The role of acute heart failure index (AHFI) combined with emergency heart failure mortality risk grade (EHMRG) in the evaluation of clinical outcomes and prognosis in patients with acute heart failure.

OBJECTIVE: To investigate clinical value for the risk model of acute heart failure index (AHFI) combined with emergency heart failure mortality risk grade (EHMRG) in evaluating clinical outcomes and prognosis of patients with acute heart failure (AHF). METHODS: The present prospective observational cohort study enrolled a total of 228 patients with AHF who were admitted to our hospital from January 2019 to January 2020. The AHF patients were divided into four groups: (1) the high AHFI and high EHMRG group, n = 61; (2) the low AHFI and low EHMRG group, n = 92; (3) the high AHFI and low EHMRG group, n = 34; (4) the low AHFI and high EHMRG group, n = 41. AHFI and EHMRG were used to identify the risk of death for AHF patients. Serum levels of Troponin I, B-type natriuretic peptide (BNP), and NT-pro-B-type natriuretic peptide (NT-proBNP) were detected by the ELISA method. Kaplan-Meier curve was performed for analysis of survival time and a logistic regression model was used to analyse 1-year mortality of patients. Pearson's analysis was used to determine the correlation between biomarkers and EHMRG. RESULTS: AHFI combined with the EHMRG model was associated with cardiac function status and EHMRG score was positively related to the level of Troponin I, BNP, and NT-proBNP. AHF high-risk AHFI and high-risk EHMRG indicated that patients might have a higher incidence of MACEs during hospitalisation. In addition, AHFI and high-risk EHMRG groups had shorter survival times, and AHFI was associated with 1-year mortality and was the risk factor for 1-year mortality. CONCLUSION: AHFI combined with a high EHMRG risk model was associated with clinical outcomes and prognosis.

Identification of a Novel NF1 Frameshift Variant in a Chinese Family with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a progressive neurocutaneous disorder in humans, mainly characterized by café-au-lait macules (CALMs) and neurofibromas. NF1 is caused by variants of the neurofibromin 1 gene (NF1), which encodes a Ras-GTPase-activating protein called neurofibromin. NF1 variants may result in loss of neurofibromin function and elevation of cell proliferation and tumor formation. In this study, a Chinese NF1 family with an autosomal dominant inheritance pattern was recruited. Exome sequencing and Sanger sequencing were performed to discover the causative variant responsible for the family, followed by molecular analysis of effect of the mutated NF1 protein on Ras activity. A novel frameshift variant c.541dupC (p.(Gln181Profs∗20)) in the NF1 gene was identified in all three affected family members. The variant cosegregated with the disease phenotypes in the pedigree and was absent in 100 healthy controls. Bioinformatic analysis showed that the variant c.541dupC (p.(Gln181Profs∗20)) was pathogenic. The further molecular analysis verified the cells expressing NF1 variant p.(Gln181Profs∗20) partially enhanced Ras activity and elevated cell proliferation and tumor formation due to loss of neurofibromin function caused by the variant. Taken together, the data strongly advocate the c.541dupC (p.(Gln181Profs∗20)) variant as the underlying genetic cause of the Chinese family with NF1. Moreover, our findings broaden the spectrum of NF1 variants and provide molecular insights into the pathogenesis of NF1.

A novel compound heterozygous mutation in the GJB2 gene is associated with non-syndromic hearing loss in a Chinese family.

Autosomal recessive (AR) non-syndromic hearing loss (NSHL) is the most common form of hereditary deafness. Mutations in the gap junction protein beta 2 (GJB2) gene encoding connexin 26 (Cx26) account for about 50% of cases of ARNSHL. In the current study, a combination of exome sequencing and Sanger sequencing in a Chinese Dong family with ARNSHL allowed identification of a novel compound heterozygous mutation c.240G>C(p. Q80H)/C.109G>A(p.V37I) in exon 2 of the GJB2 gene, which co-segregated with the disease phenotype in this family and was not evident in 100 healthy controls. Bioinformatic analysis revealed that the two mutations in the GJB2 gene were probably pathogenic. Results indicated that the compound heterozygous variants, p.Q80H and p.V37I, in the GJB2 gene are associated with ARNSHL. The Q80H variant was initially identified in patients of Dong Chinese origin with NSHL. The current results broaden the spectrum of GJB2 mutations responsible for NSHL and have important implications for molecular diagnosis, treatment, and genetic counseling for this family.

[Identification of novel compound heterozygous mutations of USH2A gene in a family with Usher syndrome type II].

OBJECTIVE: To identify potential mutations in a Chinese family with Usher syndrome type II. METHODS: Genomic DNA was obtained from two affected and four unaffected members of the family and subjected to amplification of the entire coding sequence and splicing sites of USH2A gene. Mutation detection was conducted by direct sequencing of the PCR products. A total of 100 normal unrelated individuals were used as controls. RESULTS: The patients were identified to be a compound heterozygote for two mutations: c.8272G>T (p.E2758X) in exon 42 from his mother and c.12376-12378ACT>TAA(p.T4126X) in exon 63 of the USH2A gene from his father. Both mutations were not found in either of the two unaffected family members or 100 unrelated controls, and had completely co-segregated with the disease phenotype in the family. Neither mutation has been reported in the HGMD database. CONCLUSION: The novel compound heterozygous mutations c.8272G>T and c.12376-12378ACT>TAA within the USH2A gene may be responsible for the disease. This result may provide new clues for molecular diagnosis of this disease.

Identify the signature genes for diagnose of uveal melanoma by weight gene co-expression network analysis.

AIM: To identify and understand the relationship between co-expression pattern and clinic traits in uveal melanoma, weighted gene co-expression network analysis (WGCNA) is applied to investigate the gene expression levels and patient clinic features. Uveal melanoma is the most common primary eye tumor in adults. Although many studies have identified some important genes and pathways that were relevant to progress of uveal melanoma, the relationship between co-expression and clinic traits in systems level of uveal melanoma is unclear yet. We employ WGCNA to investigate the relationship underlying molecular and phenotype in this study. METHODS: Gene expression profile of uveal melanoma and patient clinic traits were collected from the Gene Expression Omnibus (GEO) database. The gene co-expression is calculated by WGCNA that is the R package software. The package is used to analyze the correlation between pairs of expression levels of genes. The function of the genes were annotated by gene ontology (GO). RESULTS: In this study, we identified four co-expression modules significantly correlated with clinic traits. Module blue positively correlated with radiotherapy treatment. Module purple positively correlates with tumor location (sclera) and negatively correlates with patient age. Module red positively correlates with sclera and negatively correlates with thickness of tumor. Module black positively correlates with the largest tumor diameter (LTD). Additionally, we identified the hug gene (top connectivity with other genes) in each module. The hub gene RPS15A, PTGDS, CD53 and MSI2 might play a vital role in progress of uveal melanoma. CONCLUSION: From WGCNA analysis and hub gene calculation, we identified RPS15A, PTGDS, CD53 and MSI2 might be target or diagnosis for uveal melanoma.

Malattia leventinese/Doyne honeycomb retinal dystrophy in a chinese family with mutation of the EFEMP1 gene.

PURPOSE: To characterize the clinical features and molecular genetic findings in a Chinese pedigree with Malattia leventinese/Doyne honeycomb retinal dystrophy. METHODS: All patients underwent ophthalmologic examinations, including Snellen best-corrected visual acuity, fundus photography, fundus autofluorescence imaging, fundus fluorescein angiography, and optical coherence tomography. Genomic DNA was isolated from blood samples. All exons of EFEMP1 were amplified by polymerase chain reaction and sequenced. Possible structural and functional impacts of the protein because of amino acid substitution were predicted by bioinformatics analysis. RESULTS: A heterozygous missense mutation comprising C > T in exon 10 of EFEMP1 was identified in all patients of the pedigree; this resulted in an amino acid substitution at position 345 (Arg345Trp, R345W). Clinically, six patients from the Chinese family were ascertained with varying degrees of early onset drusen. Besides the drusen, choroidal neovascularization and retinal pigment epithelium changes were noted in some patients. Increased autofluorescence corresponding to the drusen was detected in the R345W mutation patients. Intrafamilial patients with Malattia leventinese/Doyne honeycomb retinal dystrophy seem to be phenotypically variable in visual loss, ophthalmoscopic findings, autofluorescence imaging, and optical coherence tomography changes. The amino acid change may have an effect on protein structure and function through bioinformatics analysis. CONCLUSION: The R345W mutation in EFEMP1 caused Malattia leventinese/Doyne honeycomb retinal dystrophy in a Chinese family. This is the first report, as per our knowledge, of the R345W mutation in EFEMP1 in a Chinese pedigree of this disease.

[Genetic diagnosis for a Chinese Han family with hereditary multiple osteochondromas].

OBJECTIVE: To identify the genetic cause for a Chinese Han family affected with hereditary multiple osteochondromas. METHODS: Two patients, five unaffected relatives of the family and 100 unrelated healthy controls were collected. The coding sequences and intron/exon boundaries of EXT1 gene were amplified with polymerase chain reaction (PCR) and sequenced. RESULTS: A heterozygous c.600G>A (p.Trp200X) mutation in exon 1 of the EXT1 gene was detected in the patients. The same mutation was not found in unaffected family members and 100 healthy controls. CONCLUSION: The hereditary multiple osteochondromas in the family is caused by a nonsense mutation (p.Trp200X) in the EXT1 gene.

Genetic analysis of the forkhead transcriptional factor 2 gene in three Chinese families with blepharophimosis syndrome.

PURPOSE: Clinically, blepharophimosis syndrome (BPES) has been divided into two subsets according to the association of ocular malformation with (type I) or without (type II) premature ovarian failure (POF). BPES is ascribed to mutations in the forkhead transcriptional factor 2 (FOXL2) gene. This study aimed at identifying clinical features and mutations within the FOXL2 gene in three Chinese families with BPES. METHODS: A clinical and molecular genetic investigation was performed in affected and unaffected members from three Chinese families with BPES. Genomic DNA was prepared from leucocytes of peripheral venous blood, the entire coding region of FOXL2 were amplified with PCR, and direct DNA sequencing of the PCR products was performed for mutations in FOXL2. RESULTS: Three mutations in FOXL2 were found in three families, including c.672_701dup30, c.663_692dup30, and c.475dupC. Of the three, the c.475dupC (p.His159fs) was novel in family C and resulted in a frameshift mutation to generate a truncated protein owing to a premature stop codon at codon 238. The new duplication mutation was associated with BPES type II. The c.672_701dup30 (p.Ala224_Ala234dup10) and the c.663_692dup30 (p.Ala221_Ala231dup10) were detected in family A and family B, respectively, leading to expansions of the polyalanine (poly-Ala) tract that is frequently the hot spot of mutations within FOXL2. CONCLUSIONS: Our results expand the spectrum of FOXL2 mutations, and further indicate the association of a novel duplication mutation leading to a truncated protein with BPES type II. The other two known mutations may support the previous hypothesis regarding expansions of the polyalanine tract associated with BPES type II as a mutational hot spot in FOXL2.

A de novo 1.38 Mb duplication of 1q31.1 in a boy with hemifacial microsomia, anophthalmia, anotia, macrostomia, and cleft lip and palate.

We reported a 2-year-old boy with developmental delay, mild mental retardation, and severe craniofacial malformation, including facial asymmetry with hypoplasia of the left zygoma, maxilla, and mandible, and left anophthalmia and anotia. A genome-wide screen revealed a 1.38 Mb duplication on chromosome 1q31.1, which was absent in his parents and 27 healthy controls. The duplication region contains two Refseq genes, PLA2G4A and C1orf99, which have not been reported to be implicated in craniofacial malformation. Functional studies of these genes and additional clinical analysis are necessary to elucidate the pathogenesis of craniofacial malformation.

Genetic variations in ADIPOQ gene are associated with chronic obstructive pulmonary disease.

BACKGROUND: Adiponectin is reported to be related to the development of chronic obstructive pulmonary disease (COPD). Genetic variants in the gene encoding adiponectin (ADIPOQ) have been reported to be associated with adiponectin level in several genome-wide linkage and association studies. However, relatively little is known about the effects of ADIPOQ gene variants on COPD susceptibility. We determined the frequencies of single-nucleotide polymorphisms (SNPs) in ADIPOQ in a Chinese Han population and their possible association with COPD susceptibility. METHODS: We conducted a case-control study of 279 COPD patients and 367 age- and gender-distribution-matched control subjects. Seven tagging SNPs in ADIPOQ, including rs710445, rs16861205, rs822396, rs7627128, rs1501299, rs3821799 and rs1063537 were genotyped by SNaPshot. Association analysis of genotypes/alleles and haplotypes constructed from these loci with COPD was conducted under different genetic models. RESULTS: The alleles or genotypes of rs1501299 distributed significantly differently in COPD patients and controls (allele: P = 0.002, OR = 1.43 and 95%CI = 1.14-1.79; genotype: P = 0.008). The allele A at rs1501299 was potentially associated with an increased risk of COPD in all dominant model analysis (P = 0.009; OR: 1.54; 95%CI: 1.11-2.13), recessive model analyses (P = 0.015; OR: 1.75; 95% CI: 1.11-2.75) and additive model analyses (P = 0.003; OR: 2.11; 95% CI: 1.29-3.47). In haplotype analysis, we observed haplotypes AAAAACT and GGACCTC had protective effects, while haplotypes AGAACTC, AGGCCTC, GGAACTC, GGACACT and GGGCCTC were significantly associated with the increased risk of COPD. CONCLUSIONS: We conducted the first investigation of the association between the SNPs in ADIPOQ and COPD risk. Our current findings suggest that ADIPOQ may be a potential risk gene for COPD. Further studies in larger groups are warranted to confirm our results.

[Clinical investigation of a Chinese family with hypotrichosis simplex of the scalp and mutational analysis of CDSN gene].

OBJECTIVE: To analyze clinical symptoms and disease-causing mutations of corneodesmosin (CDSN) gene in a Chinese family affected with hypotrichosis simplex of the scalp and to establish a method for prenatal diagnosis. METHODS: Family survey and clinical examinations were carried out to determine the inheritance pattern. Three patients and 7 unaffected relatives from the family, in addition with 100 unrelated healthy controls were recruited. Genomic DNA from peripheral blood leukocytes was extracted. Five pairs of primers were designed based on the CDSN gene sequence. Exons and flanking regions of the CDSN gene were amplified using polymerase chain reaction (PCR). Potential mutations were analyzed through direct sequencing and comparison by BLAST. RESULTS: The type of alopecia of the family was diagnosed as hypotrichosis simplex of the scalp with an autosomal dominant inheritance pattern. A nonsense mutation (C717G) in cDNA sequence of the CDSN gene was identified in all three patients of the family, which resulted in a premature stop codon (Y239X). The same mutation was not found among healthy members of the family and 100 healthy controls. CONCLUSION: A Chinese family was diagnosed with hypotrichosis simplex of the scalp, which was caused by a novel nonsense mutation (Y239X) in the CDSN gene.

[Mutation analysis of FGFR3 gene in a family featuring hereditary dwarfism].

OBJECTIVE: To investigate the clinical symptoms and potential mutation in FGFR3 gene for a family featuring hereditary dwarfism in order to attain diagnosis and provide prenatal diagnosis. METHODS: Five patients and two unaffected relatives from the family, in addition with 100 healthy controls, were recruited. Genome DNA was extracted. Exons 10 and 13 of the FGFR3 gene were amplified using polymerase chain reaction (PCR). PCR products were sequenced in both directions. RESULTS: All patients had similar features including short stature, short limbs, lumbar hyperlordosis but normal craniofacial features. A heterozygous mutation G1620T (N540K) was identified in the cDNA from all patients but not in the unaffected relatives and 100 control subjects. A heterozygous G380R mutation was excluded. CONCLUSION: The hereditary dwarfism featured by this family has been caused by hypochondroplasia (HCH) due to a N540K mutation in the FGFR3 gene.

Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum.

Oculo-auriculo-vertebral spectrum (OAVS) is a common developmental disorder involving first and second pharyngeal arches. Although some family cases and such patients showing chromosomal aberrations suggest that OAVS have a genetic basis, no consistent genetic defects have been recorded at present time. Thus, we conducted genetic studies of a three-generation family with five OAVS patients to identify a causative variant for OAVS. Cytogenetic studies revealed those family members had a normal karyotype and no causative mutations were founded in SALL1 and TCOF1, which known to be responsible for two other syndromes that have clinical overlapping with OAVS. Genotyping with commercially available BeadChips was performed on 13 individuals in the same family, showing no significant difference between the affected and normal members in terms of copy number variations (CNVs) in either number or size and no definitive causative CNV. A total of 8,224 informative autosomal SNPs that are evenly distributed throughout the genome were selected for both parametric and non-parametric linkage analysis. Significant negative LOD scores were obtained for the reported OAVS locus, providing further evidence for genetic heterogeneity of this complex disorder. The highest LOD score of 1.60 was noted on chromosome 15q26.2-q26.3 showing a potential linkage to this locus. The variable phenotypes of the affected members and the failure to identify a causative variant indicate that a complex etiology may be present even in a consanguineous family, which makes it more challenging to ascertain the cause of OAVS in further analysis.

Two neighboring microdeletions of 5q13.2 in a child with oculo-auriculo-vertebral spectrum.

We describe a patient with multiple congenital anomalies, including hemifacial microsomia, asymmetric macrostomia, dysplastic mandible, multiple preauricular tags, atresia of the external auricular canal, and vertebral anomalies, which coincide with oculo-auriculo-vertebral spectrum. G-banding ( approximately 850 band level) showed a normal 46, XY karyotype. A genome-wide screen for copy number variations (CNVs) using single nucleotide polymorphism (SNP) arrays revealed a 1Mb and a 167 kb deletion both on chromosome 5q13.2, which were absent in the parents and in 27 controls. Sixteen genes were located in the deleted region, including BIR1C and OCLN, which are involved in apoptosis. Haploinsufficiency of these genes may be contributing to the phenotype in this patient. To our knowledge, there are no previous reports of this 5q13.2 deletion in a patient with oculo-auriculo-vertebral spectrum.