Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB

Mutations in the SQSTM1 gene have been reported to be associated with amyotrophic lateral sclerosis (ALS). We sought to determine the frequency of these mutations in a UK familial ALS (FALS) cohort. Sequences of all eight exons of the SQSTM1 gene were analysed in index cases from 61 different FALS kindred lacking known FALS mutations. Six exonic variants c.463G>A, p.(Glu155Lys), c.822G>C, p.(Glu274Asp), c.888G>T, p.(=), c.954C>T, p.(=), c.1038G>A, p.(=) and c.1175C>T, p.(Pro392Leu) were identified in five FALS index cases, three of which were non-synonymous and three were synonymous. One index case harboured three variants (c.822G>C, c.888G>T and c.954C>T), and a second index case harboured two variants (c.822G>C and c.954C>T). Only the p.(Pro392Leu) and p.(Glu155Lys) mutations were predicted to be pathogenic. In one p.(Pro392Leu) kindred, the carrier developed both ALS and Paget''s disease of bone (PDB), and, in the p.(Glu155Lys) kindred, the father of the proband developed PDB. All p.(Pro392Leu) carriers were heterozygous for a previously reported founder haplotype for PDB, where this mutation has an established causal effect. The frequency of the p.(Pro392Leu) mutation in this UK FALS cohort was 2.3% and 0.97% overall including three previously screened FALS cohorts. Our results confirm the presence of the p.(Pro392Leu) SQSTM1 mutation in FALS. This mutation is the most common SQSTM1 mutation found in ALS to date, and a likely pathogenicity is supported by having an established causal role in PDB. The occurrence of the same mutation in ALS and PDB is indicative of a common pathogenic pathway that converges on protein homeostasis.     

Delineation of PIGV mutation spectrum and associated phenotypes in hyperphosphatasia with mental retardation syndrome

Three different genes of the glycosylphosphatidylinositol anchor synthesis pathway, PIGV, PIGO, and PGAP2, have recently been implicated in hyperphosphatasia-mental retardation syndrome (HPMRS), also known as Mabry syndrome, a rare autosomal recessive form of intellectual disability. The aim of this study was to delineate the PIGV mutation spectrum as well as the associated phenotypic spectrum in a cohort of 16 individuals diagnosed with HPMRS on the basis of intellectual disability and elevated serum alkaline phosphate as minimal diagnostic criteria. All PIGV exons and intronic boundaries were sequenced in 16 individuals. Biallelic PIGV mutations were identified in 8 of 16 unrelated families with HPMRS. The most frequent mutation detected in about 80% of affected families including the cases reported here is the c.1022C>A PIGV mutation, which was found in both the homozygous as well as the heterozygous state. Four further mutations found in this study (c. 176T>G, c.53G>A, c.905T>C, and c.1405C>T) are novel. Our findings in the largest reported cohort to date significantly extend the range of reported manifestations associated with PIGV mutations and demonstrate that the severe end of the clinical spectrum presents as a multiple congenital malformation syndrome with a high frequency of Hirschsprung disease, vesicoureteral, and renal anomalies as well as anorectal malformations. PIGV mutations are the major cause of HPMRS, which displays a broad clinical variability regarding associated malformations and growth patterns. Severe developmental delays, particular facial anomalies, brachytelephalangy, and hyperphosphatasia are consistently found in PIGV-positive individuals.     

Interleukin-17A gene polymorphism is associated with susceptibility to gastric cancer

We conducted a study to investigate the role of three common SNPs in the IL-17A and IL-17F genes (rs2275913G>A, rs3748067C>T and rs763780T>C) in the development of gastric cancer, and their interaction with H.pylori infection. A total of 326 patients with gastric cancer and 326 control subjects were consecutively recruited between May 2012 and May 2014. Genotyping of IL-17A rs2275913G>A and rs3748067C>T and IL-17F rs763780T>C was performed in a 384-well plate format on the Sequenom MassARRAY platform. By logistic regression analysis, individuals carrying the GA and AA genotypes of IL-17 rs2275913G>A were significantly associated with an increased risk of gastric cancer when compared with GG genotype, and the adjusted Ors (95% CI) were 1.46 (1.03-2.06) for GA genotype and 2.57 (1.51-4.43) for AA genotype. We observed that the GA+AA genotype of rs2275913 was associated with an increased risk of gastric cancer among H.pylori infection subjects (OR=2.21, 95% CI=1.29-3.79). In conclusion, we found that there was a significant association between L-17A rs2275913G>A polymorphism and increased gastric cancer risk, especially in H.pylori infection subjects.     

Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene

Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene ({"type":"entrez-nucleotide","attrs":{"text":"NM_024513.4","term_id":"1519312749"}}NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.Subject terms: Visual system, Genetics research, Clinical genetics     

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

PurposeNeurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.MethodsA total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.ResultsNone of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.ConclusionWe demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.     

Functional characterization of BRCA1 gene variants by mini-gene splicing assay

Mutational screening of the breast cancer susceptibility gene BRCA1 leads to the identification of numerous pathogenic variants such as frameshift and nonsense variants, as well as large genomic rearrangements. The screening moreover identifies a large number of variants, for example, missense, silent, and intron variants, which are classified as variants of unknown clinical significance owing to the lack of causal evidence. Variants of unknown clinical significance can potentially have an impact on splicing and therefore functional examinations are warranted to classify whether these variants are pathogenic or benign. Here we validate a mini-gene splicing assay by comparing the results of 24 variants with previously published data from RT-PCR analysis on RNA from blood samples/lymphoblastoid cell lines. The analysis showed an overall concordance of 100%. In addition, we investigated 13 BRCA1 variants of unknown clinical significance or putative variants affecting splicing by in silico analysis and mini-gene splicing assay. Both the in silico analysis and mini-gene splicing assay classified six BRCA1 variants as pathogenic (c.80+1G>A, c.132C>T (p.=), c.213−1G>A, c.670+1delG, c.4185+1G>A, and c.5075−1G>C), whereas six BRCA1 variants were classified as neutral (c.-19-22_-19-21dupAT, c.302−15C>G, c.547+14delG, c.4676−20A>G, c.4987−21G>T, and c.5278−14C>G) and one BRCA1 variant remained unclassified (c.670+16G>A). In conclusion, our study emphasizes that in silico analysis and mini-gene splicing assays are important for the classification of variants, especially if no RNA is available from the patient. This knowledge is crucial for proper genetic counseling of patients and their family members.     

A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia

Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurologic and psychiatric symptoms. In families with autosomal dominant inheritance, three causative genes have been identified: SLC20A2, PDGFRB, and, very recently, PDGFB. Whereas in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrence are rare. We report the case of a 20-year-old woman who presented laryngeal dystonia revealing IBGC. Her healthy parents'' CT scans were both normal. We identified in the proband a new nonsense mutation in exon 4 of PDGFB, c.439C>T (p.Gln147*), which was absent from the parents'' DNA. This mutation may result in a loss-of-function of PDGF-B, which has been shown to cause IBGC in humans and to disrupt the blood-brain barrier in mice, resulting in brain calcification. The c.439C>T mutation is located between two previously reported nonsense mutations, c.433C>T (p.Gln145*) and c.445C>T (p.Arg149*), on a region that could be a hot spot for de novo mutations. We present the first full demonstration of the de novo occurrence of an IBGC-causative mutation in a sporadic case.     

Association of a common genetic variant in prostate stem cell antigen with cancer risk

Introduction

Polymorphisms in the prostate stem cell antigen (PSCA) gene have been hypothesized to increase the genetic susceptibility to cancers. The common sequence variation in PSCA rs2294008 (C>T) has been implicated in cancer risk. However, results of the relevant published studies were somewhat underpowered and controversial in general.

Material and methods

To evaluate the role of PSCA rs2294008 (C>T) genotype in global cancer, we performed a pooled analysis of all the available published studies involving 22,817 cancer patients and 27,753 control subjects.

Results

The results showed evidence that PSCA rs2294008 (C>T) was associated with increased total cancer risk in the overall comparisons. Stratified analysis by cancer type indicated that PSCA rs2294008 T is associated with increased risk of gastric cancer (OR = 1.24, 95% CI = 1.09–1.42, p_{heterogeneity} < 0.001, I² = 88.0%) and bladder cancer (OR = 1.07, 95% CI = 1.04–1.11, p_{heterogeneity} = 0.108, I² = 55.0%) by allelic contrast. Furthermore, in stratified analysis by histological types of gastric cancer, this PSCA variant showed significant associations with diffuse type (OR = 1.81, 95% CI = 1.16–2.81, p_{heterogeneity} < 0.001, I² = 88.9%) but not intestinal type (OR = 1.29, 95% CI = 0.95–1.74, p_{heterogeneity} < 0.001, I² = 85.2%) in a dominant genetic model. Similar results were found in Asian and European descendents and population-based studies.

Conclusions

In all, our meta-analysis suggests that PSCA rs2294008 (C>T) may play allele-specific roles in cancer development. Further prospective studies with larger numbers of participants worldwide should be performed in different kinds of cancer and other descendents in more detail.     

Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2

Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother–son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.Subject terms: Cancer genetics, Genetic testing     

Association Between PTPN22 Polymorphisms and IgE Responses to Staphylococcal Superantigens in Chronic Urticaria

Protein tyrosine phosphatase-22 (PTPN22) gene encodes lymphoid-specific tyrosine phosphatase (Lyp), an inhibitor of T cell activation. A polymorphism of the PTPN22 gene has been found to be associated with chronic urticaria (CU). We investigated the associations between PTPN22 gene polymorphisms and CU characteristics, including serum specific IgE antibodies response to toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxin A (SEA). CU patients (n=409) and normal healthy controls (n=388) were enrolled in the present study. Serum specific IgE to TSST-1 and SEA were measured by ImmunoCAP®. Five PTPN22 single nucleotide polymorphisms, -1123G>C, 1858C>T, 13145A>G, 14943C>T, and 20628A>G, were genotyped. There were no significant differences in genotype or haplotype frequencies of these polymorphisms between the 2 groups. CU patients carrying the GG genotype at 20628A>G (P=0.035) or haplotype 3 [GGG] (P=0.047) had a significantly higher prevalence of serum specific IgE to TSST-1 compared to non-carriers. Similarly, CT/TT genotype at 14943C>T had a significantly higher prevalence of serum specific IgE to SEA (P=0.045). The findings suggest that the PTPN22 gene polymorphisms at 20628A>G and 14943C>T may enhance serum specific IgE responses to TSST-1 and SEA, which may contribute to CU pathogenesis.     

A missense mutation in TMEM67 causes Meckel-Gruber syndrome type 3 (MKS3): a family from China

Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive condition characterized by renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. Genetic heterogeneity has been demonstrated at eleven loci, MKS1-11. Here, we present the clinical and molecular characteristics of a Chinese MKS3 family with occipital encephalocele and kidney enlargement. DNA sequencing of affected fetuses revealed a homozygous c.1645C>T substitution in exon 16 of TMEM67, leading to a p.R549C substitution in meckelin. The R549 residue is highly conserved across human, rat, mouse, zebrafish, chicken, wolf and platypus genomes. Hha I restriction analysis demonstrated that the c.1645C>T mutation was absent in 200 unrelated control chromosomes of Chinese background, supporting the hypothesis that it represents causative mutation, not rare polymorphism. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype understanding of MKS.     

Pathogenic variants in PIDD1 lead to an autosomal recessive neurodevelopmental disorder with pachygyria and psychiatric features

The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outlin`e the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.Subject terms: Clinical genetics, Medical research     

HTRA1 Variants and the Interaction with Smoking Confer the Genetic Susceptibility to Ischemic Stroke

High temperature requirement protein A1 (HtrA1) was identified as the causative gene of autosomal recessive arteriopathy and associated with lacunar ischemic stroke (IS) in European. This study aimed at evaluating the association of HTRA1 with IS and four tagging single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of 4,098 Chinese. The mRNA level of HTRA1 in 72 IS cases and 72 hypertension controls were measured and compared. In whole population, SNP rs2268350 (C>T) was significantly associated with IS incidence (P=0.034). Stratification analysis observed significant association of rs2268350 in male, smoking and drinking populations, rs2672587 (C>G) in smoking and nonsmoking populations and rs3793917 (C>G) in smoking, nonsmoking and nondrinking populations with stroke respectively (P<0.05). The additive interaction and multiplicative interaction between rs2268350 and smoking were both of significant (P<0.05) after adjustment for the covariates. There was a cumulated risk of IS among genotypes of rs3793917 (P=0.009) and rs2672587 (P=0.047) in smoking population. The mRNA level of HTRA1 in non-smokers with rs2268350 CC was significantly higher than smokers with rs2268350 CT/TT (P=0.046) in IS cases. Our findings support that HTRA1 confers the genetic susceptibility to IS and smoking might modify the genetic effect of HTRA1 on IS by suppressing HTRA1 mRNA expression.     

PRICKLE2 revisited—further evidence implicating PRICKLE2 in neurodevelopmental disorders

PRICKLE2 encodes a member of a highly conserved family of proteins that are involved in the non-canonical Wnt and planar cell polarity signaling pathway. Prickle2 localizes to the post-synaptic density, and interacts with post-synaptic density protein 95 and the NMDA receptor. Loss-of-function variants in prickle2 orthologs cause seizures in flies and mice but evidence for the role of PRICKLE2 in human disease is conflicting. Our goal is to provide further evidence for the role of this gene in humans and define the phenotypic spectrum of PRICKLE2-related disorders. We report a cohort of six subjects from four unrelated families with heterozygous rare PRICKLE2 variants ({"type":"entrez-nucleotide","attrs":{"text":"NM_198859.4","term_id":"1519316443","term_text":"NM_198859.4"}}NM_198859.4). Subjects were identified through an international collaboration. Detailed phenotypic and genetic assessment of the subjects were carried out and in addition, we assessed the variant pathogenicity using bioinformatic approaches. We identified two missense variants (c.122 C > T; p.(Pro41Leu), c.680 C > G; p.(Thr227Arg)), one nonsense variant (c.214 C > T; p.(Arg72*) and one frameshift variant (c.1286_1287delGT; p.(Ser429Thrfs*56)). While the p.(Ser429Thrfs*56) variant segregated with disease in a family with three affected females, the three remaining variants occurred de novo. Subjects shared a mild phenotype characterized by global developmental delay, behavioral difficulties ± epilepsy, autistic features, and attention deficit hyperactive disorder. Computational analysis of the missense variants suggest that the altered amino acid residues are likely to be located in protein regions important for function. This paper demonstrates that PRICKLE2 is involved in human neuronal development and that pathogenic variants in PRICKLE2 cause neurodevelopmental delay, behavioral difficulties and epilepsy in humans.Subject terms: Autism spectrum disorders, Genetics of the nervous system, Paediatric neurological disorders     

Cystathionine γ-lyase: Clinical, metabolic, genetic, and structural studies

We report studies of six individuals with marked elevations of cystathionine in plasma and/or urine. Studies of CTH, the gene that encodes cystathionine γ-lyase, revealed the presence among these individuals of either homozygous or compound heterozygous forms of a novel large deletion, p.Gly57_Gln196del, two novel missense mutations, c.589C>T (p.Arg197Cys) and c.932C>T (p.Thr311Ile), and one previously reported alteration, c.200C>T (p.Thr67Ile). Another novel missense mutation, c.185G>T (p.Arg62His), was found in heterozygous form in three mildly hypercystathioninemic members of a Taiwanese family. In one severely hypercystathioninemic individual no CTH mutation was found. Brief clinical histories of the cystathioninemic/cystathioninuric patients are presented. Most of the novel mutations were expressed and the CTH activities of the mutant proteins determined. The crystal structure of the human enzyme, hCTH, and the evidence available as to the effects of the mutations in question, as well as those of the previously reported p.Gln240Glu, on protein structure, enzymatic activity, and responsiveness to vitamin B₆ administration are discussed. Among healthy Czech controls, 9.3% were homozygous for CTH c.1208G>T (p.Ser403Ile), previously found homozygously in 7.5% of Canadians for whom plasma total homocysteine (tHcy) had been measured. Compared to wild-type homozygotes, among the 55 Czech c.1208G>T (p.Ser403Ile) homozygotes a greater level of plasma cystathionine was found only after methionine loading. Three of the four individuals homozygous or compound heterozygous for inactivating CTH mutations had mild plasma tHcy elevations, perhaps indicating a cause-and-effect relationship. The experience with the present patients provides no evidence that severe loss of CTH activity is accompanied by adverse clinical effects.     

Association between E-cadherin (CDH1) polymorphisms and pancreatic cancer risk in Han Chinese population

This study was designed to investigate the associations between E-cadherin (CDH1) gene polymorphisms and pancreatic cancer (PC) risk predisposition. We undertook a case-control study to analyze three E-cadherin polymorphisms (+54T>C, -160C>A and -347G→GA) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 368 patients with PC and 376 control participants and performed E-cadherin genotyping using DNA sequencing. Overall, no statistically significant association was observed in +54T>C. Nevertheless, -347G→GA genotype was at increased risk of PC (P=0.022; odds ratio (OR) =1.128, CI 95%: 1.017-1.251). Furthermore, -347GA/GA genotype pancreatic cancers were more significantly common in cases of advanced T stage, lymph node metastasis and clinical pathological stage than G or G/GA genotypes PC. However, -160C>A genotype demonstrated a protective effect in PCs (P=0.017; OR=0.883, CI 95%: 0.798-0.977). In conclusion, polymorphism in -347G→GA was observed to be associated with susceptibility of PC. However, -160C>A polymorphism indicated to play a protective role in susceptibility to PC. Nevertheless, further investigation with a larger sample size is needed to support our results.     

TNF-α -857C>T Genotype is Predictive of Clinical Response after Treatment with Definitive 5-Fluorouracil/cisplatin-based Chemoradiotherapy in Japanese Patients with Esophageal Squamous Cell Carcinoma

Background: Genotypes of tumor necrosis factor alpha (TNF-α) and its surface receptors, TNFRSF1A and TNFRSF1B, have been examined in terms of the progression, metastasis, clinical efficacy, and prognosis of various cancers; however, little is known about their effects on clinical outcome in patients with esophageal squamous cell carcinoma (ESCC). In this study, TNF-α and TNFRSF1A genotypes were retrospectively evaluated in terms of predicting clinical response, long-term survival, and severe acute toxicities in 46 male Japanese ESCC patients treated with definitive 5-fluorouracil (5-FU)/cisplatin (CDDP)-based chemoradiotherapy (CRT).Methods: A course consisted of the continuous infusion of 5-FU at 400 mg/m²/day for days 1-5 and 8-12, the infusion of CDDP at 40 mg/m²/day on days 1 and 8, and radiation at 2 Gy/day on days 1-5, 8-12, and 15-19, with a second course being repeated after a 2-week interval. The TNF-α -1031T>C (rs1799964), -863C>A (rs1800630), -857C>T (rs1799724), -308G>A (rs1800629), -238G>A (rs361525), TNFRSF1A -609G>T (rs4149570), and 36A>G (rs767455) genotypes were evaluated.Results: The TNF-α -857C>T genotype was found to be predictive of clinical response, i.e., complete response or not (P = 0.010, Fisher''s exact test), but had no effect on long-term survival (CC^-857 vs. CT^-857 + TT^-857, P = 0.072, Fisher''s exact test, P = 0.070, Log-rank test).Conclusions: The TNF-α -857C>T genotype was found to be predictive of clinical response and was more likely to predict long-term survival in Japanese ESCC patients receiving definitive 5-FU/CDDP-based CRT. Further clinical investigations with a larger number of patients or experiments in vitro should be performed to assess the predictive value of this genotype following CRT.     

A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing

Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.Subject terms: Genetic testing, Genetic testing     

Molecular epidemiological investigation of G6PD deficiency by a gene chip among Chinese Hakka of southern Jiangxi province

In southern China, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a significant health problem, and the incidence ranged from 0.5 to 4.08% in different Chinese population. The aims of this study are to investigate the molecular epidemiological characteristic of the G6PD gene among Chinese Hakka in southern Jiangxi province. 2331 unrelated subjects were screened for G6PD deficiency by a fluorescent test. DNA from deficient individuals was analyzed by a gene chip analysis for thirteen common Chinese G6PD mutations. In total, 3.60% (82/2331; 95% CI 2.77-4.27) of the sample were found to be G6PD-deficient. Eight mutations were found from 80 samples. However, mutation(s) for the two remaining samples were unknown. The most common mutations were G6PD Canton (1376 G>T) and G6PD Kaiping (1388 G>A), and the following mutations were 1311 polymorphism (1311 C>T), G6PD Gaohe (95 A>G), G6PD Chinese-5 (1024 C>T), G6PD Maewo (1360 C>T), Shunde (592 C>T), G6PD Viangchan (871 G>A) and Chinese-3 (493 A>G). This is the first report of G6PD deficiency among Chinese Hakka population in Jiangxi province.