[A family study of the compound heterozygous mutation of the UGT1A1 gene causing Crigler-Najjar syndrome type II].

Objective: To investigate the family gene features in Crigler-Najjar syndrome (CNS) type II. Methods: The UGT1A1 gene and related bilirubin metabolism genes were comprehensively analysed in a CNS-II family (3 CNS-II, 1 Gilbert syndrome, and 8 normal subjects). The genetics basis of CNS-II were investigated from the perspective of family analysis. Results: In three cases, compound heterozygous mutations at three sites of the UGT1A1 gene (c.-3279T > G, c.211G > A and c.1456T > G) caused CNS-II. Gilbert syndrome and CNS-II were not significantly associated with distribution or diversity loci. Conclusion: The compound heterozygous pathogenic mutations (c.-3279T > G, c.211G > A, and c.1456T > G) at three loci of the UGT1A1 gene may be the feature of the newly discovered CNS-II family genes based on the CNS-II family study.

A case report of familial renal cell carcinoma / 中华泌尿外科杂志

A total of 4 patients with renal cancer were admitted to our hospital from October 2006 to September 2015 in a familial renal cancer family. Among the 4 patients, 1 patient showed unilateral multiple clear cell carcinoma, 1 patient showed bilateral multiple clear cell carcinoma, and 2 patients showed bilateral multiple chromophobe cell carcinoma. No mutation of VHL or FLCN gene was found in all patients by genetic analysis.

Clinical characteristics and genetic mutation analysis in a family with familial vitreous amyloidosis / 中华实验眼科杂志

Objective:To analyze the clinical characteristics and transthyretin ( TTR) gene mutation of a family with familial vitreous amyloidosis (FVA). Methods:A pedigree investigation was performed.The clinical data of 20 family members of a Han family with FVA treated in the Affiliated Hospital of Guizhou Medical University from May 2005 to March 2019 were collected, including demographic data and ophthalmic examination results.Nine eyes of five patients underwent vitrectomy successively, and vitreous samples collected during operation were sent for pathological examination by Congo red staining.The best corrected visual acuity (BCVA) and intraocular pressure (IOP) were measured, and the anterior segment as well as fundus was observed under the slit lamp microscope at 1 week and 6 months after surgery.Peripheral venous blood (4 ml) was collected from 20 members in this family and DNA was extracted.The next-generation sequencing technology was used for gene detection of proband, and Sanger sequencing was performed in 20 family members including the proband.The pathogenicity of the mutation sites was analyzed according to ACMG guidelines.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of Affiliated Hospital of Guizhou Medical University (No.2019-296). Written informed consent was obtained from each subject.Results:The preoperative BCVA of the nine eyes (5 patients) remained 0.1 to 0.2 in 6 eyes, and counting fingers to 50 cm in 3 eyes, and the mean value of preoperative IOP was (15.18±1.32) mmHg (1 mmHg=0.133 kPa). Cotton-wool like opacity in the vitreous and white pedal disc punctate granule on the posterior lens capsule were seen in the 9 eyes under the slit lamp microscope.Vitreous specimens of patients were Congo red stain positive.The BCVA remained 0.8 in 8 eyes and 0.6 in 1 eye at 1 week after vitrectomy, and remained 0.8 in 6 eyes, 0.6 in 2 eyes and light perception in 1 eye at 6 months after surgery.Mean values of postoperative IOP were (15.32±2.11) mmHg and (16.13±1.25) mmHg at 1 week and 6 months after surgery, respectively.Secondary glaucoma occurred in 8 eyes at 3 to 14 years postoperatively.Mean BCVA of the 13 phenotypic normal family members (26 eyes) remained 0.8 to 1.0, and the mean value of IOP was (15.52±1.15) mmHg, and abnormalities were not found in anterior segment or fundus.Additionally, two members (4 eyes) failed to take examinations.Genetic testing revealed heterozygous mutation in p. Gly103Arg of TTR gene in 15 family members.According to ACMG guidelines, the variation score was PS1+ PM2+ PP3, and it was likely pathogenic. Conclusions:The secondary glaucoma is of relatively high incidence in patients with FVA after vitrectomy.The heterozygous mutation of TTR gene (p.Gly103Arg) might be the variation site of the family with vitreous amyloidosis.

Genetic testing and clinical phenotypic analysis of familial vitreous amyloidosis in two Han Chinese families / 中华实验眼科杂志

Objective:To investigate the clinical characteristics of two Han families with familial vitreous amyloidosis (FVA) and the gene mutation.Methods:A pedigree investigation was performed.Two Han Chinese families with FVA treated in Xiangya Hospital of Central South University from January 2015 to December 2018 were collected.General examination and ophthalmic examination were performed among 112 members of the two families.Peripheral blood samples were collected from 32 family members (15 patients in MZ001 pedigree, 7 patients in MZ002 pedigree, and 5 persons with normal clinical phenotype from each pedigree) for DNA extraction, polymerase chain reaction (PCR) amplification, transthyretin ( TTR) gene screening and sequencing.Vitreous biopsy following three-channel 23-gauge pars plana vitrectomy was performed on the two probands in the two families.Vitreous specimens were sent for pathological examination.This study adhered to the Declaration of Helsinki.The study protocol was approved by an Ethics Committee of Xiangya Hospital of Central South University (No.201412463), and written informed consent was obtained from all subjects before any medical examination. Results:In MZ001, there were 15 cases of the 63 members presented bilateral vitreous opacity at an average age of (43.6±5.8) years.No lesion was found in nervous system, cardiovascular system, kidney or liver in general inspection.The vitreous of the proband (Ⅲ13) was so sticky that could not be totally removed during vitrectomy.The vitreous specimen showed positive Congo red staining.Ⅲ13 had elevated intraocular pressure after vitrectomy and was diagnosed as open-angle glaucoma.Gene sequencing revealed Gly83Arg mutation in the exon 3 of TTR gene.In MZ002, 7 cases of 49 members had bilateral vitreous opacity at an average age of (50.4±5.5) years, among which, 3 cases appeared symptoms of limb numbness and decreased muscle strength.The vitreous body of the proband (Ⅱ11) in MZ002 pedigree was looser and easier to remove during vitrectomy than that of Ⅲ13 in MZ001 pedigree.Vitreous specimen of Ⅱ11 was positive with Congo red staining.Gene sequencing revealed an Ala36Pro variant in the exon 3 of TTR gene. Conclusions:Gly83Arg or Ala36Pro mutation of TTR gene can cause FVA.Different mutations can lead to different clinical phenotypes such as age of onset, clinical symptoms and complications of other systems.

Polygenic basis for adaptive morphological variation in a threatened Aotearoa | New Zealand bird, the hihi (Notiomystis cincta).

To predict if a threatened species can adapt to changing selective pressures, it is crucial to understand the genetic basis of adaptive traits, especially in species historically affected by severe bottlenecks. We estimated the heritability of three hihi (Notiomystis cincta) morphological traits known to be under selection (nestling tarsus length, body mass and head-bill length) using 523 individuals and 39 699 single nucleotide polymorphisms (SNPs) from a 50 K Affymetrix SNP chip. We then examined the genetic architecture of the traits via chromosome partitioning analyses and genome-wide association scans (GWAS). Heritabilities estimated using pedigree relatedness or genomic relatedness were low. For tarsus length, the proportion of genetic variance explained by each chromosome was positively correlated with its size, and more than one chromosome explained significant variation for body mass and head-bill length. Finally, GWAS analyses suggested many loci of small effect contributing to trait variation for all three traits, although one locus (an SNP within an intron of the transcription factor HEY2) was tentatively associated with tarsus length. Our findings suggest a polygenic nature for the morphological traits, with many small effect size loci contributing to the majority of the variation, similar to results from many other wild populations. However, the small effective population size, polygenic architecture and already low heritabilities suggest that both the total response and rate of response to selection are likely to be limited in hihi.

[A study on the pedigree of the academic inheritance of Li Shicai].

Li Shicai, a famous physician of Ming Dynasty had a large number of students. Shen Langzhong, who was a student of Li Shicai, was the teacher of Ma Yuanyi, and one of Ma's student was You Zaijing. This inheritance pedigree was called "Li Shicai School" in academic communities. There were little of study on its later physicians after You Zaijing. This paper collated the medical works, genealogy, local chronicles and medical records of Li Shicai and doctors of different generations. We clarified the academic inheritance genealogy of the past four hundred years. Up to now, there have been twelve generations totally.

Study on the birth order of patients with gastric cancer in Shanxi Provincial Cancer Hospital / 肿瘤研究与临床

Objective To analyze the birth order of gastric cancer patients in Shanxi Provincial Cancer Hospital,and to explore the relationship between environmental factors,genetic factors and gastric cancer.Methods The Greenwood and Yule,Haldane and Smith birth order methods were used to conduct an epidemiological investigation on 554 patients with gastric cancer surgery from January 2004 to December 2007 in Shanxi Provincial Cancer Hospital,and the birth order of their siblings was studied.Results Results from the Greenwood and Yule method showed that there was a tendency for patients with gastric cancer in birth order first to third.However,the Haldane and Smith method showed that the results were quite different between actual value and the average theory value of 6A [6A(actual value)=7 644,(x)6A(average theory value)=8 511,x=|6A-(x)6A|/√v6A=4.86,x＞2,P <0.01] which suggested that the birth order had some effects on the occurrence of gastric cancer.In addition,the actual value of 6A was lower than theoretic average value,and the parents at younger productive age or baby at the first birth was easy to develop gastric cancer.Conclusions Gastric cancer patients in Shanxi Provincial Cancer Hospital is related with the birth order,especially at early order.There are certain effects of environmental risk factors on gastric cancer.

Feasibility of collecting tumor samples of breast cancer patients diagnosed up to 50 years ago in the Child Health and Development Studies.

Environmental exposures during pregnancy may increase breast cancer risk for mothers and female offspring. Tumor tissue assays may provide insight regarding the mechanisms. This study assessed the feasibility of obtaining tumor samples and pathology reports from mothers (F0) who were enrolled in the Child Health and Development Studies during pregnancy from 1959 to 1967 and their daughters (F1) who developed breast cancer over more than 50 years of follow-up. Breast cancer cases were identified through linkage to the California Cancer Registry and self-report. Written consent was obtained from 116 F0 and 95 F1 breast cancer survivors to access their pathology reports and tumor blocks. Of those contacted, 62% consented, 13% refused and 24% did not respond. We obtained tissue samples for 57% and pathology reports for 75%, and if diagnosis was made ⩽10 years we obtained tissue samples and pathology reports for 91% and 79%, respectively. Obtaining pathology reports and tumor tissues of two generations is feasible and will support investigation of the relationship between early-life exposures and molecular tumor markers. However, we found that more recent diagnosis increased the accessibility of tumor tissue. We recommend that cohorts request consent for obtaining future tumor tissues at study enrollment and implement real-time tissue collection to enhance success of collecting tumor samples and data.

Study on DNA methylation in three neural tube defects pedigrees / 中华实用儿科临床杂志

Objective To investigate the methylation alteration of genomic DNA (gDNA) and its significance in pedigree neural tube defects (NTDs).Methods Twelve subjects from 3 NTDs pedigrees were enrolled in this study.NTDs patients were served as the case group,and their family members with normal phenotype were served as the control group.Peripheral vein blood was extracted,then gDNA was extracted.The extracted gDNA was treated with sodium bisulfite propagated as DNA segments in the way of whole genome amplification,which was put in I11umina Infinium human methylation 450k bead chip to perform hybridization,elution,extension,and imaging.The chip was scanned by iScan.Genome Studio was used to read the outcome.Illumina methylation analyzer software was used to analyze the methylation data.Results Gene differential methylation analysis showed that differential methylation sites only accounted for 0.2％ of the detected CpG sites and there were 617 differential hypermethylation sites (P ＜ 0.05),and 63 of them represented significant difference(P ＜ 1 × 10-4),including zinc finger E-box binding homebox 2,5,10-methylenetetrahydrofolate dehydrogenase 1 etc;there were 104 differential hypomethylation sites (P ＜ 0.05),and 65 of them represented significant difference (P ＜ 0.01),including Homeobox B7 and runt-related transcription factor 3 etc.Clustering analysis indicated that the tendency of DNA hypermethylation was consistent with NTDs patients,but the tendency of DNA hypomethylation was consistent with the controls.Conclusion In NTDs pedigree,the abnormal DNA methylation alterations may be the risk factor for NTDs occurrence.

Study on DNA methylation in three neural tube defects pedigrees / 中华实用儿科临床杂志

Objective To investigate the methylation alteration of genomic DNA (gDNA) and its significance in pedigree neural tube defects (NTDs).Methods Twelve subjects from 3 NTDs pedigrees were enrolled in this study.NTDs patients were served as the case group,and their family members with normal phenotype were served as the control group.Peripheral vein blood was extracted,then gDNA was extracted.The extracted gDNA was treated with sodium bisulfite propagated as DNA segments in the way of whole genome amplification,which was put in I11umina Infinium human methylation 450k bead chip to perform hybridization,elution,extension,and imaging.The chip was scanned by iScan.Genome Studio was used to read the outcome.Illumina methylation analyzer software was used to analyze the methylation data.Results Gene differential methylation analysis showed that differential methylation sites only accounted for 0.2％ of the detected CpG sites and there were 617 differential hypermethylation sites (P ＜ 0.05),and 63 of them represented significant difference(P ＜ 1 × 10-4),including zinc finger E-box binding homebox 2,5,10-methylenetetrahydrofolate dehydrogenase 1 etc;there were 104 differential hypomethylation sites (P ＜ 0.05),and 65 of them represented significant difference (P ＜ 0.01),including Homeobox B7 and runt-related transcription factor 3 etc.Clustering analysis indicated that the tendency of DNA hypermethylation was consistent with NTDs patients,but the tendency of DNA hypomethylation was consistent with the controls.Conclusion In NTDs pedigree,the abnormal DNA methylation alterations may be the risk factor for NTDs occurrence.

Genome-wide genetic and transcriptomic investigation of variation in antibody response to dietary antigens.

Increased immunoglobulin G (IgG) response to dietary antigens can be associated with gastrointestinal dysfunction and autoimmunity. The underlying processes contributing to these adverse reactions remain largely unknown, and it is likely that genetic factors play a role. Here, we estimate heritability and attempt to localize genetic factors influencing IgG antibody levels against food-derived antigens using an integrative genomics approach. IgG antibody levels were determined by ELISA in >1,300 Mexican Americans for the following food antigens: wheat gliadin; bovine casein; and two forms of bovine serum albumin (BSA-a and BSA-b). Pedigree-based variance components methods were used to estimate additive genetic heritability (h(2) ), perform genome-wide association analyses, and identify transcriptional signatures (based on 19,858 transcripts from peripheral blood lymphocytes). Heritability estimates were significant for all traits (0.15-0.53), and shared environment (based on shared residency among study participants) was significant for casein (0.09) and BSA-a (0.33). Genome-wide significant evidence of association was obtained only for antibody to gliadin (P = 8.57 × 10(-8) ), mapping to the human leukocyte antigen II region, with HLA-DRA and BTNL2 as the best candidate genes. Lack of association of known celiac disease risk alleles HLA-DQ2.5 and -DQ8 with antigliadin antibodies in the studied population suggests a separate genetic etiology. Significant transcriptional signatures were found for all IgG levels except BSA-b. These results demonstrate that individual genetic differences contribute to food antigen antibody measures in this population. Further investigations may elucidate the underlying immunological processes involved.

Clinical and genetic research in a Chinese family with Stickler syndrome type 1 / 中华实验眼科杂志

Background Stickler syndrome is a genetic connective tissue disorder that affects the ocular,skeletal,orofacial and auditory systems.To determine the gene mutation loci can offer a basis for genetic diagnosis and management of Stickler syndrome.Objective The aim of this study was to research the clinical characteristics of a pedigree with Stickler syndrome and identify the disease-causing gene mutation.Methods This study was approved by Ethic Committee of Peking Union Medical College Hospital.The clinical study and pedigree analysis were performed in one family with Stickler syndrome type Ⅰ (STL Ⅰ).Nine family members were examined with informed consent.The entire coding regions of COL2A1 gene with flanking intronic regions were amplified by PCR and directly sequenced.The detected sequence change was confirmed to be mutationloci by examining whether they existed in normal control individuals.Mutant proteins were predicted with online software.Results There were 4 generations and 11 members in this family,and 2 members died,including 1 patient.Three patients were found in 9living families.Inheritance of this family complicd with an autosomal dominant inheritance mode.All affected individuals showed the consistent phenotypes with STL Ⅰ,including high myopia,membranous vitreous anomaly and surface central flat,short nose,palatoschisis,etc.Mutation screening of COL2A1 gene revealed that the first base of intron 12 was deleted(IVS12+1G del).Nucleotide sequence analysis showed that this mutation led to the functional abnormal of this gene by forming termination cordon in advance.This mutation occurred in all affected individuals,however,no mutation was observed in any unaffected member or 100 normal unrelated individuals.Conclusions This study identifies a novel splice-site mutation(IVS12+ 1G del)in COL2A1 gene in a Chinese STL Ⅰ pedigree.This is the first report on a mutation in a Chinese STL Ⅰ family.

Study on the birth order of patients with esophagus cancer in Shanxi province / 中华流行病学杂志

Objective To explore the relationship between esophagus cancer patients and both environmental and genetic factors,through analyzing the data on birth orders from esophagus cancer patients of Shanxi province.Methods Both Greenwood and Haldane methods on birth order were used to study the 1101 cases with esophagus cancer from Shanxi province.All the patients had received surgery and were diagnosed,by pathological evidence.First certificates of the patients were confirmed through the standard genetic epidemiologic investigation.Birth order was investigated on probands of the 1101 cases with esophagus cancer and their 44 siblings.Results Results form the Greenwood method showed that there was a tendency for cases with esophagus cancer in birth orders First to Third.However,the Haldane method showed that the results were quite different between actual value and the average theory value of 6A (6A(actual value)=17 118,(X)6A(average theory value) =19 290,X=∣6A-(X)6A∣/√V6A =7.63,X ＞ 2) which suggested that the birth order had some effects on the occurrence of esophagus cancer.In addition,the actual value of 6A was lower than the theoretic average value,and the parents at younger productive age or baby at the first birth was easy to develop esophagus cancer.Conclusion Esophagus cancer was related with the birth order,especially at early order,which was not consistent with the national reports on esophagus cancer.Results from this study suggested that there were certain effects of environmental risk factors on esophagus cancer patients.

Identification of G7304A Mutation in the Ryanodine Receptor Type 1 Gene in a Patient with Malignant Hyperthermia and an Extended Pedigree Study in a Korean Malignant Hyperthermia Family / 대한마취과학회지

BACKGROUND: Malignant hyperthermia (MH) is a disorder of the skeletal muscle manifested as a life threatening hypermetabolic crisis in susceptible individuals following exposure to inhalation anesthetics and depolarizing muscle relaxants. MH susceptibility (MHS) is inherited as an autosomal dominant trait and mutations in the gene encoding skeletal muscle ryanodine receptor (RYR1) are considered a common cause of the disorder. To date, more than 25 RYR1 mutations have been reported in families from Europe and North America. In Korea, however, little is known about the mutations in this candidate gene. METHODS: For the analysis of novel or previously published known RYR1 mutations in 13 exons of the RYR1 gene, PCR amplification and direct sequencing were performed in the proband. After identification of RYR1 mutation in the proband, we performed an extended pedigree study with informed consent from 160 members of a Korean MH family. DNA from 160 members of this family was screened for the presence or absence of RYR1 mutation identified in the proband. RESULTS: We identified a heterozygous G7304A mutation (Arg2435His) in exon 45 of the RYR1 gene in the proband. Six members of the family suffered fatal MH reaction and died. Two members including this proband had a fulminant MH episodes but survived. Two members of the family had presented with severe muscle hypotonia. PCR amplification for the screening of the site yields a fragment of 256 base pair (bp), which is fully cleaved into two fragments of 169 bp and 87 bp by Hga1 in normal individuals and 50% cleaved in individuals with a heterozygous mutation. We found the heterozygous G7304A mutation in 30 individuals from the 160 family members. CONCLUSIONS: This result is the first report to identify the mutation of RYR1 in patients with malignant hyperthermia in Korea. Further larger scale studies will provide important data regarding the frequency of occurrence of the RYR1 mutations in Korea and insight into the practicality of genetic screening relative to diagnosis of MHS and prevention of MH episodes and MH-related problems.