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PubMed2006

Is FKBP5 a genetic marker of affective psychosis? A case control study and analysis of disease related traits.

BACKGROUND: A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as an important pathogenic factor in depression. Genetic variants of FKBP5, a protein of the HPA system modulating the glucocorticoid receptor, have been reported to be genetically associated with improved response to medical treatment and an increase of depressive episodes. METHODS: We examined three single nucleotide polymorphisms (SNPs) in FKBP5, rs4713916 in the proposed promoter region, rs1360780 in the second intron and rs3800373 in the 3'-untranslated region (3'-UTR), in a case-control study of Caucasian origin (affective psychosis: n = 248; controls: n = 188) for genetic association and association with disease related traits. RESULTS: Allele and genotype frequencies of rs4713916, rs1360780 and rs3800373 were not significantly different between cases and controls. Two three-locus haplotypes, G-C-T and A-T-G, accounted for 86.2% in controls. Odds ratios were not increased between cases and controls, except the rare haplotype G-C-G (OR 6.81), representing 2.1% of cases and 0.3% of controls. The frequency of rs4713916AG in patients deviated from expected Hardy-Weinberg equilibrium, the genotype AA at rs4713916 in monopolar depression (P = 0.011), and the two-locus haplotype rs1360780T--rs3800373T in the total sample (overall P = 0.045) were nominally associated with longer continuance of disease. CONCLUSION: Our data do not support a significant genetic contribution of FKBP5 polymorphisms and haplotypes to affective psychosis, and the findings are inconclusive regarding their contribution to disease-related traits.

Bipolar Disorder↗
PubMed2026

Precision medicine and parental experience: a longitudinal study of psychosocial responses to germline genomic results in pediatric oncology.

INTRODUCTION: Precision medicine has become central to pediatric oncology, with germline genomic sequencing commonly integrated into routine care. Families must interpret complex genomic findings during emotionally vulnerable periods, generating mixed reactions ranging from clarity and relief to anxiety and uncertainty. Palliative care clinicians, genetic counselors, psychologists, social workers, and oncology providers may each contribute to supporting families as they interpret and integrate these findings over the course of a child's cancer care and beyond. Little is known about the trajectory of parental emotional and cognitive responses after receiving germline sequencing results, limiting clinicians' ability to anticipate support needs across the cancer care continuum. This study quantitatively examines parental emotional and cognitive responses across time following disclosure of germline sequencing results in a pediatric oncology setting. METHODS: Parents (n = 218) self-reported sequencing-related distress, positive feelings, intrusive thoughts, certainty, and self-efficacy using validated measures at two longitudinal follow-up points after disclosure of their child's germline test results. Outcomes were compared across germline test result types (pathogenic/likely pathogenic [P/LP], n = 31 [14%]; variants of uncertain significance [VUS], n = 86 [39%]; and negative, n = 101[46%]). RESULTS: Parents of children receiving P/LP or P/LP+VUS results reported significantly higher distress yet greater positive feelings than parents receiving negative results. Notably, certainty and self-efficacy increased from Timepoint 1 (median 254 days following return of results) to Timepoint 2 (median 537 days). Intrusive thoughts did not significantly differ by genetic result type or change over time; however, the factors contributing to intrusive thoughts could not be determined from the current study. DISCUSSION: These findings provide insight into how families adapt to germline genomic information following a pediatric cancer diagnosis. As precision medicine becomes increasingly embedded in pediatric oncology, structured follow-up and communication that address families' evolving informational and psychosocial needs are essential to ensure care that is scientifically precise, emotionally attuned, and centered on the family experience.

family-centered care↗
PubMed2001

Managing influenza: amantadine, rimantadine and beyond.

Amantadine and rimantadine are effective in the treatment and prophylaxis of influenza A. Neither drug, however, has achieved widespread acceptance because of the rapid development of viral resistance, their lack of activity against influenza B and, in the case of amantadine, adverse events. Complete cross-resistance occurs with these compounds and is associated with a single nucleotide change in the M2 protein. Resistant variants are transmissible and fully pathogenic. Zanamivir is the first widely approved neuraminidase inhibitor for the treatment of influenza. It is delivered directly to the primary site of viral replication, the respiratory tract, and is well tolerated and effective in the treatment of both influenza A and B. Data in prophylaxis are also encouraging. During the extensive clinical programme no evidence for the emergence of drug-resistant strains with acute therapy was found. Zanamivir represents a significant advance over older agents in the management of influenza A and B.

Adolescent↗
PubMed2004

[Amplification test-systems in the diagnosis of hemorrhagic fever with renal syndrome and in studies of viral pathogens].

The "VectoHantivirus-ampli" test system based on rtPCR was shown as fitting the detection of virus RNA in blood samples of patients with hemorrhagic fever with renal syndrome (HFRS) made at early stages and no later than 7 days from the disease onset. A sequence analysis of viral nucleotide sequences of PCR products produced by the test-system ensured the identification of Hantaviruses (pathogens of HFRS). Two genetic variants of Puumula virus were shown to circulate in the territory of the Bashkortostan Republic; they differ by 10.0-13.8%, one of them is absolutely new. The Hantan virus FE genetic variant was detected in the studied samples from the Khabarovsk Territory.

Bashkiria↗
PubMed2006

[A comparative analysis of molecular-genetic peculiarities of the genomes of cholera, plague and anthrax agents and their evolutional transformations].

Cholera, plague, and anthrax, the diseases that have accounted for millions of human victims, still endanger the entire mankind by possible development of epidemic outbreaks due to their spread or application as bioterrorist agents. Generalized results of research into the genomic features of the Vibrio cholerae, Yersinia pestis, and Bacillus anthracis are discussed. Despite different frequencies of evolutional transformations occurring in their genomes, that are likely to be associated with diverse life cycles of the pathogens, clones with altered diagnostic, and virulence characteristics were shown to have a fair probability of formation. Also presented in the review, are literature data concerning the main evolutional stages for any of these pathogens, determination of new genetic variants, consideration of the mechanisms facilitating maintenance of the microbial agents during the interepidemic periods.

Anthrax↗
PubMed1993

Current status of models for testing antibiotic residues.

Models for testing the effect of antibiotic residues on the human gut flora should be (i) feasible (quality of data, statistics, price, duration), (ii) sensitive (baseline resistance, background variability, response to low doses), and (iii relevant (composition and ecology of the flora, predictive value). An evaluation of existing models led to the following conclusions: 1. Flora. Relevant models must include anaerobic flora that antagonize colonization by minor bacterial populations. In vitro tests on pure strains, batch or continuous flow cultures, do not take this barrier effect into account. 2. Drug treatment. Treatment should be long enough to allow the detection of indirect selection due to a weakening of the barrier effect (i.e., greater than 15 days). For dose response analysis, trials should include at least 3 groups: a control group, an experimental group given the antibiotic at residue levels, and a positive control group given a high dose of the same drug. 3. Target strain(s). The target bacteria should be identified, resident in the gut, accurately countable, drug susceptible but with drug resistant variants, and related to a pathogen. Some gut aerobes meet these requirements: sensitive to the ecosystem balance, easy to count accurately, opportunistic pathogens, and R-plasmid carriers. Total anaerobes are not suitable. An anaerobe species may serve as a target strain if it is particularly susceptible to, or selected by, the test antibiotic. Thus, each in vivo protocol should be based on in vitro data. 4. Measure of resistance. The determination of the minimum inhibitory concentration (MIC) of selected clones from the model flora is time consuming, does not detect subdominant resistance (less than 1%); and a MIC shift is difficult to test statistically. In contrast, direct counting of bacteria on drug supplemented media allows for the rapid measure of minor resistant populations. 5. Statistics. Most published designs do not include a power calculation, nor yield enough data points for accurate statistical analysis. Sufficient statistical power is critical for studies using conventional humans and animals, because the data are highly variable and not normally distributed. 6. Human trials. The lowest level of antibiotic tested in human volunteers (2 mg oxytetracycline/day for 7 days in 6 subjects) increased the proportion of resistant fecal enterobacteria (p = 0.05). However, the large day-to-day and inter individual variation in the human flora limit the significance of this change. Confirmation of this finding would require a large number of volunteers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA.

In order to identify putative adaptive human mitochondrial DNA (mtDNA), transfer RNA (tRNA), and ribosomal RNA (rRNA) variants, we assembled a sequential mutational tree from 2,460 human mtDNA coding sequences, thus providing the relative age of all mtDNA sequence variants. Deleterious mutations affect evolutionarily conserved nucleotides and have been eliminated from the older internal branches of the tree by purifying selection, while beneficial mutations also alter conserved nucleotides but have been enriched in the internal branches of the tree by adaptive selection. Neutral polymorphisms alter poorly conserved nucleotides and are distributed throughout the tree. Stem nucleotides are more constrained than loop nucleotides. The functional importance of both types of nucleotide variants was assessed by comparison to the average evolutionary conservation index (CI) of all known pathogenic tRNA mutations, thus permitting discrimination between internal branch neutral and adaptive tRNA variants. This revealed that 19% of the stem and 13% of the loop internal branch tRNA variants were potentially adaptive. Since few pathogenic rRNA mutations are known, evidence for adaptive rRNA variation was revealed by higher stem to loop variant ratios and elevated CIs in the internal branches vs. external branches. Moreover, variants among stem noncanonical apposition bases predominantly created new Watson-Crick (WC) base pairs, thus also suggesting adaptive selection. Among the putative adaptive tRNA and rRNA polymorphisms, a number were found to occur at the base of the branches of the tree, to have recurred multiple times, and to be associated with altered human phenotypes. Therefore, a significant portion of ancient tRNA and rRNA polymorphisms appear to have been adaptive, and these are affecting human health today.

Animals↗
PubMed2000

[Contagious impetigo--pathogen spectrum and therapeutic consequences].

OBJECTIVE: The aim of this prospective study was to compare the clinical picture of contagious impetigo (C.I.) with the causative organism and to generate data of the susceptibility of bacteria as the basis for adequate therapy. PATIENTS AND METHODS: In 126 patients with C.I. (86 children, 66 of them younger than 10 years) bacterial swabs were taken and antibiotic sensitivity testing for isolated organisms was tested. RESULTS: In all cases in which contents of vesicles or pustules were analysed, Staphylococcus aureus was the only pathogen isolated. In non-bullous variants of C.I. Staphylococcus aureus was the most often isolated organism as well. Both staphylococci and streptococci were isolated in 12 cases, whereas in just 9 cases streptococci were the only pathogen detected. All Staphylococcus aureus isolates were sensitive to flucloxacillin and cefotaxime. Erythromycin-resistance amounted to more than 20 percent. The percentage of resistant staphylococci against the predominantly topically applied antibiotics fusidinic acid and mupirocin was 2 and 0 per cent, respectively. CONCLUSION: For all manifestations of C.I. Staphylococcus aureus is at present the leading organism which has to be taken into consideration for treatment. If oral antibiotic therapy is indicated, penicillinase-stable penicillins or cephalosporins, preferably of the cefalexin-type, are the drugs of choice. Macrolides are no longer recommended for initiating of C.I. treatment.

Adult↗
PubMed2026

A Novel Splice Variant in the COL1A1 Gene Leads to Exon 46 Skipping and Osteogenesis Imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a clinical and genetic disorder characterised by bone fragility, growth deficiency and skeletal deformity. Ninety per cent of OI cases are attributable to autosomal dominant variants in the COL1A1 and COL1A2 genes. METHODS: Candidate variants were identified and verified through trio whole-exome sequencing (trio-WES), copy number variation sequencing (CNV-seq) and Sanger sequencing. Minigene splicing assays were performed in HeLa and HEK293T cells with pcDNA3.1 and pcMINI-C vectors to investigate the function of the candidate variants. A systematic review of COL1A1 splicing variants and the corresponding genotype-phenotype spectrum was performed. RESULTS: Trio-WES revealed a novel heterozygous variant in the C-terminal region of the COL1A1 gene: NM_000088.4:c.3423+5G>A. Sanger sequencing confirmed the variant in both the proband (II-2) and her foetus (III-1) who were clinically suspected of having OI. The c.3423+5G>A variant causes complete skipping of Exon 46, as demonstrated by a minigene splicing assay. We retrieved 419 COL1A1 splicing variants from PubMed, excluded 15 without phenotypic data and 2 linked to Ehlers-Danlos syndrome and stratified the remaining 402 variants into three types on the basis of splice site location: (1) Variants at canonical splicing sites (77.8%, 313/402) mostly cause mild phenotypes, whereas a minority may be severe. (2) Intron variants in other locations, such as splice region variants (17.9%, 72/402), usually cause mild clinical phenotypes, and deep intronic splice variants (0.4%, 2/402) that may result in severe phenotypes. (3) Other variants (3.7%, 15/402), such as exon variants or fragment loss, are extremely rare. We also preliminarily discuss the mechanisms underlying phenotypic variability and the characteristics of C-terminal variants. CONCLUSIONS: This intron variant in COL1A1 was classified as likely pathogenic and was confirmed to disrupt COL1A1 expression. The summary analysis results also revealed a correlation among splicing variants, C-terminal region variants and disease, suggesting that variant location provides a useful framework for prognosis prediction.

Female↗
PubMed1990

Infectious but nonpathogenic isolate of Borrelia burgdorferi.

We document for the first time an infectious but nonarthritogenic variant of Borrelia burgdorferi. Strain 25015, previously isolated from an Ixodes dammini larva collected in upstate New York, was infectious but failed to produce arthritis or carditis in laboratory rats and mice. By contrast, pathogenic strain N40 invariably caused arthritis. This nonarthritogenic variant, with proteins with molecular weights different from those of the standard B31 strain, was frequently isolated from normal joint tissues of experimentally infected rats. Outer surface proteins A and B of strain 25015 have molecular weights of about 32,500 and 35,500, respectively, in contrast to molecular weights of approximately 31,000 and 34,000, respectively, for outer surface proteins A and B of strains B31 and N40. A prominent low-molecular-weight protein of about 23,500 also characterizes strain 25015. Test animals infected for 30 to 60 days had relatively high antibody titers (greater than or equal to 1:1,280). The nonarthritogenic variant will be useful, along with pathogenic strains, in providing comparative insight into the pathogenesis of Lyme borreliosis. Homologous immunoblotting of sera from rats and mice inoculated with both the arthritogenic and nonarthritogenic strains revealed antibody reactivities to proteins of B. burgdorferi different from those revealed in the heterologous tests.

Animals↗
PubMed1979

[Immunological characteristics of the protein antigens of the family Neisseriaceae. II. The importance of an immunochemical analysis of the protein complexes for a study of taxonomy problems].

The study of antigenic interrelations in the family Neisseriaceae resulted in the isolation of 2 main immunologically separated variants of protein complexes: the first variant was characteristic of nonpathogenic and pathogenic species of the genus Neisseria as well as of 7 taxonomically undefined Neisseria species (N. lactamicus, N. cuniculi, N. ellongata, N. ovis, N. animalis, N. cinerea, N. canis) and Gemella haemolysans; the second variant was represented by the genera Branhamella and Acinetobacter. N. caviae and 3 out of 14 Neisseria strains of undefined species had no common antigens with the genera Neisseria and Branhamella. The importance of the immunotyping of protein complexes for studying the problems connected with the taxonomy of the family Neisseriaceae was considered.

Antigens, Bacterial↗
PubMed1992

Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily.

The F1 progeny of autoimmune NZB and normal SWR mice uniformly develop severe and accelerated lupus nephritis. The (SWR x NZB)F1 mice produce an oligoclonally expanded population of nephritogenic anti-DNA autoantibodies that share a recurrent cross-reactive idiotype (Id564), use highly homologous VH genes and surprisingly have the CH region allotype of the normal SWR parent. From extensive library analyses, we isolated 15 SWR germ-line genes which are most closely related to the pathogenic autoantibody VH564 gene and which also belong to the NPb subfamily of J558 VH genes. We found that the pathogenic VH genes are probably somatic variants of a SWR germ-line VH gene, SW6-3, and they have several basic amino acid substitutions, in addition to those already present in the SW6-3 germ-line gene. Since these pathogenic autoantibodies are not detectable in the sera of the normal SWR mice despite the presence of the SW6-3 gene, strong selection and expansion of B cells expressing the SW6-3 VH gene is probably occurring in (SWR x NZB)F1 lupus-prone mice. We also isolated eight germ-line genes from the NZB mouse which are homologous to SW6-3. The autoimmune NZB parent that rarely develops nephritis lacks the SW6-3 gene, but has several highly homologous germ-line VH genes that would encode less cationic antibodies. These results establish a correlation between structure and pathogenic potential of VH genes.

Amino Acid Sequence↗
PubMed2006

A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan.

Mutations in the LRRK2 gene are a cause of autosomal dominant Parkinson's disease (PD). Whether LRRK2 variants influence susceptibility to the commoner, sporadic forms of PD remains largely unknown. Data are particularly limited concerning the Asian population. In search for novel, biologically relevant variants, we sequenced the LRRK2 coding region in Taiwanese patients with PD. Four newly identified variants and another variant recently found in a Taiwanese PD family were tested for association with the disease in a sample of 608 PD cases and 373 ethnically matched controls. Heterozygosity for the Gly2385Arg variant was significantly more frequent among PD patients than controls (nominal p value=0.004, corrected for multiple comparisons=0.012, gender- and age-adjusted odds ratio=2.24, 95% C.I.: 1.29-3.88); this variant was uniformly distributed across genders and age strata. Two novel variants, Met1869Val and Glu1874Stop, were found in one PD case each; their pathogenic role remains, therefore, uncertain. The remaining two novel variants (Ala419Val and Pro755Leu) were present with similar frequency in cases and controls, and were therefore, interpreted as disease-unrelated polymorphisms. Our findings suggest that the LRRK2 Gly2385Arg is the first identified, functionally relevant variant, which acts as common risk factor for sporadic PD in the population of Chinese ethnicity.

Adolescent↗
PubMed2026

[Genetic and phenotypic analysis of three children with Neurodevelopmental disorders due to variants of DEAF1 gene].

OBJECTIVE: To explore the genetic characteristics and clinical phenotypes of three children with novel DEAF1 gene variants. METHODS: Three children who were referred to Capital Children's Medical Center Affiliated to Capital Medical University between January 2018 and December 2025 were selected as study subjects and underwent whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing, and their pathogenicity was evaluated based on the guidelines from American College of Medical Genetics and Genomics (ACMG). A systematic search of databases including PubMed and CNKI was conducted to compile previously reported cases of DEAF1 variants for clinical phenotype comparison. For the non-canonical splice site variant c.870+5G>C located in the intronic region, wild-type and mutant minigene reporter vectors were constructed and transfected into HeLa and 293T cells, respectively, and the splicing patterns were analyzed by RT-PCR and Sanger sequencing. This study was approved by the Medical Ethics Committee of Capital Institute of Pediatrics (Ethics No.: SHERLL 2020001). RESULTS: All three children were found to have carried de novo heterozygous variants of the DEAF1 gene, including two missense variants (c.764G>A, c.641T>C) in the important SAND domain and a splice site variant (c.870+5G>C) in a non-canonical splicing region. The c.764G>A and c.870+5G>C variants were unreported previously. All children had presented with intellectual developmental delay, and two were accompanied by autism spectrum disorder, and two had epilepsy and sleep disorders. In vitro minigene splicing assay showed that the c.870+5G>C variant can lead to abnormal splicing. CONCLUSIONS: This study reported three children with novel DEAF1 variants, two of which have not been previously described, thereby enriched the mutational spectrum of the DEAF1 gene. In vitro functional assay combined with the clinical manifestations of the patients confirmed the pathogenicity of the non-canonical splice site variant in the intronic region.

Humans↗
PubMed2005

Patients with an unclassified genetic variant in the BRCA1 or BRCA2 genes show different clinical features from those with a mutation.

PURPOSE: To obtain and compare the probabilities of finding a mutation in the BRCA1 or BRCA2 genes, the clinical features, and the family history among patients with an unclassified variant (UV) and those with a pathogenic mutation. PATIENTS AND METHODS: The study included 70 patients: 24 with a UV (BRCA1, n = 4; BRCA2, n = 19; both, n = 1), and 46 with a mutation (BRCA1, n = 32; BRCA2, n = 14). Two of the UVs were novel variants; the rest had been reported previously as UVs. Probabilities of finding a mutation were retrospectively obtained using BRCAPRO and Myriad II programs. RESULTS: The probability to detect a mutation was significantly lower in the group of patients with a UV than in those with a mutation (BRCAPRO [mean +/- standard deviation], 0.297 +/- 0.312 v 0.627 +/- 0.315, P = .001; and Myriad II, 0.124 +/- 0.090 v 0.283 +/- 0.176, P = .001, respectively). Independent predictive factors of finding either a UV or a mutation were number of affected relatives (2.9 +/- 1.4 v 4.0 +/- 1.9; P = .039) and number of tumors among relatives (3.3 +/- 1.4 v 4.4 +/- 1.8; P = .031), respectively. CONCLUSION: The combined data about the predictive models show significant differences between both groups. Individual probabilities can be regarded as a help to guide the clinical management of patients with a UV in those genes. However, a definitive conclusion about the pathogenicity of a UV can not be obtained from the clinical features alone, but only in combination with biochemical and epidemiologic data.

Adult↗
PubMed2025

Whole-exome sequencing uncovers the genetic basis of hereditary concomitant exotropia in ten Chinese pedigrees.

PURPOSE: To explore possible pathogenic genes for concomitant exotropia using whole-exome sequencing. METHODS: In this study, 47 individuals from 10 concomitant exotropia (including intermittent exotropia and constant exotropia) pedigrees were enrolled. Whole-exome sequencing was used to screen mutational profiles in 25 affected individuals and 10 unaffected individuals. Sanger sequencing and in silico analysis were performed for all participants. Two target genes were used to capture the sequences of 220 sporadic samples. RESULTS: All 10 concomitant exotropia pedigrees presented autosomal dominant inheritance with childhood onset (3.35 ± 1.51 years old). Eleven different missense variants were identified among seven potential pathogenic genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that cosegregated with pedigree members. All variants were predicted to be deleterious and had low frequencies in the general population. Distinct variants of COL4A2 were present in three pedigrees, and distinct variants of SYNE1 were present in two pedigrees. Fifteen variants in AUTS2 and four variants in GTDC2 were identified in 220 patients with sporadic concomitant exotropia using a target-capture sequencing approach. CONCLUSION: This is the first study to explore the genetic mechanism of concomitant exotropia and identify seven associated genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that may be candidate genes causing concomitant exotropia. More samples and in-depth studies are needed to verify these findings.

Adult↗
PubMed2006

Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India.

BACKGROUND: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Indian women. We investigated the distribution and the nature of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of 204 Indian breast cancer patients and 140 age-matched controls. METHOD: Cases were selected with regard to early onset disease (< or =40 years) and family history of breast and ovarian cancer. Two hundred four breast cancer cases along with 140 age-matched controls were analyzed for mutations. All coding regions and exon-intron boundaries of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis followed by direct sequencing of detected variants. RESULTS: In total, 18 genetic alterations were identified. Three deleterious frame-shift mutations (185delAG in exon 2; 4184del4 and 3596del4 in exon 11) were identified in BRCA1, along with one missense mutation (K1667R), one 5'UTR alteration (22C>G), three intronic variants (IVS10-12delG, IVS13+2T>C, IVS7+38T>C) and one silent substitution (5154C>T). Similarly three pathogenic protein-truncating mutations (6376insAA in exon 11, 8576insC in exon19, and 9999delA in exon 27) along with one missense mutation (A2951T), four intronic alterations (IVS2+90T>A, IVS7+75A>T, IVS8+56C>T, IVS25+58insG) and one silent substitution (1593A>G) were identified in BRCA2. Four previously reported polymorphisms (K1183R, S1613G, and M1652I in BRCA1, and 7470A>G in BRCA2) were detected in both controls and breast cancer patients. Rare BRCA1/2 sequence alterations were observed in 15 out of 105 (14.2%) early-onset cases without family history and 11.7% (4/34) breast cancer cases with family history. Of these, six were pathogenic protein truncating mutations. In addition, several variants of uncertain clinical significance were identified. Among these are two missense variants, one alteration of a consensus splice donor sequence, and a variant that potentially disrupts translational initiation. CONCLUSION: BRCA1 and BRCA2 mutations appear to account for a lower proportion of breast cancer patients at increased risk of harboring such mutations in Northern India (6/204, 2.9%) than has been reported in other populations. However, given the limited extent of reported family history among these patients, the observed mutation frequency is not dissimilar from that reported in other cohorts of early onset breast cancer patients. Several of the identified mutations are unique and novel to Indian patients.

Adolescent↗