facial dysmorphism. SRS phenotypes evolve with age from childhood to adulthood. Methods: Whole exome sequencing was performed to know the causative gene/pathogenic variant. Later we confirmed the pathogenic variant through Sanger sequencing. Furthermore, we also performed the mutational analysis through HOPE SERVER and SWISS-MODEL. Also, radiographs were also obtained for affected individual to confirm the disease features. Results: In this article, we report the first Pakistani family consisting of three patients with SRS and a novel missense pathogenic variant in the SMS gene (c.905 C>T p.(Ser302Leu)). In addition to the typical phenotypes, one patient presented with early-onset seizures. Clinical features, genetic and in-silico analysis linked the affected patients of the family with Snyder-Robinson and suggest that this novel mutation affects the spermine synthase activity Conclusion: A novel missense variant in the SMS, c.905C >T p. (Ser302Leu), causing Snyder- Robinson Syndrome (SRS) is reported in three members of Pakistani Family.
