BMC MEDICAL GENETICS 是一本开放获取期刊，发表有关个人、家庭和人群之间遗传变异对人类健康和疾病的影响的原创同行评审研究文章。

BMC Medical Genetics is an open-access journal that publishes original peer-reviewed research articles on the impact of genetic variations among individuals, families, and populations on human health and disease.

BMC Medical Genetics 是一本开放获取的期刊，专注于发表原创的同行评审研究文章，探讨个人、家庭和人群之间的遗传变异如何影响人类健康和疾病。

BMC Medical Genetics

Abstract Background Disc degeneration (DD) is a common condition that progresses with aging. Although the events leading to DD are not well understood, a significant genetic influence has been found. This study was undertaken to assess the association between relevant candidate gene polymorphisms and moderate DD in a well-defined and characterized cohort of young adults. Focusing on young age can be valuable in determining genetic predisposition to DD. Methods We investigated the associations of existing candidate genes for DD among 538 young adults with a mean age of 19 belonging to the 1986 Northern Finland Birth Cohort. Nineteen single nucleotide polymorphisms (SNP) in 16 genes were genotyped. We evaluated lumbar DD using the modified Pfirrmann classification and a 1.5-T magnetic resonance scanner for imaging. Results Of the 538 individuals studied, 46% had no degeneration, while 54% had DD and 51% of these had moderate DD. The risk of DD was significantly higher in subjects with an allele G of IL6 SNPs rs1800795 (OR 1.45, 95% CI 1.07-1.96) and rs1800797 (OR 1.37, 95% CI 1.02-1.85) in the additive inheritance model. The role of IL6 was further supported by the haplotype analysis, which resulted in an association between the GGG haplotype (SNPs rs1800797, rs1800796 and rs1800795) and DD with an OR of 1.51 (95% CI 1.11-2.04). In addition, we observed an association between DD and two other polymorphisms, SKT rs16924573 (OR 0.27 95% CI 0.07-0.96) and CILP rs2073711 in women (OR 2.04, 95% CI 1.07-3.89). Conclusion Our results indicate that IL6 , SKT and CILP are involved in the etiology of DD among young adults.

Anthi Kelempisioti

Pasi J Eskola

Annaleena Okuloff

Ulla Karjalainen

Jani Takatalo

Iita Daavittila

Jaakko Niinimäki

Roberto B Sequeiros

Osmo Tervonen

Svetlana Solovieva

Patrick YP Kao

You-Qiang Song

Kenneth MC Cheung

Danny Chan

Leena Ala-Kokko

Marjo-Riitta Järvelin

Jaro Karppinen

Minna Männikkö

Genetic susceptibility of intervertebral disc degeneration among young Finnish adults

年轻芬兰成人椎间盘退变的遗传易感性

Gaucher disease is a rare pan-ethnic disorder which occurs due to an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. A beta-Glucosidase (GBA) gene defect results in glucocerebrosidase enzyme deficiency. Though the disease is mainly diagnosed in childhood, the adult manifestation is often missed or identified late due to the failure to recognize the heterogeneous clinical presentation. The present study includes seven unrelated Indian adult patients (age range: 20–40 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality. The biochemical investigation implicated measuring plasma chitotriosidase enzyme activity followed by confirmatory test of β-Glucosidase enzyme activity from the leukocytes. The molecular characterization involved patients' initial screening for the common Gaucher mutation (Leu444Pro). Later, all patients were subjected to whole GBA gene coding region study using bidirectional Sanger sequencing. The population screening for common Gaucher disease mutation (Leu444Pro) was executed in 1200 unrelated and healthy Indian subjects by Restriction Fragment Length Polymorphism-Polymerase Chain Reaction technique. The allele frequency was calculated using Hardy-Weinberg formula. The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all the patients. Also, an elevated level of plasma Chitotriosidase activity in five patients supported their diagnosis of Gaucher disease. Sanger sequencing established four patients with homozygous variation and three patients with compound heterozygous variation in GBA gene. This study uncovers two missense variants (Ala448Thr and Val17Gly) not previously reported in Gaucher disease patients. Also the known mutations like Leu444Pro, Arg329Cys, Asp315Asn, Ser125Arg, and Arg395Cys were identified in these patients. The homology modeling suggested the destabilization of the protein structure due to novel variants. The Leu444Pro mutation screening in the Indian population spotted two people as a carrier. This emerged the carrier frequency of 1:600 along with wild-type allele frequency 0.97113 and mutant allele frequency 0.02887. The study reports novel and known variants identified in the GBA gene in seven adult patients. The given study is the first report on the carrier frequency of the Leu444Pro mutant allele in an Indian population which will help understanding the burden and susceptibility of Gaucher disease to affect next generation in India.

Jayesh Sheth

Dhairya Pancholi

Mehul Mistri

Payal Nath

Chitra Ankleshwaria

Riddhi Bhavsar

Ratna Puri

Shubha Phadke

Frenny Sheth

Biochemical and molecular characterization of adult patients with type I Gaucher disease and carrier frequency analysis of Leu444Pro - a common Gaucher disease mutation in India

I型戈谢病成年患者的生化和分子特征及Leu444Pro常见突变的携带频率分析

Combined methylmalonic aciduria and homocystinuria, cobalamin(cbl)C deficiency, is a rare disorder of intracellular vitamin B12(cbl) metabolism caused by mutations in the MMACHC gene. Both genetic and biochemical approach have been established to diagnose children and fetuses with cblC deficiency, while in China there is no report of prenatal genetic diagnosis of cblC deficiency. The aim of the present study was to characterize the mutational spectrum of cblC deficiency and investigate the feasibility of genetic-sequencing-based prenatal diagnosis for cblC deficiency. 10 pedigrees were recruited in this study with the probands clinically and biochemically confirmed combined methymalonic aciduria and homocystinuria. Peripheral blood samples were collected for MMACHC genetic test from the probands and their parents (4 probands had already dead) and 50 control subjects. The entire coding region and adjacent splice sites of MMACHC were sequenced. After the genotypes of the pedigrees were identified, chorionic villi sampling were performed for 3 high-risk pregnant women for prenatal genetic diagnosis. A total of 7 mutations were identified: c.217C > T (R73X), c.394C > T (R132X), c.463G > C (G155R), c.609G > A (W203X), c.616C > T (R206W), c.658-660delAAG (220delK), and c.567dupT (I190YfsX13), as well as 2 polymophsims: c.321G > A(V107V), c.-302G > T. And G155R is a novel mutation that haven't been reported in the literatures. All the 6 probands identified with compound heterozygous mutations or homozygous mutations of MMACHC gene, and all the parents of the probands were found to have one MMACHC mutation at a heterozygous level. Prenatal diagnosis of fetuses from 3 families with a child affected cblC deficiency showed that one fetus had the same compound heterozygous mutations as the proband, one did not have MMACHC mutation, and the third fetus had a mutation at a heterozygous level of MMACHC gene. Results from the follow-ups were consistent with the prenatal diagnosis. A novel mutation p.G155R of the MMACHC gene is identified. Genetic diagonsis is an accurate and convenient method for prenatal diagnosis and early intervention of combined methylmalonic aciduria and homocystinuria.

Yanan Zong

Ning Liu

Zhenhua Zhao

Xiangdong Kong

BMC Med Genet

Prenatal diagnosis using genetic sequencing and identification of a novel mutation in MMACHC

使用基因测序进行产前诊断及发现MMACHC新突变

Gaucher disease is a rare pan-ethnic, lysosomal storage disorder resulting due to beta-Glucosidase (GBA1) gene defect. This leads to the glucocerebrosidase enzyme deficiency and an increased accumulation of undegraded glycolipid glucocerebroside inside the cells' lysosomes. To date, nearly 460 mutations have been described in the GBA1 gene. With the aim to determine mutations spectrum and molecular pathology of Gaucher disease in India, the present study investigated one hundred unrelated patients (age range: 1 day to 31 years) having splenomegaly, with or without hepatomegaly, cytopenia and bone abnormality in some of the patients. The biochemical investigation for the plasma chitotriosidase enzyme activity and β-Glucosidase enzyme activity confirmed the Gaucher disease. The mutations were identified by screening the patients' whole GBA gene coding region using bidirectional Sanger sequencing. The biochemical analysis revealed a significant reduction in the β-Glucosidase activity in all patients. Sanger sequencing established 71 patients with homozygous mutation and 22 patients with compound heterozygous mutation in GBA1 gene. Lack of identification of mutations in three patients suggests the possibility of either large deletion/duplication or deep intronic variations in the GBA1 gene. In four cases, where the proband died due to confirmed Gaucher disease, the parents were found to be a carrier. Overall, the study identified 33 mutations in 100 patients that also covers four missense mutations (p.Ser136Leu, p.Leu279Val, p.Gly383Asp, p.Gly399Arg) not previously reported in Gaucher disease patients. The mutation p.Leu483Pro was identified as the most commonly occurring Gaucher disease mutation in the study (62% patients). The second common mutations identified were p.Arg535Cys (7% patients) and RecNcil (7% patients). Another complex mutation Complex C was identified in a compound heterozygous status (3% patients). The homology modeling of the novel mutations suggested the destabilization of the GBA protein structure due to conformational changes. The study reports four novel and 29 known mutations identified in the GBA1 gene in one-hundred Gaucher patients. The given study establishes p.Leu483Pro as the most prevalent mutation in the Indian patients with type 1 Gaucher disease that provide new insight into the molecular basis of Gaucher Disease in India.

Ashish Bavdekar

Ashwin Dalal

Prajnya Ranganath

Katta M Girisha

Anju Shukla

Inusha Panigrahi

Anupriya Kaur

Mamta Muranjan

Manisha Goyal

Radha Ramadevi

Raju Shah

Sheela Nampoothiri

Sumita Danda

Chaitanya Datar

Seema Kapoor

Seema Bhatwadekar

Gaucher disease: single gene molecular characterization of one-hundred Indian patients reveals novel variants and the most prevalent mutation

戈谢病：对一百名印度患者进行单基因分子特征分析揭示了新变异和最常见的突变

Abstract Background Polymorphisms in genes modulating xenobiotics metabolism, in particular the ABCC2 c.3972C &gt; T single nucleotide polymorphism (SNP) at exon 28, have been suggested to increase primary liver cancer (PLC) risk. Conversely, the occurrence of PLCs in Wilson disease patients is a rare event, in contrast with the occurrence observed in other chronic liver diseases. Here we report the clinical case of five siblings carrying the ABCC2 c.3972C &gt; T SNP; three of them were affected by Wilson disease and two brothers with Wilson disease also developed PLCs. Methods The presence of the ABCC2 c.3972C &gt; T SNP was assessed by Sanger sequencing and the exposure of PLC risk factors by standardized questionnaires. Results Notably, PLCs occurred only in the two brothers with the ABCC2 c.3972C &gt; T SNP and Wilson disease who resulted exposed to asbestos and cigarette smoking, but not in the other siblings with the ABCC2 c.3972C &gt; T SNP, alone or in association with Wilson disease, not exposed to these carcinogens and/or to other known risk factors for PLCs. Conclusions These findings suggest that ABCC2 c.3972C &gt; T SNP and WD, also in association, may not represent a sufficient condition for PLC development, but that co-occurrence of further host/exogenous risk factors are needed to drive this process, reinforcing the notion that liver carcinogenesis is the result of a complex interplay between environmental and host genetic determinants. Due to the sporadic cases of this study and the paucity of data currently available in literature on this issue, future investigations in a larger population are needed to confirm our findings.

Giovanni Brandi

Alessandro Rizzo

Marzia Deserti

Valeria Relli

Valentina Indio

Sofia Bin

Milena Pariali

Andrea Palloni

Stefania De Lorenzo

Francesco Tovoli

Simona Tavolari

Wilson disease, ABCC2 c.3972C &gt; T polymorphism and primary liver cancers: suggestions from a familial cluster

威尔逊病、ABCC2 c.3972C > T多态性与原发性肝癌：来自家族聚集的提示

Abstract Background Hepatitis B is known to cause several forms of liver diseases including chronic hepatitis B (CHB), and hepatocellular carcinoma. Previous genome-wide association study of CHB risk has demonstrated that rs12614 of complement factor B ( CFB) was significantly associated with CHB risk. In this study, fine-mapping study of previously reported GWAS single nucleotide polymorphism (SNP; CFB rs12614 ) was performed to validate genetic effect of rs12614 on CHB susceptibility and identify possible additional causal variants around rs12614 in a Korean population. This association study was conducted in order to identify genetic effects of CFB single nucleotide polymorphisms (SNPs) and to identify additional independent CHB susceptible causal markers within a Korean population. Methods A total of 10 CFB genetic polymorphisms were selected and genotyped in 1716 study subjects comprised of 955 CHB patients and 761 population controls. Results A non-synonymous variant, rs12614 (Arg32Trp) in exon2 of CFB, had significant associations with risk of CHB (odds ratio = 0.43, P = 5.91 × 10 − 10 ). Additional linkage disequilibrium and conditional analysis confirmed that rs12614 had independent genetic effect on CHB susceptibility with previously identified CHB markers. The genetic risk scores (GRSs) were calculated and the CHB patients had higher GRSs than the population controls. Moreover, OR was found to increase significantly with cumulative GRS. Conclusions rs12614 showed significant genetic effect on CHB risk within the Korean population. As such rs12614 may be used as a possible causal genetic variant for CHB susceptibility.

Jung Yeon Seo

Joong-Gon Shin

Byeong Ju Youn

Suhg Namgoong

Hyun Sub Cheong

Lyoung Hyo Kim

Ji On Kim

Hyoung Doo Shin

Yoon Jun Kim

A non-synonymous variant rs12614 of complement factor B associated with risk of chronic hepatitis B in a Korean population

补体因子B的非同义变异rs12614与韩国人群慢性乙型肝炎风险相关

Abstract Background In Morocco, consanguinity rate is very high; which lead to an increase in the birth prevalence of infants with autosomal recessive disorders. Previously, it was difficult to diagnose rare autosomal recessive diseases. Next Generation Sequencing (NGS) techniques have considerably improved clinical diagnostics. A genetic diagnosis showing biallelic causative mutations is the requirement for targeted carrier testing in parents, prenatal and preimplantation genetic diagnosis in further pregnancies, and also for targeted premarital testing in future couples at risk of producing affected children by a known autosomal recessive disease. Methods In this report, we present our strategy to advise a future couple of first cousins, whose descendants would risk cystinosis; an autosomal recessive lysosomal disease caused by mutations in the CTNS gene. Indeed, our future husband’s sister is clinically and biochemically diagnosed with cystinosis in early childhood. First, we opted to identify the patient’s CTNS gene abnormality by using (NGS), then we searched for heterozygosity in the couple’s DNA, which allows us to predict the exact risk of this familial disease in the future couple’s offspring. Results We have shown that the future husband, brother of the patient is heterozygous for the familial mutation. On the other hand, his future wife did not inherit the familial mutation. Therefore, genetic counseling was reassuring for the risk of familial cystinosis in this couple’s offspring. Conclusions We report in this study, one of the major applications of (NGS), an effective tool to improve clinical diagnosis and to provide the possibility of targeted premarital carrier testing in couples at risk.

Mouna Ouhenach

Abdelali Zrhidri

Imane Cherkaoui Jaouad

Wiam Smaili

Abdelaziz Sefiani

Application of next generation sequencing in genetic counseling a case of a couple at risk of cystinosis

下一代测序在遗传咨询中的应用：一例胱氨酸病高风险夫妇的案例

Abstract Background Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 ( DGAT1 ) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. Case presentation Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. Conclusions This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

Luojia Xu

Weizhong Gu

Youyou Luo

Jingan Lou

Jie Chen

DGAT1 mutations leading to delayed chronic diarrhoea: a case report

DGAT1突变导致慢性腹泻延迟发作：一例报告

An amendment to this paper has been published and can be accessed via the original article.

Min Hu

Yaowu Han

Ying Zhang

Yuanfeng Zhou

Lin Ye

Retraction Note: lncRNA TINCR sponges miR-214-5p to upregulate ROCK1 in hepatocellular carcinoma

撤稿说明：lncRNA TINCR 通过吸附 miR-214-5p 上调肝细胞癌中的 ROCK1 表达

Abstract Background Progressive familial intrahepatic cholestasis (PFIC) type 3 is an autosomal recessive disorder arising from mutations in the ATP-binding cassette subfamily B member 4 ( ABCB4 ) gene. This gene encodes multidrug resistance protein-3 (MDR3) that acts as a hepatocanalicular floppase that transports phosphatidylcholine from the inner to the outer canalicular membrane. In the absence of phosphatidylcholine, the detergent activity of bile salts is amplified and this leads to cholangiopathy, bile duct loss and biliary cirrhosis. Patients usually present in infancy or childhood and often progress to end-stage liver disease before adulthood. Case presentation We report a 32-year-old female who required cadaveric liver transplantation at the age of 17 for cryptogenic cirrhosis. When the patient developed chronic ductopenia in the allograft 15 years later, we hypothesized that the patient’s original disease was due to a deficiency of a biliary transport protein and the ductopenia could be explained by an autoimmune response to neoantigen that was not previously encountered by the immune system. We therefore performed genetic analyses and immunohistochemistry of the native liver, which led to a diagnosis of PFIC3. However, there was no evidence of humoral immune response to the MDR3 and therefore, we assumed that the ductopenia observed in the allograft was likely due to chronic rejection rather than autoimmune disease in the allograft. Conclusions Teenage patients referred for liver transplantation with cryptogenic liver disease should undergo work up for PFIC3. An accurate diagnosis of PFIC 3 is key for optimal management, therapeutic intervention, and avoidance of complications before the onset of end-stage liver disease.

Mariam Goubran

Ayodeji Aderibigbe

Emmanuel Jacquemin

Catherine Guettier

Safwat Girgis

Vincent Bain

Andrew L. Mason

Case report: progressive familial intrahepatic cholestasis type 3 with compound heterozygous ABCB4 variants diagnosed 15 years after liver transplantation

病例报告：肝移植15年后诊断为复合杂合ABCB4变异的进行性家族性肝内胆汁淤积症3型

Abbreviation	BMC Med. Genet.
Journal Impact	1.85

Publication Information	Publisher: BioMed Central Ltd，Publishing cycle: Irregular，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2000，Proportion of original research papers: 0.00%，Self Citation Rate:N.A.， Gold OA Rate: 99.08%
Journal Fees	$Details
Average review cycle	网友分享经验：平均12月
Average recruitment ratio	网友分享经验：约75%

BMC Medical Genetics

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