SLC12A3基因新突变致Gitelman综合征伴代谢综合征一例报道

回顾性分析1例Gitelman综合征(GS)伴MS患者临床资料,对患者及其父母进行相关基因测序。SLC12A3_ex14 c.1717GC(p.G573R)推测为SLC12A3基因新突变,分析GS伴MS的可能机制。     

儿童Mowat-Wilson综合征的临床特点及基因变异和遗传情况

目的 总结儿童Mowat-Wilson综合征(MWS)的临床特点，了解本病的基因变异和遗传情况。方法 回顾性分析2017年1月—2022年12月南京医科大学附属南京儿童医院收治的8例MWS患儿的临床资料。结果 8例患儿均有发育迟缓、特殊面容及先天性畸形(如先天性心脏病、骨骼发育畸形、先天性巨结肠、肾脏异常等)。患儿1的ZEB2基因上存在c. 2350＿c. 2351insT(p. S784F^*11)杂合移码变异，其父母均无该基因变异，为新生变异；患儿2的ZEB2基因上存在c. 1150C>T(p. Q384^*,831)杂合无义变异，其父母均无该基因变异，为新生变异；患儿3和患儿6的ZEB2基因均存在c. 2073G>A(p. W691^*,524)杂合无义变异，2例患儿父母均无该基因变异，为新生变异；患儿4的ZEB2基因上存在c. 3179G>A(p. C1060Y)杂合错义变异，其父母均无该基因变异，为新生变异；患儿5的ZEB2基因上存在c. 904C>T(p. R302^*,...     

Gitelman综合征合并甲状腺疾病:两例患者SLC12A3基因分析

对合并甲状腺疾病的2例Gitelman综合征可疑患者及家庭成员进行SLC12A3基因分析,证实2例患者均为SLC12A3基因的复合杂合突变,3个新突变位点被发现.本研究提示Gitelman综合征有时与其他低血钾相关的疾病,如甲亢并存,临床应注意鉴别.     

1例1型肢端发育不全的诊断

目的 总结1例肢端发育不全1型患儿临床特征及诊断方法。方法 对1例肢端发育不全患儿临床特征和诊断过程作回顾性分析。结果 患儿主要临床表现为身材矮小、短指（趾）和双下肢不等长。遗传性骨病相关基因测序结果显示，患儿存在PRKAR1A基因第17号外显子c. 1102C>T(p. R368X)杂合突变，其父母均无该位点变异，明确诊断为肢端发育不全1型。结论 肢端发育不全1型患儿临床表现为身材矮小、短指（趾）、双下肢不等长等，遗传学显示PRKAR1A基因第17号外显子存在c. 1102C>T(p. R368X)杂合突变，通过临床表现结合基因检测可明确诊断。     

Gitelman综合征伴2型糖尿病一例报道

59岁女性患者因"反复低血钾24年,多尿、口干、多饮2个月"入院.实验室检查示低钾血症性碱中毒、低镁血症、继发性醛固酮增多症、低尿钙以及血糖偏高.第一代测序检测到SLC12A3基因有2个杂合突变,即外显子4区c.506?1G>A和c.536T>A,诊断为Gitelman综合征伴T2DM.经降糖、补钾、补镁联合醛固酮拮抗...     

家族性发作性疼痛综合征3型1例

家族性发作性疼痛综合征(FEPS)是一种罕见病, 为一种主要累及四肢远端的阵发性非炎症性疼痛综合征, 是家族常染色体显性遗传病, 可分为3种类型。本文报道1例因"全身多处疼痛"就诊的患者, 结合临床资料并进行全外显子组高通量测序, 结果显示携带SCN11A基因NM₀14139.2: c.673C>T: p.R225C杂合突变, 综合临床症状诊断为FEPS。     

伴食管胃静脉曲张出血的儿童Alstr?m综合征1例

Alstr?m综合征(AS)是一种罕见的伴有糖尿病的单基因遗传综合征, 食管胃静脉曲张出血在AS患者中更为罕见。该文报道了1例临床主要表现为畏光、视力差、感音神经性耳聋、智力低下、身材偏矮、早发性肥胖、胰岛素抵抗、2型糖尿病、肝功能异常、高脂血症的AS患者, 其ALMS1基因存在c.10825C>T(p.R3609X)和c.11107C>T(p.R3703X)复合杂合变异。然而该患儿确诊后仅14个月就出现了心脏扩大、肺动脉高压以及食管胃静脉曲张破裂出血, 病情重且进展迅速。同时该文还结合文献探讨了AS的诊疗进展, 以提高内分泌医师对该病的认识。     

突变位点c.868C>T年轻的成年发病型糖尿病1型家系一例报道

报道1例突变位点为c. 868C>T,p. Arg290Cys的MODY1家系，分析其临床特点及分子遗传学特征。先证者使用目标序列捕获高通量测序技术检测致病基因，发现其携带肝细胞核因子4α基因突变，收集家系成员外周血基因组DNA，使用Sanger测序技术均检测到同一突变位点c. 868C>T的杂合变异。根据检测结果调整治疗方案，从而提高患者血糖达标率。     

SLC37A4基因新突变致糖原累积病Ⅰb型一家系报道并文献复习

糖原累积病(GSD)是一种以糖原代谢异常为主要特征的常染色体隐性遗传病,主要临床表现为肝脏增大、高乳酸血症、高尿酸血症、高脂血症、低糖血症、生长发育迟缓、中性粒细胞计数减少、中性粒细胞功能损伤及炎症性肠病等。本文报道了GSDⅠb型一家系,通过分析其临床特征、肝脏穿刺病理学检查结果及SLC37A4基因测序结果,证实SLC37A4基因c.273C>A(p.N91K)突变(杂合突变),为新型突变,并进行了文献复习以提高临床医师对GSDⅠb型的认识。     

一例组织非特异性碱性磷酸酶基因突变所致的围生期致死型低磷酸酶症病例

目的对1例围生期致死型(新生儿型)低磷酸酶症(HPP)患者及其父母进行临床分析及基因突变检测,以期能更好地认识该病。方法对l例罕见的围生期致死型低磷酸酶症患者的临床表现、实验室及影像学检查结果进行总结。提取患儿及其亲属外周血基因组DNA,采用针对组织非特异性碱性磷酸酶(ALPL)基因调控区及编码区的特异性引物进行PCR扩增,直接对产物进行测序分析。结果患儿血碱性磷酸酶水平显著降低,血钙增高;骨骼显示骨软骨发育障碍类疾病样改变。ALPL基因测序结果显示患儿为复合杂合突变,同时携带位于第5外显子及第10外显子上c.346G>A(p.A116T)和c.1171C>T(p.R391C)的错义突变。临床表现正常的父亲、母亲为杂合子,分别携带c.346G>A(p.A116T)和c.1171C>T(p.R391C)的错义突变。该家系符合常染色体隐性遗传。结论围生期致死型HPP死亡率很高,骨骼发育异常、高血钙、血清低碱性磷酸酶在其鉴别诊断中非常重要。     

Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy

Summary Glycine encephalopathy, or nonketotic hyperglycinaemia (NKH; Mckusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P-, T-, H- and L-proteins. A P-protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high-performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease-causing: two large deletions, four one-base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1-base insertion (c.1002_1003insT), one 4-base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402−1C > G, c.2316−1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H-protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized. Communicating editor: Guy Besley Competing interests: None declared     

Mutational spectrum in congenital dyserythropoietic anemia type II: identification of 19 novel variants in SEC23B gene

SEC23B gene encodes an essential component of the coat protein complex II (COPII)-coated vesicles. Mutations in this gene cause the vast majority the congenital dyserythropoietic anemia Type II (CDA II), a rare disorder resulting from impaired erythropoiesis. Here, we investigated 28 CDA II patients from 21 unrelated families enrolled in the CDA II International Registry. Overall, we found 19 novel variants [c.2270 A>C p.H757P; c.2149-2 A>G; c.1109+1 G>A; c.387(delG) p.L129LfsX26; c.1858 A>G p.M620V; c.1832 G>C p.R611P; c.1735 T>A p.Y579N; c.1254 T>G p.I418M; c.1015 C>T p.R339X; c.1603 C>T p.R535X; c.1654 C>T p.L552F; c.1307 C>T p.S436L; c.279+3 A>G; c. 2150(delC) p.A717VfsX7; c.1733 T>C p.L578P; c.1109+5 G>A; c.221+31 A>G; c.367 C>T p.R123X; c.1857_1859delCAT; p.I619del] in the homozygous or the compound heterozygous state. Homozygosity or compound heterozygosity for two nonsense mutations was never found. In four cases the sequencing analysis has failed to find two mutations. To discuss the putative functional consequences of missense mutations, computational analysis and sequence alignment were performed. Our data underscore the high allelic heterogeneity of CDA II, as the most of SEC23B variations are inherited as private mutations. In this mutation update, we also provided a tool to improve and facilitate the molecular diagnosis of CDA II by defining the frequency of mutations in each exon.     

Genetic studies on myeloperoxidase deficiency in Italy

Hereditary myeloperoxidase (MPO) deficiency is the most common neutrophil biochemical defect characterized by the lack of peroxidase activity. In order to extend the epidemiological studies on hereditary MPO deficiency in Italy, approximately 40,000 individuals were analyzed and 7 partial and 8 total MPO deficient subjects were identified. The genetic characterization of the subjects showed the presence of 3 already-known mutations (c.752T>C, c.1705C>T and c.1566_1579del14) and 6 novel mutations: four missense mutations (c.995C>T, c.1112A>G, c.1715T>G and c.1927T>C), then a deletion of an adenine within exon 3 (c.325delA) and a mutation within the 3' splice site of intron 11 (c.2031-2A>C). The novel missense mutations cause the substitution of residues the p.A332V, p.D371G, p.L572W and p.W643R, respectively, and can cause potential structural changes. The c.325delA deletion causes a shift of the reading frame with the occurrence of a premature stop codon within the pro-peptide. An eukaryotic expression system was set up to investigate how the c.2031-2A>C mutation alters the MPO pre-mRNA splicing. The activation of a cryptic 3' splice site located 109nt upstream of the authentic 3' splice site was observed. The 109nt-insertion might cause the rapid degradation of the MPO mRNA or, alternatively, might lead to the generation of an abnormal MPO precursor lacking the enzymatic activity.     

Additive effect of mutations in LDLR and PCSK9 genes on the phenotype of familial hypercholesterolemia

Patients homozygous or compound heterozygous for LDLR mutations or double heterozygous for LDLR and apo B R3500Q mutation have higher LDL-C levels, more extensive xanthomatosis and more severe premature coronary disease (pCAD) than simple heterozygotes for mutations in either these genes or for missense mutations in PCSK9 gene. It is not known whether combined mutations in LDLR and PKCS9 are associated with such a severe phenotype. We sequenced Apo B and PCSK9 genes in two patients with the clinical diagnosis of homozygous FH who were heterozygous for LDLR gene mutations. Proband Z.P. (LDL-C 13.39 mmol/L and pCAD) was heterozygous for an LDLR mutation (p.E228K) inherited from her father (LDL-C 8.07 mmol/L) and a PCSK9 mutation (p.R496W) from her mother (LDL-C 5.58 mmol/L). Proband L.R. and her sister (LDL-C 11.51 and 10.47 mmol/L, xanthomatosis and carotid atherosclerosis) were heterozygous for an LDLR mutation (p.Y419X) inherited from their mother (LDL-C 6.54 mmol/L) and a PCSK9 mutation (p.N425S) probably from their deceased father. The LDL-C levels in double heterozygotes of these two families were 56 and 44% higher than those found in simple heterozygotes for the two LDLR mutations, respectively. The two PCSK9 mutations are novel and were not found in 110 controls and 80 patients with co-dominant hypercholesterolemia. These observations indicate that rare missense mutations of PCSK9 may worsen the clinical phenotype of patients carrying LDLR mutations.     

Novel mutation in a Chinese patient with progressive familial intrahepatic cholestasis type 3

Genotyping is conclusive for the diagnosis of progressive familial intrahepatic cholestasis type 3(PFIC3). Here we report a Chinese patient of PFIC3 with compound mutations in the ABCB4 gene. Liver biopsy was performed on a 17-year-old male patient with intrahepatic cholestasis of unknown etiology. Liver histology findings are indicative of intrahepatic cholestasis with extensive fibrosis. Genotyping revealed c.175C>T(p.L59L) mutation in exon 4, c.504C>T(p.N168N) mutation in exon 6, c.711A>T(p.I237I) mutation in exon 8, c.874A>T(p.K292X) in exon 9 and a novel mutation, c.1804G>T(p.G602W) in exon 15. Based on these findings, the patient was diagnosed with PFIC3. The novel mutation p.G602 W in exon 15 was predicted as probably damaging by Poly Phen-2 with a score of 0.986(sensitivity: 0.54; specificity: 0.94) and was predicted to affect protein function with a SIFT score of 0.01.     

Detection of 12 new mutations in Gaucher disease Brazilian patients

Gaucher disease is the most frequent lysosome storage disease and presents an autosomal recessive mode of inheritance. It is caused by mutations at the GBA gene leading to deficient activity of the glucocerebrosidase enzyme. This report describes 12 new mutations [c.38A>G (K-27R), c.220G>A (G35S), c.448G>A (E111K), IVS4+1G>A, c.746C>T (A210V), c.776A>G (Y220C), c.793delC (Q226_fs4X), c.1102C>T (R329C), c.1300C>T (R395C), c.1309G>A (V398I), c.1324-1326delATT (delI403) and c.1583T>C (I489T)] and 4 novel silent alterations [c.342C>T (F75), c.528C>T (D137), c.1011C>T (D298) and c.1092G>A (G325)] detected among 40 unrelated Brazilian type 1 Gaucher disease patients by a combination of RFLP, dHPLC and DNA sequencing procedures. The R329C mutation, previously described in a Parkinson's disease patient (A. Lwin, E. Orvisky, O. Goker-Alpan, M.E. LaMarca, E. Sidransky. Glucocerebrosidase mutations in subjects with Parkinsonism. Mol. Genet. Metab. 81 (2004) 70-73), is described here for the first time in a Gaucher disease patient. Several genotype-phenotype correlations could be established, contributing significantly to the panel of reported mutations and conferring predictive value to their detection.     

Mutation prevalence among 51 unrelated Spanish patients with Gaucher disease: identification of 11 novel mutations.

Gaucher disease is an autosomal recessive disorder caused by mutations in the lysosomal beta-glucocerebrosidase (GBA) gene. Gaucher disease is a very heterogeneous entity due to the large number of different mutations existing in the GBA gene, resulting in a defective protein whose impaired activity is the cause of the disease. We present a mutation analysis of the GBA gene in 51 unrelated Spanish Gaucher disease patients together with clinical findings. Two common mutations, c.1226A>G (N370S) and c.1448T>C (L444P), were determined by restriction enzyme digestion after PCR amplification of genomic DNA. The remaining alleles were screened by amplifying the entire GBA gene followed by nested PCR and SSCP analysis under four different conditions. The c.1226A>G (N370S) and c.1448T>C (L444P) mutations were common, accounting for 56 alleles (55%) and 16 alleles (15%), respectively. In addition, 25 different mutations were found, 11 of which are described here for the first time: c.(-203)A>G, c.160G>A (V15M), c.256C>T (R47X), c.445-2a>g (IVS4-2a>g), c.485T>C (M123T), c.914C>T (P266L), c.953delT, c.1124T>C (L336P), c.1207A>C (S364R), c.1214delG,C, and c.1510delT,C,T (465delSer). Two mutations, S364R and P266L, were associated with neuronopathic forms of Gaucher disease: S364R mutation in heterozygosity with the L444P mutation and the P266L mutation in a homozygous state. Two type 1 patients were found to be carriers of two mutations in the same allele (genotypes [N370S] + [E326K + N188S] and [N370S] + [IVS4-2a>g+c.(-203)A>G]). This study allowed us to identify 100% of mutant alleles, and therefore we conclude that the method used to screen for mutations in the GBA gene is very reliable and there is a broad spectrum of mutations in the GBA gene in the Spanish population.     

Identification and characterization of a novel mutation c.1090G>T (G325W) and nine common mutant alleles leading to Gaucher disease in Spanish patients

BACKGROUND: Gaucher disease is an autosomal recessive disorder resulting from mutations in the glucocerebrosidase gene (GBA). The lack of full genotype/phenotype correlation complicates counseling regarding clinical outcome and treatment recommendations. SUBJECTS AND METHODS: Several mutations in the human beta-glucosidase gene associated with Gaucher disease in 16 Spanish families were identified utilizing a combination of methods: enzymatic restriction, PCR-SSCP, and sequence analyses. Expression studies were performed following the introduction of the mutagenized human acid beta-glucosidase cDNA into COS-1 cells, and the residual enzyme activities of the mutant protein were measured and compared with the normal cDNA. RESULTS: The identified mutations and corresponding residual enzyme activities of the expressed protein are as follows: c.517A>C (T134P), 1%; c.721G>A (G202R), 17%; c.1090G>T (G325W), 13.9%; c.1093G>A (E326K), 26%; c.1208G>A (S364N), 4.1%; c.1226A>G (N370S), 17,8%; c.1246G>A (G377S), 17.6%; c.1289C>T (P391L), 8.5%; c.1448T>C (L444P), 3%; and c.1504C>T (R463C), 24.5%. CONCLUSIONS: Site-directed mutagenesis and expression in COS-1 cells are useful methods to increase our understanding of causality in Gaucher disease and the correlation between disease severity, gene defects, and residual enzyme activity. Our study demonstrates the functional consequences of the identified human beta-glucosidase mutations (T134P, S364N, G377S, P391L, and G325W) and provide evidence for the molecular and biochemical basis of Gaucher disease, among patients of Spanish ancestry.     

一个G6PC新复合杂合突变引起的糖原贮积病Ia型继发痛风

目的:探讨1例痛风伴高脂血症患者的临床特点及其可能的遗传机制。方法:详细收集患者临床资料,包括病史、体格检查、实验室检查结果。提取患者及其父母的外周血DNA进行全外显子测序分析,对新突变进行蛋白功能预测。结果:患者为22岁男性,有低血糖、高尿酸血症、痛风和高脂血症的典型临床表现。患者葡萄糖-6-磷酸酶(G6PC)基因第...