OBJECTIVE: To explore the genetic basis for a male with breast cancer and a sister who had deceased of the disease. METHODS: Medical and family history of the proband was collected. Next-generation sequencing was carried out to detect potential variant associated with breast cancer, and Sanger sequencing was used to verify the result. RESULTS: The proband was found to harbor a novel heterozygous c.6018dupT variant of the BRCA2 gene which may cause premature termination of mRNA translation, resulting in a truncated protein. Combined with the family history, the variant was deduced to be a germline mutation. Based on the American College of Medical Genetics and Genomics standards and guidelines, c.6018dupT variant of BRCA2 gene was predicted to be pathogenic (PVS1+PM1/2+PP4). CONCLUSION The germline variant of the BRCA2 gene probably underlay the breast cancer in this pedigree.
BRCA2 Protein/genetics* ; Breast Neoplasms, Male/genetics* ; Genes, BRCA2 ; Genomics ; Germ Cells ; Germ-Line Mutation ; Humans ; Male

Male ; Humans ; Germ-Line Mutation ; Prostatic Neoplasms/genetics* ; BRCA2 Protein/genetics* ; Genetic Predisposition to Disease

OBJECTIVE: To analyze the clinical features and genetic basis for a Chinese pedigree affected with familial adenomatous polyposis (FAP). METHODS: Clinical information of the patient was collected. Genomic DNA was extracted from peripheral blood sample of the patient and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The proband, a 33-year-old female, was found to have multiple adenomatous polyps in the intestine. WES revealed that she has harbored a heterozygous variant of the APC gene, namely c.1922dupA (p.N641fs*10), which was unreported previously. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic. CONCLUSION The c.1922dupA (p.N641fs*10) variant of the APC gene probably underlay the FAP in this pedigree. Above finding has enabled genetic counseling for this family.
Female ; Humans ; Adult ; Pedigree ; Adenomatous Polyposis Coli Protein/genetics* ; Germ-Line Mutation ; Adenomatous Polyposis Coli/genetics* ; China ; Mutation

Dinucleotide repeat polymorphism based genetic analysis is a powerful approach to gain insight into rare genetic events like germline mosaicism and de novo mutations. The loss of heterozygosity of polymorphic dinucleotide loci at "deletional hotspot" of dystrophin gene can provide direct evidence of carrier status in female relatives of affected DMD patients with overlapped exonic deletions. We have used 4 STR loci of the central deletional hotspot of the dystrophin gene for genetic analysis in sporadic unrelated DMD families. Twenty-nine mothers of sporadic deletional cases were analysed and their carrier status was determined. Eighteen of them showed heterozygosity in the deleted loci suggesting the occurrence of de novo mutations. In 9 cases, the carrier status was indeterminate while 2 showed germline mosaicism. Our observations reiterated the importance of STR analysis in determining the status of mothers of sporadic deletional DMD cases in order to provide proper genetic counselling.
DNA Mutational Analysis ; Dystrophin/*genetics ; Female ; Germ-Line Mutation/genetics ; Haplotypes/genetics ; Heterozygote Detection ; Human ; Male ; Mosaicism/genetics ; Muscular Dystrophy, Duchenne/*genetics ; Mutation/*genetics ; Pedigree ; Sequence Deletion/genetics

OBJECTIVETo investigate the protein expression, methylation promoter, somatic and germ-line mutations of E-cadherin gene (CDH1) in hereditary gastric cancer in China and to investigate its possible roles.

METHODSEight probands diagnosed with ICG-HGC criterion were enrolled in our database from June 1994 to October 2007. Tumor tissues were detected for CDH1 expression by using immunohistochemistry (IHC) methods. CDH1 DNA sequencing was performed for all its 16 exons both in tumor and normal tissues of the same patients to detect somatic and germ-line mutations. Methylation promoter study was performed by using specific primers and polymerase chain reaction (PCR) methods.

RESULTSIHC analysis confirmed that the CDH1 expression was negative in 7 probands and downregulated in the other on proband. Six mutations in five probands were found with DNA sequencing: two silent mutations and four missense mutations. All six mutations were absent in normal tissues, thereby excluded its presence in germ-line cells. Both DNA missense mutations and gene silencing through promoter methylation was found in 4 probands. Two probands has only promoter methylation and one proband had only silent mutation. No DNA missense mutations or promoter methylation was found in one proband.

CONCLUSIONSCDH1 gene germ-line mutations are relatively rare in hereditary gastric cancer in China, and whereas CDH1 somatic mutations and promoter methylation synergistically induce CDH1 downregulation in these patients.

Cadherins ; genetics ; DNA Methylation ; DNA Mutational Analysis ; Germ-Line Mutation ; Humans ; Promoter Regions, Genetic ; genetics ; Stomach Neoplasms ; genetics

Lynch syndrome (LS), an autosomal dominantly inherited disease previously known as hereditary non-polyposis colorectal cancer (HNPCC), leads to a high risk of colorectal cancer (CRC) as well as malignancy at certain sites including endometrium, ovary, stomach, and small bowel (Hampel et al., 2008; Lynch et al., 2009). Clinically, LS is considered the most common hereditary CRC-predisposing syndrome, accounting for about 3% of all CRC cases (Popat et al., 2005). LS is associated with mutations of DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM (Ligtenberg et al., 2009; Lynch et al., 2009), which can trigger a high frequency of replication errors in both microsatellite regions and repetitive sequences in the coding regions of various cancer-related genes. Immunohistochemistry (IHC) tests followed by genetic analysis of these mutations play a significant role in diagnosis, treatment determination, and therapeutic response prediction of LS (Lynch et al., 2009; Alex et al., 2017; Ryan et al., 2017). Here, we report substitution of one base-pair in exon 1 of MLH3 (c.1397C>A) and a frameshift mutation in exon 19 of MLH1 (c.2250_2251ins AA) in a 43-year-old Chinese male with an LS pedigree.
Adult ; Asian People/genetics* ; China ; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics* ; Exons ; Female ; Frameshift Mutation ; Germ-Line Mutation ; Humans ; Male ; MutL Protein Homolog 1/genetics* ; MutL Proteins/genetics* ; Pedigree

OBJECTIVE: To carry out genetic testing and prenatal diagnosis for a family affected with Duchenne muscular dystrophy (DMD). METHODS: Multiplex ligation dependent probe amplification (MLPA) was used to detect potential deletion and duplication of the Dystrophin gene. Haplotype analysis was performed using five short tandem repeat polymorphism loci (3'-STR, 5'-STR, 45-STR, 49-STR, 50-STR of the DMD gene. RESULTS: A same deletional mutation (exons 51-55) of the DMD gene was detected in two brothers but not in their mother. The patients and fetus have inherited different haplotypes of the Dystrophin gene from their mother, suggesting that the fetus was unaffected. CONCLUSION The mother was very likely to harbor germline mosaicism for the Dystrophin gene variant. Genetic testing of peripheral blood samples cannot rule out germline mosaicism in the mother. Prenatal diagnosis should be provided for subsequent pregnancies in this family.
Dystrophin ; genetics ; Exons ; Female ; Gene Deletion ; Germ-Line Mutation ; Humans ; Male ; Mosaicism ; Muscular Dystrophy, Duchenne ; genetics ; Pregnancy ; Prenatal Diagnosis

Genes, p53 ; Genetic Predisposition to Disease ; Germ-Line Mutation ; Humans ; Li-Fraumeni Syndrome/genetics* ; Tumor Suppressor Protein p53/genetics*

OBJECTIVEThis study was aimed at establishing an efficient mutation analysis technique system to screen the germline mutations in the adenomatous polyposis coli (APC) gene that predisposes the disease susceptibility in familial adenomatous polyposis (FAP) and to investigate the relationship between genotype and phenotype of APC gene.

METHODSGenomic DNA was extracted from the peripheral blood lymphocytes of 22 patients with clinically diagnosed FAP and was forwarded to screening for germline mutations by using denaturing high-performance liquid chromatography(DHPLC), protein truncation test (PTT) and DNA sequencing in APC gene. Analysis of genotype-phenotype was also performed on the clinical data of the FAP patients.

RESULTSThirteen APC germline mutations were identified in 22 FAP patients. All of the mutations were nonsense or framshift mutations. Analysis of genotype-phenotype demonstrated that the FAP patients with mutations in the 5'or 3'extreme parts of the APC gene showed mild clinical symptoms. However, the FAP patients with mutations in the middle of the APC gene displayed typical or severe clinical symptoms.

CONCLUSIONThe technique system established in this study can efficiently and sensitively detect the mutations in APC gene. It is useful in the molecular diagnosis of pre-symptomatic FAP cases in FAP family. The clinical features of FAP patients may be related to their genotypes of APC gene.

Adenomatous Polyposis Coli ; genetics ; Adenomatous Polyposis Coli Protein ; genetics ; Chromatography, High Pressure Liquid ; DNA Mutational Analysis ; Frameshift Mutation ; genetics ; Genotype ; Germ-Line Mutation ; Humans ; Phenotype ; Polymerase Chain Reaction

MUTYH, one of base-excision repair enzymes, is associated with human genetic disorders. Inherited biallelic mutations in the human MUTYH gene are responsible for an autosomal recessive syndrome-adenomatous colorectal polyposis (MUTYH associated polyposis, MAP), which significantly increases the risk of colorectal cancer (CRC). In this article we review the relationship between BER and the oxidative damage to DNA, the functional overlap of BER with other repair proteins, the molecular mechanism of tumourigenesis in MAP, and delineate the MUTYH polyposis phenotype and its prevention.
Adenomatous Polyposis Coli ; complications ; enzymology ; genetics ; Colorectal Neoplasms ; enzymology ; etiology ; genetics ; DNA Damage ; DNA Glycosylases ; genetics ; Germ-Line Mutation ; Humans ; Mutation ; Risk Factors