Identification Of Novel Mutation Research Articles

Identification of novel mutations in TPK1 and SLC19A3 genes in families exhibiting thiamine metabolism dysfunction syndrome

Background and aimsThe occurrence of thiamine metabolism dysfunction syndrome (THMD), a rare autosomal recessive condition, may be linked to various mutations found in the TPK1 and SLC19A3 genes. The disease chiefly manifests through ataxia, muscle hypotonia, abrupt or subacute onset encephalopathy, and a decline in developmental milestones achieved during the early stages of infancy. We present findings from an investigation that involved two individuals from Iran, both of whom experienced seizures along with ataxia and hypotonia. The underlying genetic causes were found with the use of next-generation sequencing (NGS) technology, which has facilitated the detection of causal changes in a variety of genetic disorders. Material and methodsThe selection of cases for this study was based on the phenotypic and genetic information that was obtainable from the Center for Comprehensive Genetic Services. The genetic basis for the problems observed among the participants was determined through the application of whole-exome sequencing (WES). Subsequently, sanger sequencing was employed as a means of validating any identified variations suspected to be causative. ResultsThe first patient exhibited a homozygous mutation in the TPK1 gene, NM_022445.4:c.224 T > A:p.I75 N, resulting in the substitution of isoleucine for asparagine at position 75 (p.I75 N). In our investigation, patient 2 exhibited a homozygous variant, NM_025243.4:c.1385dupA:pY462X, within the SLC19A3 gene. ConclusionsCollectively, when presented with patients showcasing ataxia, encephalopathy, and basal ganglia necrosis, it is essential to account for thiamine deficiency in light of the potential advantages of prompt intervention. At times, it may be feasible to rectify this deficiency through the timely administration of thiamine dosages. Accordingly, based on the results of the current investigation, these variations may be useful for the diagnosis and management of patients with THMD.

Molecular analysis of mucopolysaccharidosis type I in Morocco: Identification of novel mutation

Molecular analysis of mucopolysaccharidosis type I in Morocco: Identification of novel mutation

Identification of Novel Mutations in the MMAA and MUT Genes among Methylmalonic Aciduria Families.

Methylmalonic aciduria is a rare inherited metabolic disorder with autosomal recessive inheritance pattern. There are still MMA patients without known mutations in the responsible genes. This study aimed to identify mutations in Iranian MMA families using autozygosity mapping and NGS. Multiplex PCR was performed on DNAs isolated from 12 unrelated MMA patients and their family members using 19 STR markers flanking MUT, MMAA, and MMAB genes, followed by Sanger sequencing. WES was carried out in the patients with no mutation. Haplotype analysis and Sanger sequencing revealed two novel, mutations, A252Vf*5 and G87R, within the MMAA and MUT genes, respectively. Three patients showed no mutations in either autozygosity mapping or NGS analysis. High-frequency mutations within exons 2 and 3 of MUT gene and exon 7 of MMAB gene are consistent with the global expected frequency of genetic variations among MMA patients.

Identification of novel mutations in patients with Diamond-Blackfan anemia and literature review of RPS10 and RPS26 mutations.

Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome characterized by erythroid aplasia, physical malformation, and cancer predisposition. Twenty ribosomal protein genes and three non-ribosomal protein genes have been identified associated with DBA. To investigate the presence of novel mutations and gain a deeper understanding of the molecular mechanisms of disease, targeted next-generation sequencing was performed in 12 patients with clinically suspected DBA. Literatures were retrieved with complete clinical information published in English by November 2022. The clinical features, treatment, and RPS10/RPS26 mutations were analyzed. Among the 12 patients, 11 mutations were identified and 5 of them were novel (RPS19, p.W52S; RPS10, p.P106Qfs*11; RPS26, p.R28*; RPL5, p.R35*; RPL11, p.T44Lfs*40). Including 2 patients in this study, 13 patients with RPS10 mutations and 38 patients with RPS26 mutations were reported from 4 and 6 countries, respectively. The incidences of physical malformation in patients with RPS10 and RPS26 mutations (22% and 36%, respectively) were lower than the overall incidence in DBA patients (~50%). Patients with RPS26 mutations had a worse response rate of steroid therapy than RPS10 (47% vs. 87.5%), but preferred RBC transfusions (67% vs. 44%, p = 0.0253). Our findings add to the DBA pathogenic variant database and demonstrate the clinical presentations of the DBA patients with RPS10/RPS26 mutations. It shows that next-generation sequencing is a powerful tool for the diagnosis of genetic diseases such as DBA.

Identification of Novel Mutations in the Tyrosinase Gene (TYR) Associated with Pigmentation in Chinese Giant Salamanders (Andrias davidianus)

The Chinese giant salamander (Andrias davidianus), an endangered amphibian species endemic to China, has been previously evaluated with regards to its phyletic evolution, zooecology, and ethology, but molecular mechanisms underlying its skin pigmentation remain unknown. Herein, a skin transcriptome database of different colored salamanders was established using RNA-seq, and a total of 47,911 unigenes were functionally annotated. Among these unigenes, a total of 1252 differentially expressed genes (DEGs) were annotated in the seven public databases, and six DEGs were validated by qPCR between five different skin colors and eight tissues. The results showed that TYR, TYRP1, and ASIP were significantly differentially expressed between different body colors, while TYR, TYRP1, and DCT were highly expressed in skin tissue. The full-length complementary DNA of TYR was cloned and analyzed between normal and yellow phenotypes. Three nucleotide sequence deletion sites were identified in the coding region of TYR, leading to premature termination of transcription and translation in yellow individuals. Our study provides useful data for the further study of the molecular mechanisms of melanin formation, and a valuable reference for the breeding of specific skin colors in other salamanders.

Deciphering the mechanism of resistance by novel double mutations in pncA in Mycobacterium tuberculosis using protein structural graphs (PSG) and structural bioinformatic approaches

The evolution of MDR and XDR-TB is a growing concern and public health safety threat around the world. Gene mutations are the prime cause of drug resistance in tuberculosis, however the reports of double mutations further aggravated the situation. Despite the large-scale genomic sequencing and identification of novel mutations, structure investigation of the protein is still required to structurally and functionally characterize these novel mutations to design novel drugs for improved clinical outcome. Hence, we used structural bioinformatics approaches i.e. molecular modeling, residues communication and molecular simulation to understand the impact of novel double S59Y-L85P, D86G-V180F and S104G-V130 M mutation on the structure, function of pncA encoded Pyrazinamidase (PZase) and resistance of Pyrazinamide (PZA). Our results revealed that these mutations alter the binding paradigm and destabilize the protein to release the drug. Protein commination network (PCN) revealed variations in the hub residues and sub-networks which consequently alter the internal communication and signaling. The region 1–75 demonstrated higher flexibility in the mutant structures and minimal by the wild type which destabilize of the internally arranged beta-sheets which consequently reduce the binding of PZA and potentially Fe ion in the mutants. Hydrogen bonding analysis further validated the findings. The total binding free energy (ΔG) for each complex i.e. wild type −7.46 kcal/mol, S59Y-L85P −5.21 kcal/mol, S104G-V130 M −5.33 kcal/mol while for the D86G-V180F mutant the TBE was calculated to be −6.26 kcal/mol. This further confirms that these mutations reduce the binding energy of PZA for PZase and causes resistance in the effective therapy for TB. The trajectories motion was also observed to be affected by these mutations. In conclusion, these mutations use destabilizing approach to reduce the binding of PZA and causes resistance. These features can be used to design novel structure-based drugs against Tuberculosis.

Identification of novel mutations in β-thalassemia patients in Maysan Governorate, Iraq.

In homozygous β-thalassemia, the primary genetic modifiers affecting the clinical severity of β-thalassemia are genetic variants and the ability to reduce globin chain imbalance, thus resulting in a milder form of thalassemia. However, there are few reports on the molecular genetics of β-thalassemia in Iraq. We performed PCR and DNA sequencing on 40 Iraqi patients who were clinically suspected of having β-thalassemia. The first genetic sequencing study was conducted in Maysan Governate, Iraq, using patients from various locations to identify novel mutations. There were five novel mutations: 294.T>C 12% (city center and Almajar district), 205. C>T 25% (city center, Alsalam, and Almashrah districts), 289.G>A 38% (Almaymuna and Gleat Salih districts), 49.T>C 32% (city center), and 624.C>A 32% (city center). These mutations were identified among β-thalassemia patients by two regions of HBB gene 696bp and 861bp. The discovery of new genetic variants helps predict the severity of β-thalassemia disease. There are relatively few studies in molecular genetics of β-thalassemia in Iraq, and the new mutations reported here will provide valuable data for the prevention and control of β-thalassemia in Maysan Governate, Iraq. The results can lead to new genetic sequencing investigations for other Iraqi regions.

The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis.

Citrin deficiency (CD), a disorder caused by mutations in the SLC25A13 gene, may result in neonatal intrahepatic cholestasis. This study was purposely to explore the mutation spectrum of SLC25A13 gene in Vietnamese CD patients. The 292 unrelated CD patients were first screened for four high-frequency mutations by PCR/PCR-RFLP. Then, Sanger sequencing was performed directly for heterozygous or undetected patients. Novel mutations identified would need to be confirmed by their parents. 12 pathogenic SLC25A13 mutations were identified in all probands, including three deletions c.851_854del (p.R284Rfs*3), c.70-63_133del (p.Y24_72Ifs*10), and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]), two splice-site mutations (IVS6+5G>A and IVS11+1G>A), one nonsense mutations c.1399C>T (p.R467*), one duplication mutation c.1638_1660dup (p.A554fs*570), one insertion IVSl6ins3kb (p.A584fs*585), and four missense mutation c.2T>C (p.M1T), c.1231G>A (p.V411M), c.1763G>A (p.R588Q), and c.135G>C (p.L45F). Among them, c.851_854del (mut I) was the most identified mutant allele (91.78%) with a total of 247 homozygous and 42 heterozygous genotypes of carriers. Interestingly, two novel mutations were identified: c.70-63_133del (p.Y24_72Ifs*10) and c.[1956C>A;1962del] (p.[N652K;F654Lfs*45]). The SLC25A13 mutation spectrum related to intrahepatic cholestasis infants in Vietnam revealed a quite similar pattern to Asian countries' reports. This finding supports the use of targeted SLC25A13 mutation for CD screening in Vietnam and contributed to the SLC25A13 mutation spectra worldwide. It also helps emphasize the role of DNA analysis in treatment, genetic counseling, and prenatal diagnosis.

Identification of Novel Mutations Associated with Bedaquiline Resistance in Mycobacterium Marinum

Objective: Because infections caused by nontuberculous mycobacteria (NTM) are rapidly increasing globally, a need exists for developing novel antibiotics and discovering the mechanism of resistance. This research was aimed at understanding the mechanism of bedaquiline resistance in the model NTM species Mycobacterium marinum (M. marinum). Methods: The Mycobacterium marinum M strain was subjected to mutant selection with different concentrations of BDQ. After three rounds of evolution, 58 BDQ-resistant mutants were isolated and subjected to WGS. The results were confirmed through PCR and Sanger sequencing. Results: We identified seven genetic mutations among these mutants. The highest drug resistance (6–10× MIC) was associated with a mutation in AtpB, the primary biochemical target of BDQ in Mtb. Numerous mutations and insertions mapped to the gene MMAR_1007(46/58), which encodes the homolog of Rv0678 (MmpR) in Mtb. More than 93% of mutants (54/58) contained a single mutation (G563A) in MMAR_4049, which encodes the integral membrane protein YrbE3A-1. Conclusion: Both target-based and efflux-based actions contribute to BDQ resistance in M. marinum. Our findings may aid in developing novel potent anti-NTM (BDQ-based) drug regimens and diagnostic assays for the detection of BDQ-resistant M. marinum.

Identification of Novel Mutations in Children with Hereditary Spherocytosis by Targeted Exome Sequencing: A Single Center Experience

Aim: Hereditary spherocytosis (HS) is a prevalent cause of congenital hemolytic anemia in Northern
 Europeans. It is characterized by spherocytes resulting from defects in the erythrocyte structural
 membrane proteins spectrin and ankyrin. To date, more than five candidate genes, including ANK1,
 SPTB, SPTA1, SLC4A1, and EPB42 have been linked to HS. Here, we aim to investigate the presence
 of novel as well as known mutations in eight Turkish children with clinically suspected HS.
 Material and Methods: We presented the clinical features of the patients and identified the causative
 gene variants using targeted exome sequencing. Eight children who were clinically suspected of having
 HS enrolled in this study. A family and medical history, clinical examination, relevant laboratory test
 results, osmotic fragility test (OFT), and genetic results were evaluated.
 Results: Six causative variants, including three ANK1 variants, two SPTB variants and one SLC4A1
 variant were detected. All these mutations were novel variants. ANK1 and SPTB are the most common
 mutant genes in children with HS.
 Conclusion: This study expanded the mutation spectrum of ANK1, SPTB and SLC4A1. This is the first
 study to determine the genetic and clinical characteristics of children with HS in Turkey.

Whole Genome Sequencing for Detection of Structural Variants in Patients with Retinitis Pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited retinal diseases characterized by the progressive degeneration of rod then cone photoreceptors. Most of the known mutations that cause RP reside in the protein-coding portions of DNA; however, a growing number of pathogenic mutations have been identified within the non-coding portions. This chapter details a brief method for the detection of structural variants throughout the genome for the identification of novel mutations and to ultimately provide patients with a precise molecular diagnosis.

I.15 Neuromuscular Disorders with Founder Effects in French Canada: why, where and how they contribute to the NMD field

The French settlers of North America during the French Regime (1604-1763) were few and sparse on a vast continent. Understanding the early pioneer period and the subsequent growth of their descendants is key to explain the higher regional prevalence of certain Neuromuscular Disorders (NMD) in Canada. We will review the genetic impact of the various population bottlenecks that shaped the French Canadian gene pool. We will present a history of the identification of NMD with Canadian regional founder effects to emphasize how these large cohorts played a role in gene identification. Using oculopharyngeal muscular dystrophy (OPMD) as a prototype of FC founder diseases, we will chart how large FC cohorts disproportionally continue to contribute to our knowledge of these conditions. Myotonic muscular dystrophy type 1 (DM1) and Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) will also be discussed to underline the value of large cohort characterizations for granular clinical phenotyping and natural history studies. Lastly, we will discuss the contribution of rare recessive mutations and dominant mutations with variable prevalence to the identification of novel mutations relying on the mixed European and First Nation backgrounds of the French Canadian population.

Genetic and Functional Identifying of Novel STAT1 Loss-of-Function Mutations in Patients with Diverse Clinical Phenotypes.

Mutations in signal transducer and activator of transcription 1 (STAT1) cause a broad spectrum of disease phenotypes. Heterozygous STAT1 loss-of-function (LOF) mutations cause Mendelian susceptibility to mycobacterial diseases (MSMD) infection, which is attributable to impaired IFN-γ signaling. The identification of novel mutations may extend the phenotypes associated with autosomal dominant (AD) STAT1 deficiency. Five patients with heterozygous STAT1 variations were recruited and their clinical and immunologic phenotypes were analyzed, with particular reference to JAK-STAT1 signaling pathways. Four, heterozygous STAT1 deficiency mutations were identified, three of which were novel mutations. Two of the mutations were previously unreported mRNA splicing mutations in AD STAT1-deficient patients. Patients with heterozygous STAT1 deficiency suffered not only mycobacterial infection, but also intracellular non-mycobacterial bacterial infection and congenital multiple malformations. AD-LOF mutation impaired IFN-γ-mediated STAT1 phosphorylation, gamma-activated sequence (GAS), and IFN-stimulated response element (ISRE) transcription activity and IFN-induced gene expression to different extents, which might account for the diverse clinical manifestations observed in these patients. The infectious disease susceptibility and phenotypic spectrum of patients with AD STAT1-LOF are broader than simply MSMD. The susceptibility to infections and immunological deficiency phenotypes, observed in AD-LOF patients, confirms the importance of STAT1 in host-pathogen interaction and immunity. However, variability in the nature and extent of these phenotypes suggests that functional analysis is required to identify accurately novel, heterozygous STAT1 mutations, associated with pathogenicity. Aberrant splice of STAT1 RNA could result in AD-LOF for STAT1 signaling which need more cases for confirmation.

Hereditary Systemic Autoinflammatory Diseases: Therapeutic Stratification.

Hereditary systemic autoinflammatory diseases (SAIDs) are rare, often severe conditions characterised by mutations in the key regulators of innate immune responses. Dramatic advances in the molecular genetics and next-generation sequencing in the past decade enabled identification of novel mutations that play a pivotal role in the mechanistic pathways of inflammation. Although genetic testing may not always provide straightforward guidance in diagnosis and clinical decision making, through translational research, it sheds light into molecular immunopathogenesis, particularly in IL-1 inflammasome and cytokine signalling pathways. These remarkable insights provided a better understanding of autoinflammatory conditions and their association with the innate and adaptive immune systems, as well as leading to development of cytokine-targetted biologic treatments. Use of targetted therapeutics not only helps control disease flares, reduce acute-phase responses and prevent devastating complications such as amyloidosis, but also improves health-related quality of lives and support patients to pursue almost a normal life. Herein, we discuss the commonest monogenic SAIDs, describe their immunopathology, and summarise the approaches in the management and targetted treatment of these conditions, including presentation of novel data based on a cohort of children with these rare diseases from a single quaternary referral centre in London.

Novel biallelic USH2A variants in a patient with usher syndrome type IIA- a case report

BackgroundUsher Syndrome is the commonest cause of inherited blindness and deafness. The condition is clinically and genetically heterogeneous, with no current treatment. We report a case carrying novel biallelic variants in USH2A causing progressive early adolescent onset visual and hearing impairment consistent with Usher Syndrome Type IIA.Case presentationOur patient presented at age 13 with progressive visual field loss and hearing loss, associated with early onset of cataract in her 40s requiring lens extraction. Now 52 years old, latest best corrected visual acuity (BCVA) stands at Logmar Right Eye (RE) 0.8 and Left Eye (LE) 0.2, with significantly constricted visual fields bilaterally. She was registered partially sighted age 46. Clinical and molecular genetic assessment of the proband was consistent with a diagnosis of Usher Syndrome Type IIA. Genetic testing identified two novel USH2A variants, resulting in the premature termination codon p.Leu30Ter and a missense mutation p.Cys3251Tyr. Segregation analysis confirmed that these variants were biallelic in the affected case. Comprehensive in silico analysis confirmed that these mutations are the probable cause of Usher Syndrome Type IIA in this individual.ConclusionsThe identification of novel mutations in USH2A increases the spectrum of genetic variations that lead to Usher Syndrome, aiding genetic diagnosis, assessment of patient prognosis, and emphasising the importance of genetic testing to identify new mutations in patients with undiagnosed progressive visual loss.

Identification of Novel Mutations in Chinese Infants With Citrullinemia.

Citrullinemia is a rare autosomal recessive disorder characterized by elevated concentrations of citrulline in the blood resulting from malfunction of the urea cycle. It is categorized into two types, types I and II, which are caused by argininosuccinate synthase 1 (ASS1), and citrin (SLC25A13) gene mutations, respectively. In this study, we performed genetic analysis on nine Chinese infants with citrullinemia using next-generation sequencing, which identified a novel mutation (p.Leu313Met) and a rare mutation (p.Thr323Ile, rs1250895424) of ASS1. We also found a novel splicing mutation of SLC25A13: c.1311 + 4_+7del. Functional analysis of the ASS1 missense mutations showed that both significantly impaired the enzyme activity of ASS1, with the p. Thr323Ile mutation clearly affecting the interaction between ASS1 and protein arginine methyltransferase 7 (PRMT7). These findings expand the mutational spectrum of ASS1 and SLC25A13, and further our understanding of the molecular genetic mechanism of citrullinemia in the Chinese population.

Emergence of amoxicillin resistance and identification of novel mutations of the pbp1A gene in Helicobacter pylori in Vietnam

BackgroundAmoxicillin-resistant Helicobacter pylori (H. pylori) strains seem to have increased over time in Vietnam. This threatens the effectiveness of H. pylori eradication therapies with this antibiotic. This study aimed to investigate the prevalence of primary resistance of H. pylori to amoxicillin and to assess its association with pbp1A point mutations in Vietnamese patients.Materials and methodsNaive patients who presented with dyspepsia undergoing upper gastrointestinal endoscopy were recruited. Rapid urease tests and PCR assays were used to diagnose H. pylori infection. Amoxicillin susceptibility was examined by E-tests. Molecular detection of the mutant pbp1A gene conferring amoxicillin resistance was carried out by real-time PCR followed by direct sequencing of the PCR products. Phylogenetic analyses were performed using the Tamura-Nei genetic distance model and the neighbor-joining tree building method.ResultsThere were 308 patients (46.1% men and 53.9% women, p = 0.190) with H. pylori infection. The mean age of the patients was 40.5 ± 11.4 years, ranging from 18 to 74 years old. The E-test was used to determine the susceptibility to amoxicillin (minimum inhibitory concentration (MIC) ≤ 0.125 μg/ml) in 101 isolates, among which the rate of primarily resistant strains to amoxicillin was 25.7%. Then, 270 sequences of pbp1A gene fragments were analysed. There were 77 amino acid substitution positions investigated, spanning amino acids 310–596, with the proportion varying from 0.4 to 100%. Seven amino acid changes were significantly different between amoxicillin-sensitive (AmoxS) and amoxicillin-resistant (AmoxR) samples, including Phe366 to Leu (p < 0.001), Ser414 to Arg (p < 0.001), Glu/Asn464–465 (p = 0.009), Val469 to Met (p = 0.021), Phe473 to Val (p < 0.001), Asp479 to Glu (p = 0.044), and Ser/Ala/Gly595–596 (p = 0.001). Phylogenetic analyses suggested that other molecular mechanisms might contribute to amoxicillin resistance in H. pylori in addition to the alterations in PBP1A.ConclusionsWe reported the emergence of amoxicillin-resistant Helicobacter pylori strains in Vietnam and new mutations statistically associated with this antimicrobial resistance. Additional studies are necessary to identify the mechanisms contributing to this resistance in Vietnam.

Identification of novel mutations by targeted next-generation sequencing in Moroccan families clinically diagnosed with a neuromuscular disorder

The identification of underlying genes of genetic conditions has expanded greatly in the past decades, which has broadened the field of genes responsible for inherited neuromuscular diseases. We aimed to investigate mutations associated with neuromuscular disorders phenotypes in 2 Moroccan families. Next-generation sequencing combined with Sanger sequencing could assist with understanding the hereditary variety and underlying disease mechanisms in these disorders. Two novel homozygous mutations were described in this study. The SIL1 mutation is the first identified in the Moroccan population, the mutation was identified as the main cause of Marinesco-Sjogren syndrome in one patient. While the second mutation identified in the fatty acid 2-hydroxylase gene (FA2H) was associated with the Spastic paraplegia 35 in another patient, both transmitted in an autosomal recessive pattern. These conditions are extremely rare in the North African population and may be underdiagnosed due to overlapping clinical characteristics and heterogeneity of these diseases. We have reported in this studymutations associated with the diseases found in the patients. In addition, we have narrowed the phenotypic spectrum, as well as the diagnostic orientation of patients with neuromuscular disorders, who might have very similar symptoms to other disease groups.Keywords: Neuromuscular Disorders; Next-Generation Sequencing; Hereditary Spastic Paraplegia Type 35; North Africa; Marinesco-Sjogren syndrome.

Identification of novel mutations among Iranian NPC1 patients: a bioinformatics approach to predict pathogenic mutations

BackgroundNiemann-Pick disease type C (NPC) is a rare lysosomal neurovisceral storage disease caused by mutations in the NPC 1 (95%) or NPC2 (5%) genes. The products of NPC1 and NPC2 genes play considerable roles in glycolipid and cholesterol trafficking, which could consequently lead to NPC disease with variable phenotypes displaying a broad spectrum of symptoms.MaterialsIn the present study 35 Iranian NPC unrelated patients were enrolled. These patients were first analysed by the Filipin Staining test of cholesterol deposits in cells for NPC diagnostics. Genomic DNA was extracted from the samples of peripheral blood leukocytes in EDTA following the manufacturer's protocol. All exon–intron boundaries and coding exons of the NPC1gene were amplified by polymerase chain reaction (PCR) using appropriate sets of primers. Thereafter, the products of PCR were sequenced and analysed using the NCBI database (https://blast.ncbi.nlm.nih.gov/Blast.cgi). The variants were reviewed by some databases including the Human Gene Mutation Database (HGMD) (http://www.hgmd.cf.ac.uk/ac/index.php) and ClinVar (https://www.ncbi.nlm.nih.gov/clinvar (. Moreover, all the variants were manually classified in terms of the American College of Medical Genetics and Genomics (ACMG) guideline.ResultsThe sequence analysis revealed 20 different variations, 10 of which are new, including one nonsense mutation (c.406C > T); three small deletions, (c.3126delC, c.2920_2923delCCTG, and c.2037delG); and six likely pathogenic missense mutations, (c.542C > A, c.1970G > A, c.1993C > G, c.2821 T > C, c.2872C > G, and c.3632 T > A). Finally, the pathogenicity of these new variants was determined using the ACMG guidelines.ConclusionThe present study aimed to facilitate the prenatal diagnosis of NPC patients in the future. In this regard, we identified 10 novel mutations, and verified that the majority of them occurred in six NPC1 exons (5, 8, 9, 13, 19, and 21), that should be considered with a high priority for Iranian patients' cost-effective evaluation.

Truncating mutation in TANC2 in a Chinese boy associated with Lennox-Gastaut syndrome: a case report

BackgroundLennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy that can be caused by brain malformations or genetic mutations. Recently, genome-wide association studies have led to the identification of novel mutations associated with LGS. The TANC2 gene, encodes a synaptic scaffolding protein that interacts with other proteins at the postsynaptic density to regulate dendritic spines and excitatory synapse formation. The TANC2 gene mutations were reported in neurodevelopmental disorders and epilepsy but not in LGS ever.Case presentationHere we describe the case of a boy with LGS who presented with multiple seizure patterns, such as myoclonic, atonic, atypical absence, generalized tonic-clonic, focal seizures, and notable cognitive and motor regression. The seizures were refractory to many antiepileptic drugs. He got seizure-free with ketogenic diet combined with antiepileptic drugs. A de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene was identified by the whole-exome sequencing and confirmed by Sanger sequencing.ConclusionWe described the first Chinese case with LGS associated to a de novo nonsense mutation c.4321C > T(p.Gln1441Ter) in TANC2 gene, which would expand the clinical spectrum related to TANC2 mutations and contribute to better understanding of genotype-phenotype relationship to guide precision medicine.