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PubMed2005

Detection and frequency estimation of rare variants in pools of genomic DNA from large populations using mutational spectrometry.

DNA variants underlying the inheritance of risk for common diseases are expected to have a wide range of population allele frequencies. The detection and scoring of the rare alleles (at frequencies of <0.01) presents significant practical problems, including the requirement for large sample sizes and the limitations inherent in current methodologies for allele discrimination. In the present report, we have applied mutational spectrometry based on constant denaturing capillary electrophoresis (CDCE) to DNA pools from large populations in order to improve the prospects of testing the role of rare variants in common diseases on a large scale. We conducted a pilot study of the cytotoxic T lymphocyte-associated antigen-4 gene (CTLA4) in type 1 diabetes (T1D). A total of 1228 bp, comprising 98% of the CTLA4 coding sequence, all adjacent intronic mRNA splice sites, and a 3' UTR sequence were scanned for unknown point mutations in pools of genomic DNA from a control population of 10,464 young American adults and two T1D populations, one American (1799 individuals) and one from the United Kingdom (2102 individuals). The data suggest that it is unlikely that rare variants in the scanned regions of CTLA4 represent a significant proportion of T1D risk and illustrate that CDCE-based mutational spectrometry of DNA pools offers a feasible and cost-effective means of testing the role of rare variants in susceptibility to common diseases.

Adult↗

PubMed2004

Chordoid meningioma: rare variant of meningioma.

Chordoid meningioma is a rare variant of meningioma that bears a striking histological resemblance to chordoma and has greater likelihood of recurrence. Although most meningiomas occur in the intracranial, orbital and intravertebral cavities, rare meningiomas have been reported in extracranial organs; thus, it is important to be able to distinguish them from other neoplasms that have similar histology but different biological behavior and therapies. A case of chordoid meningioma in a 48-year-old woman who did not have Castleman's syndrome is described in the present report. The patient presented with a mass in her left frontoparietal region, and had been suffering from headaches for many years. Magnetic resonance imaging of the brain demonstrated an expansive lytic lesion in the squamous portion of the left temporal bone. The lesion extended in both directions. Histological examination of the surgical specimen revealed a tumor composed of cords and nests of eosinophilic vacuolated cells embedded in a myxoid matrix. A typical meningiomatous pattern was observed focally, and positive staining of the tumor cells for vimentin and epithelial membrane antigen confirmed the diagnosis of chordoid meningioma.

Choroid Plexus Neoplasms↗

PubMed2006

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels.

An approach to understand quantitative traits was recently proposed based on the finding that nonsynonymous (NS) sequence variants in certain genes are preferentially enriched at one extreme of the population distribution. The NS variants, although individually rare, are cumulatively frequent and influence quantitative traits, such as plasma lipoprotein levels. Here, we use the NS variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (LDLs). The ratio of plasma campesterol (a plant sterol) to lathosterol (a cholesterol precursor) was used to estimate relative cholesterol absorption in a population-based study. Nonsynonymous sequence variations in NPC1L1 were five times more common in low absorbers (n = 26 of 256) than in high absorbers (n = 5 of 256) (P < 0.001). The rare variants identified in low absorbers were found in 6% of 1,832 African-Americans and were associated with lower plasma levels of LDL cholesterol (LDL-C) (96 +/- 36 mg/dl vs. 105 +/- 36 mg/dl; P = 0.005). These data, together with prior findings, reveal a genetic architecture for LDL-C levels that does not conform to current models for quantitative traits and indicate that a significant fraction of genetic variance in LDL-C is due to multiple alleles with modest effects that are present at low frequencies in the population.

Absorption↗

PubMed2005

Rare variants of the gene encoding the potassium chloride co-transporter 3 are associated with bipolar disorder.

Recessive mutations of the potassium chloride co-transporter 3 gene ( SLC12A6 , KCC3 ) cause severe peripheral neuropathy frequently associated with agenesis of the corpus callosum and psychoses (ACCPN). SLC12A6 is localized on chromosome 15q14, a region where linkage to schizophrenia and bipolar disorder has previously been shown. Mutation analysis of SLC12A6 was carried out by direct sequencing of PCR-generated DNA fragments in two affected members of a multiplex family, and three non-affected individuals. A case-control study was performed to assess association of variants with bipolar disorder and schizophrenia in a large sample. Several variants including two rare single nucleotide polymorphisms (G/A, G/A) in the promoter and 5'-UTR, and a thymidine insertion in intron 4 were found. The two G variants and the insertion variant were co-inherited with chromosome 15-related schizophrenia in a large family that strongly supports the region on chromosome 15q14-15 between markers D15S144 and D15S132. Furthermore, they are in linkage disequilibrium with each other, and significantly associated with bipolar disorder in a case-control study. Our data strongly suggest that rare variants of SLC12A6 may represent risk factors for bipolar disorder.

5' Untranslated Regions↗

PubMed2006

Cutaneous intravascular NK-cell lymphoma: report of a rare variant associated with Epstein-Barr virus.

Intravascular lymphoma (IVL) is a rare variant of non-Hodgkin lymphoma with a predilection for skin and brain. Except a few cases of T-cell lineage, most of the reported cases were large B-cell lymphomas. We encountered a case of cutaneous IVL in a 71-year-old woman presenting with multiple erythematous patches and nodules on her trunk and extremities. The intravascular large cells showed an immunophenotype of CD3epsilon(+);, CD5(-), CD20(-), CD30(-), CD56(+), and TIA-1(+). The lymphoma cells were also positive for Epstein-Barr virus by Epstein-Barr virus-encoded RNA in situ hybridization test and the T-cell receptor gene was germline. This IVL differs from nasal type NK/T-cell lymphoma only by its intravascular nature. Only 3 cases of intravascular NK-cell lymphoma have been reported before. Because this variant is extremely rare, our case is documented and compared with the 3 previously reported cases.

Aged↗

PubMed2026

Integrating multi-ancestry common and rare variant mapping accelerates therapeutic target discovery.

Integrating human genetics into therapeutic discovery accelerates drug development. However, ancestral biases in historical cohorts have left critical functional variation largely uncharted. Here, we leverage the diverse NIH All of Us Research Program to conduct comprehensive common- and rare-variant association analyses for 624 quantitative traits across 369,655 ancestrally diverse individuals. We identified 6,181 genome-wide significant locus-trait associations (526 novel) and 416 gene-trait associations (105 novel) via rare-variant burden testing. By integrating fine-mapping with computational variant-effect predictors, we systematically prioritized rare, likely causal variants driving these signals. Jointly modeling common and rare variation with protein-class annotations significantly improved the identification of known drug targets compared to common-variant analysis alone. Notably, we identified NRG4 as a high-confidence candidate therapeutic target for preserving kidney function. Our findings demonstrate that characterization of rare and common variation across diverse populations enhances causal gene discovery and identifies novel, actionable therapeutic targets.

Journal Article↗

PubMed2025

Rare variants in MIR184 are a novel genetic cause of Fuchs endothelial corneal dystrophy.

PURPOSE: To identify novel genetic causes of Fuchs endothelial corneal dystrophy (FECD) within a genetically unsolved patient cohort lacking repeat expansions in the TCF4 gene (Exp-). METHODS: A rare variant analysis framework (CoCoRV) was applied to exome data, in combination with in silico modeling, luciferase reporter, and RNA-seq analysis to characterize transcriptome-wide consequences of identified variants. RESULTS: A gene burden analysis identified MIR184, a microRNA encoding gene, to be enriched for rare pathogenic variants within the studied Exp- FECD cohort. In total, 2 noncoding rare variants were identified in 4 unrelated FECD probands: NR_029705.1:n.58G>A and n.73G>T. Both variants altered highly conserved mature sequence residues, were predicted to induce hairpin structural changes, and were experimentally determined to disrupt microRNA-mRNA interactions. RNA-seq of transfected human corneal endothelial cells revealed that the mutants elicited distinct transcriptomic profiles. Enriched KEGG pathways included PI3K-Akt signaling, focal adhesion, and immune response, revealing shared pathogenic mechanisms between MIR184-associated FECD and the more common TCF4 repeat expansion-mediated form of disease. CONCLUSION: MIR184 variants are a novel rare genetic cause of FECD, and common pathways of transcriptomic dysregulation are shared across genetically distinct subtypes of the disease. These pathways may serve as future gene agnostic targets for therapeutic interventions.

Humans↗

PubMed2024

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Humans↗

PubMed2002

Carcinoma cuniculatum of the jaw: a rare variant of oral carcinoma.

Carcinoma cuniculatum is a rare variant of carcinoma usually involving the foot. Only 13 cases have been described in the oral cavity, none of which was in the English-language literature. We describe a 56-year-old man who presented with a soft exophytic mass in the maxillary gingiva, alveolar bone destruction, and loosening of the teeth. Histopathologic study revealed thin papillary projections covered by a thick keratin layer in the superficial areas and multiple, branching keratin-filled crypts surrounded by well-differentiated squamous epithelium with only mild cytologic atypia but frequent mitosis. Immunohistochemistry results of p53 and polymerase chain reaction analyses for human papillomavirus 6, 11, 16, and 18 DNA were negative. The diagnosis was carcinoma cuniculatum of the jaw. The literature on this unusual oral pathosis is reviewed and the diagnostic challenge described. We suggest that carcinoma cuniculatum may sometimes be misdiagnosed as squamous cell carcinoma or verrucous carcinoma and, therefore, might be more prevalent than the small number of published cases implies.

Carcinoma, Verrucous↗

PubMed1975

Surgical correction of a rare variant of cor triatriatum.

Cor triatratum is a rare congenital malformation. Problems in diagnosis and surgery arise due to associated anomalies such as atrial septal defects and anomalous pulmonary venous drainage. A 21-year-old man proved to have a rare variant of cor triatiatum in which both the upper and lower compartments of the left atrium communicated with the right atrium through two separate atrial septal defects. In addition, he had anomalous drainage of the right superior pulmonary vein into the superior vena cava. Intracardiac repair was undertaken successfully.

Adult↗

PubMed1993

Osteogenic melanoma. A rare variant of malignant melanoma.

Osteogenic melanoma is a rare variant of malignant melanoma; only eight cases have been reported. To characterize this unusual neoplasm further, we present four new cases. Two patients were men and two were women (average age, 56 years; range, 47-78 years). All tumors arose from acral lentiginous melanomas. Three were subungual finger lesions and one was on the sole of the foot. All four had been previously diagnosed as or were suspected to have been primary osseous lesions. The vertical growth components were high-grade, amelanotic sarcomatoid malignancies with abundant osteoid matrix. Two tumors also had chondroblastic differentiation. Cells with epithelioid features, including prominent eosinophilic nucleoli, were discernible in every tumor. Regional lymph node metastases in two cases retained osteocartilaginous differentiation, whereas metastatic cells in another case were purely epithelioid. Tumor cells in every case were immunoreactive for S-100 protein and vimentin, and non-reactive for cytokeratin. Two tumors also expressed HMB-45. Melanosomes were identified ultrastructurally in every tumor. Follow-up information was available on every patient. Three developed regional lymph node metastases and are currently alive and well after 14, 39, and 101 months. The fourth patient died of metastatic uterine carcinoma 20 months postoperatively. The differential diagnosis of osteogenic melanoma includes osteosarcoma as well as atypical fibro-osseous proliferations. Clinico-pathologic features that support a diagnosis of osteogenic melanoma include junctional activity, absence of primary bony involvement, regional nodal metastases, immunoreactivity for S-100 protein and/or HMB-45, lack of cytokeratin reactivity, and ultrastructural identification of melanosomes.

Aged↗

PubMed2026

Systematic common and rare variant association testing in 392,030 whole genomes in All of Us.

Large-scale genome-wide association studies (GWAS) and rare variant association studies (RVAS) from population biobanks provide valuable resources for gene discovery in complex human traits. We present an analysis of the All of Us Research Program v8 release, which includes whole genome sequencing data and harmonized phenotypic information of 392,030 participants after quality control, enabling a unified investigation of rare and common variants across a spectrum of human traits and diseases. We build an extensive phenome- and genome-wide ("All by All") computational framework to perform GWAS and RVAS on 3,602 phenotypes and identify 49,863 approximately independent, high-quality single-variant and gene-level associations. Meta-analyses of All of Us and UK Biobank, with sample sizes as large as 786,871 participants, further enhance statistical power and find 193 pLoF gene-phenotype associations that are not significant in either cohort alone, including 22 associations not highlighted by previous studies. We also present a public interactive browser that integrates association results for common and rare variants to facilitate interpretation and rapid querying of summary statistics, along with supporting documentation, and a Featured Workspace in the All of Us Researcher Workbench. Our framework will apply to iterative data releases as All of Us grows, empowering researchers worldwide to uncover insights into the functional effects of genetic components on complex traits and diseases.

Journal Article↗

PubMed2026

Genome-Wide and Rare Variant Association Studies of Amblyopia in Admixed American and African Ancestry Groups.

OBJECTIVE: To identify genetic variants associated with amblyopia in African (AFR) and Admixed American (AMR) ancestry groups, expanding on previous studies conducted in European ancestry. DESIGN: Retrospective ancestry-stratified genome-wide association study (GWAS) and gene-level rare variant association study (RVAS). PARTICIPANTS: Participants in the All of Us Research Program from AFR and AMR ancestry groups who had whole-genome sequencing available. Cases and controls were distinguished based on the presence of International Classification of Diseases 9/10/SNOMED diagnosis codes for amblyopia in electronic health records. This yielded ancestry-stratified subsets of 269 cases and 71 585 controls of AMR ancestry and 366 cases and 79 460 controls of AFR ancestry. METHODS: Stratified logistic regression models were adjusted for age, biological sex, and the top 10 principal components of genomic ancestry. GWAS was limited to common variants (minor allele frequency ≥1%), and RVAS was limited to rare variants with coding sequence-altering effects (minor allele frequency >1%, exonic only, excluding synonymous variants) aggregated at the gene level using the SKAT algorithm. Downstream analyses of the significant variants were performed using KEGG and GO pathway analysis and STRING database queries for protein-protein interactions and gene-gene interactions. MAIN OUTCOME MEASURES: Single-nucleotide polymorphisms were determined to have genome-wide significance if P < 5e-8 in the GWAS, and genes were determined to have significant association with amblyopia in the RVAS if P < 8.0 × 10-4. RESULTS: In the AMR GWAS, 245 unique single-nucleotide polymorphisms mapping to 97 distinct loci were identified, notably within neurodevelopmental and axonal guidance genes, including ROBO1, SEMA4B, PTPRD, NRXN1, and CAMK2D. The AFR GWAS identified 11 significant variants corresponding to 6 loci mapping primarily to long noncoding RNAs and pseudogenes. The AMR RVAS identified 15 genes, including axonal transport genes (KIF1B and KIF7) and growth factor signaling genes (EGF, ERBIN, and AKAP17A). The AFR RVAS identified a single gene, DLG2, which encodes the postsynaptic protein PSD-93, which promotes the closure of the sensitive period of neuroplasticity for vision in early childhood. CONCLUSIONS: Genetic risk architectures for amblyopia differ across ancestries but fundamentally converge on neurodevelopmental signaling, cortical synapse assembly, and sensitive period plasticity rather than ocular structural dynamics. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Amblyopia↗

PubMed1996

New rare variants and interpretation of the genetic diversity at the group-specific component (GC) locus in populations of India.

As part of our ongoing genetic studies, 2635 samples from 30 populations of the Indian subcontinent have been analyzed for GC subtype variation. Several rare variants were found and have been characterized using isoelectric focusing in 3 M urea and with an immobilized pH gradient and by comparison with known standards. Six new variants, 1A33, 2A22, 2A23, 2A24, 1C56, and 1C59, have been discovered in geographically and ethnically distant populations of the Indian subcontinent. Variants 1C11 and 1C21 have been reported previously in the French population and variant 1C36 has been reported in Nepalis, but all three variants were observed for the first time in the populations of India. The distribution of the rare variants in the Indian subcontinent was examined for anthropological usefulness for differentiation of Indian populations. The data for GC allele frequencies from 144 populations of India were compared for geographic and ethnic variation. A high frequency of the GC*IF allele was observed in populations of eastern India, and various ethnic groups from the eastern zone were clearly differentiated from similar ethnic populations from the rest of India. GC*2 allele frequency data were further correlated with various geographic and climatic variables, such as longitude, latitude, sunshine, solar radiation, and mean annual temperature. A significant positive correlation between GC*2 frequency and latitude was observed. The GC*2 allele frequency showed a cline increasing from south to north. Significant negative correlation was also observed between GC*2 frequency and sunshine, solar radiation, and mean temperature. A possible interpretation for selection of the GC*2 allele in areas with low levels of insolation is provided.

Climate↗

PubMed2005

Rare variant hypothesis for multifactorial inheritance: susceptibility to colorectal adenomas as a model.

The rare variant hypothesis postulates that genetic susceptibility to colorectal neoplasia within the general population is due to a number of low frequency variants in a variety of different genes. Each variant confers a moderate, but detectable, increase in relative risk of developing the disease. Recent evidence suggests that a quarter of patients with multiple adenomatous polyps are due to rare but functionally important variants in just five genes.

Adenoma↗

PubMed2006

Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses.

Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.

Case-Control Studies↗

PubMed1997

Covered exstrophy: a rare variant of classical bladder exstrophy.

Covered exstrophy is an extremely rare variant of exstrophy-epispadias complex. It is less distressing and easier to manage than classical exstrophy of the bladder. We report three cases of this entity, two associated with anorectal malformation and one with unilateral renal agenesis, along with a review of the literature.

Abnormalities, Multiple↗

PubMed1978

Rare variants, private polymorphisms, and locus heterozygosity in Amerindian populations.

The results of 21,103 electrophoretic typings distributed across 28 polypeptides in members of 12 Amerindian tribes are reported, and the accumulated results of electrophoretic studies on these same polypeptides in 21 Amerindian tribes are then analyzed. Thus far 11 'private' polymorphisms have been identified in these tribes. When the tribal samples are combined and traits achieving polymorphic proportions in the total sample excluded from consideration, the average frequency of rare variants is 2.8 per 1,000 determinations. For a subset of 23 of these polypeptides also studied in Caucasians and Japanese, variant frequencies per 1,000 determinations are: Indians, 2.2; Caucasians (British), 1.6; and Japanese, 1.5. Average locus heterogeneity for these polypeptides (based on rare variants plus polymorphisms) is: Indians, .049; Caucasians, .078; and Japanese, .077. A higher proportion of loci are monomorphic within tribes than within civilized urban populations. It is argued that for inferences concerning the forces maintaining genetic variability within populations, studies on samples from tribespeople are much more appropriate than studies on samples from civilized urban populations.

Blood Proteins↗