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PubMed2026

Identification of rare maternal copy number variants by genome-wide analysis of noninvasive prenatal screening data in 113,017 pregnant women.

OBJECTIVES: Knowledge of copy number variants (CNVs) is relevant to maternal and fetal health and can be obtained from noninvasive prenatal screening (NIPS) of pregnancy. However, genome-wide analysis of maternal CNVs using NIPS data has not been conducted in large populations. METHODS: For CNV analysis, the human genome was segmented into 10 kilobase pairs (Kb) bins, and the relative sequencing depth of each bin was calculated. The circular binary segmentation algorithm was used to estimate CNVs. Detected CNVs from two pregnancies of the same participant were compared to validate the reproducibility. All CNVs were merged into CNV regions (CNVRs) to evaluate their frequency, distributions, and relationship with disease-related genes and regions. RESULTS: In this study, 113,017 pregnant women were recruited. A total of 363,886 CNVs larger than 50 Kb were detected in 101,779 individuals and merged into 43,005 CNVRs. For evaluating the reproducibility of CNVs, 90.18% of deletions and 88.07% of duplications were consistent. In general, 78.13% of individuals carried CNVRs that overlapped protein-coding genes, while 14.76% overlapped OMIM genes. We detected 246 novel CNVRs, 134 (54.47%) involving protein-coding genes. For the perspective of maternal-fetal health, we identified 4,984 (4.41%) individuals as carriers of 5,243 CNVs containing known pathogenic or likely pathogenic regions, including 22q11.2 region and DMD gene.. CONCLUSIONS: NIPS sequencing data is a reliable source for maternal CNV detection. These CNVs constitute an integrate component in maternal-fetal health management.

Humans↗
PubMed1978

Semiquantitative computerized image analysis of fetal hemoglobin distribution patterns in sickle cell anemia and its variants.

Computerized, semiquantitative image analysis of 2913 erythrocytes from 29 young patients with sickle cell anemia and its variants was conducted utilizing a modified method for determination of fetal hemoglobin distribution by an acid elution procedure. Histograms of eight arbitrary levels of staining intensity, proportional to fetal hemoglobin levels, were analyzed in relationship to both computer-generated, mathematical parameters of erythrocytic shape abnormalities and clinical parameters of disease severity. Shifts in fetal hemoglobin distribution were observed in analysis of sequential specimens. An inverse correlation was observed between angularity of erythrocytes and their individual fetal hemoglobin content (p less than or equal to 0.05). A positive correlation was noted between growth percentiles and percentage erythrocyte ghosts by acid elution (p less than or equal to 0.01).

Anemia, Sickle Cell↗
PubMed2026

Genotype-structure-phenotype correlations define divergent natural history in early-onset spastic paraplegia type 4.

Hereditary spastic paraplegia type 4 (SPG4), caused by variants in SPAST, is the most common form of HSP and exhibits a remarkable phenotypic heterogeneity ranging from late-onset pure presentations to severe, early-onset complex disease. Robust genotype-phenotype correlations and detailed natural history data are lacking, limiting clinical trial readiness. We analyzed 206 patients with genetically confirmed SPG4 enrolled across seven international centers, complemented by high-quality literature-derived cases. Deep phenotyping included standardized motor scales, spasticity ratings, developmental milestones, and patient-reported outcomes. We developed an extended essentiality-mapping framework to classify SPAST missense variants by integrating in silico pathogenicity predictions, evolutionary constraint, physicochemical residue connectivity, and variant enrichment within the human spastin hexamer structure. Plasma neurofilament light chain (pNfL) using was quantified using Simoa in 26 patients and 101 controls. We identified 136 distinct SPAST variants, including 10 novel variants. Variant class segregated strongly by inheritance, with de novo cases enriched for missense variants and inherited cases showing a variety of variant classes with enrichment for truncating variants. Longitudinal analysis revealed two latent trajectories: a rapidly progressive severe subgroup enriched for de novo missense variants, and a biphasic moderate subgroup enriched for inherited truncating variants. Patient stratification integrating spastin essentiality mapping (missense variants affecting essential, neutral, or context-dependent residues) with established genetic modifiers (biallelic pathogenic variants or modifier variants in trans) classified patients into predicted severe and moderate subgroups with divergent age at onset and clinical disease progression. The severe subgroup showed early developmental delays, rapid loss of ambulation, and declining quality of life, while the moderate subgroup displayed delayed but accelerating disease progression. pNfL levels were elevated in both subgroups, most pronounced in severe early disease. This study provides the most detailed natural history of SPG4 to date and introduces a biologically informed stratification framework that links variant class and location to divergent clinical trajectories. These data establish clinically meaningful benchmarks and offer a genotype-based framework to improve anticipatory care and optimize trial design for SPG4.

SPAST↗
PubMed1976

[Polymorphism of near-centromeric heterochromatin in a population of normal humans].

Polymorphism of constitutive heterochromatin of metaphase chromosomes 1,9 and 16 in 6 normal humans (both men and women) in studied by means of C-staining. Only slight variability in size of C-blocks in one individium (from cell to cell) and a high frequency of C-chromation heteromorphism variants within the population studied is observed. 8 variants of C-heterochromatin (heteromorphic homologues) are found: 4 individuals had 1-2 variants and 1 individual - 3 variants. Quantitative analysis based on measurements of C-blocks confirmed the reliability of the existence of these variants.

Chromosomes, Human, 1-3↗
PubMed2025

Clinical and Genetic Findings in Patients With Palmoplantar Keratoderma.

IMPORTANCE: Palmoplantar keratoderma poses diagnostic challenges due to its clinical and genetic heterogeneity, and knowledge on the value of systematic genetic testing on clinically well-described patient cohorts is sparse. OBJECTIVE: To improve knowledge of the clinical and genetic spectrum of patients with palmoplantar keratoderma. DESIGN, SETTING, AND PARTICIPANTS: This cohort study prospectively recruited patients and affected family members with palmoplantar keratoderma between September 1, 2016, and December 31, 2022. Patients were recruited from private practitioners in dermatology and dermatology departments in Denmark. Study participants were patients 18 years or older either newly diagnosed with palmoplantar keratoderma or being followed up for the disease at referral centers. MAIN OUTCOMES AND MEASURES: Phenotypes and clinical subtypes were classified. Genetic testing was performed by whole-exome or genome sequencing using an in silico panel containing genes related to palmoplantar keratoderma, or by Sanger sequencing for specific variants. Descriptive analysis, such as proportions and frequency, were used to describe clinical characteristics, distribution of disease-causing variants, and genotype-phenotype associations. RESULTS: This study included 142 study participants from 76 families (90 [63%] female; median [range] age, 52 [18-92] years). Clinical subtypes included 42 punctate (55%), 26 diffuse (34%), 5 focal (7%), and 3 striate (4%). A genetic diagnosis was found in 63 of 76 families (83%), including 27 disease-causing variants within 13 different genes: AAGAB (n = 39), DSG1 (n = 8), KRT1 (n = 3), DSP (n = 2), KRT9 (n = 2), AQP5 (n = 2), KRT16 (n = 1), SERPINA12 (n = 1), ABCA12 (n = 1), COL7A1 (n = 1), CARD14 (n = 1), DST (n = 1), and LORICRIN (n = 1). All participants with AAGAB variants presented with punctate palmoplantar keratoderma, showing a clear genotype-phenotype correlation. The other subtypes (diffuse, focal, and striate) proved more challenging to clinically subclassify, and disease-causing variants were identified in 12 genes, contributing to more complex genotype-phenotype patterns. Patients with palmoplantar keratoderma due to DSP variants were found, which is important to identify because of an associated risk of cardiomyopathy. CONCLUSION AND RELEVANCE: This study provides novel insights into the clinical and genetic spectrum of patients with palmoplantar keratoderma. It demonstrates the value of genetic testing for accurate diagnoses and to distinguish between different subtypes. The established and well-described cohort lays the foundation for future research in palmoplantar keratoderma.

Humans↗
PubMed2026

Longitudinal ctDNA tracking in early and recurrent breast cancer using an ultrasensitive structural variant-based assay: an extended analysis from the TRACER study.

BACKGROUND: Detection of circulating tumor DNA (ctDNA) following curative-intent therapy is prognostic of disease recurrence in early-stage breast cancer (EBC). An ultrasensitive structural variant (SV)-based ctDNA assay was evaluated previously in a 100-patient EBC cohort treated with neoadjuvant therapy, demonstrating high sensitivity, specificity, and a long lead-time to relapse. The stability of primary tumor-specific SVs at and after metastatic recurrence and their utility for longer-term ctDNA monitoring had not been established. PATIENTS AND METHODS: An updated retrospective analysis of ctDNA dynamics was conducted in an expanded cohort of 121 patients with EBC treated with neoadjuvant therapy. Plasma samples were collected at key clinical timepoints and serially in several patients who experienced metastatic recurrence. Clinical variables were abstracted from medical records. Associations between ctDNA detection, dynamics, and clinical outcomes were evaluated in the early-stage and metastatic settings. RESULTS: Thirty of 121 patients experienced clinical recurrence (28 distant, 2 local) over a median follow-up of 4.2 years (range 0.5-8.8; 25 ctDNA evaluable with adjuvant timepoints). All patients with detectable ctDNA in the adjuvant setting developed metastatic recurrence (22/22). Median lead time from ctDNA detection to metastatic recurrence was 346 days (range 0-1937). Among recurrent cases, 79% of primary tumor-specific SVs (n = 17 patients, tumor fraction ≥0.1%) remained detectable in plasma [range 7% (1/14 SV)-100% (15/15); median: 92%]. ctDNA dynamics in the recurrent metastatic setting demonstrated a strong relationship with radiographic outcomes in evaluable patients (n = 9). CONCLUSION: This SV-based digital PCR assay provided ultrasensitive ctDNA detection in an expanded EBC cohort, maintaining 100% positive predictive value for metastatic recurrence. In patients with recurrence, ctDNA dynamics were concordant with radiographic outcomes. Prospective studies evaluating the clinical utility of longitudinal ctDNA monitoring are warranted.

MRD↗
PubMed1975

The role of adenosine 3',5'-monophosphate in the transformation of Cloudman mouse melanoma cells.

The role of adenosine 3',5'-monophosphate (cyclic AMP) in the regulation of mouse melanoma cell growth and differentiation was investigated. A variant melanoma (Cloudman S91-F) which displays a greater degree of transformation than the parental cell (Cloudman S91) was isolated. A correlation between cyclic AMP metabolism and transformation was made. Dibutyryl cyclic AMP depressed cell growth and increased pigmentation in both parental and variant cell lines. The parental cell line, however, was more responsive to melanocyte-stimulating hormone (MSH) which was found to affect cell growth and pigmentation by increasing cyclic AMP levels. The more transformed S91-F cell line contained lower levels of cyclic AMP than the parental cell line, and this fact correlated well with the higher degree of growth and lesser degree of pigmentation in the variant. Enzymatic analysis revealed that the hydrolysis of cyclic AMP in both cell lines was similar, while the adenylate cyclase activity of the variant cell line was lower than that of the parental cell line. Lineweaver-Burk plots demonstrated that the Km's for the enzymes in the two cell lines were the same but that the Vmax of the S91-F cell line was significantly less that that of the S91 cell line. Thus, the lesion in the S91-F cell which is responsible for its more transformed characteristics seems to be one which affects adenylate cyclase at the level of the cell membrane.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2025

The burden of TTN variants in the genomic era: Analysis of 18,462 individuals from the Solve-RD consortium and general recommendations.

PURPOSE: Titin, the largest protein in the human body, has been associated with several disease phenotypes caused by variants in the TTN gene. With around 20% of the population carrying a rare TTN variant and over 60 million genomes expected to have been sequenced worldwide by 2025, interpreting these findings presents major challenges. This study analyzed TTN variants in the Solve-RD cohort, the European network for unsolved rare disease cases. METHODS: We collected data from 11,072 individuals with suspected rare diseases and 7390 healthy relatives from the Solve-RD consortium, checking and manually reviewing TTN variants. We then used a filtering approach focused on clinical relevance, and we provided updated recommendations based on recent literature. RESULTS: Among the cohort, 240 individuals (1.3%) carried at least one heterozygous TTN truncating variant (TTNtv), with a 3.8% prevalence in the neuromuscular subgroup, primarily composed of unsolved cases. Four individuals received a titinopathy diagnosis. Additionally, 99 participants (0.5%) had a TTNtv in a high cardiac percent spliced in exon (>80%), and 4 had an overt cardiomyopathy. CONCLUSION: This study highlights the need for standardized approach to TTN variants, and investigation of missing heritability in individuals with skeletal myopathy with het TTNtv. Establishing consensus on percent spliced in-based thresholds will be essential for assessing cardiac risk and guiding the management of asymptomatic individuals.

Humans↗
PubMed2025

Personalizing CA125 Levels Using Tumor Marker Variants: A Case-Control Analysis of Diagnostic Performance for Pancreatic Cancer.

BACKGROUND: Cancer antigen 125 (CA125) is widely recognized as a useful biomarker for the surveillance of patients with ovarian and other cancers. Prior genome-wide association studies have identified variants that influence CA125 levels. We evaluated the utility of stratifying CA125 levels by such variants and evaluated diagnostic performance in control subjects and patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We measured CA125 levels in 807 control subjects and 450 patients with PDAC and genotyped 10 variants involving four genes (GAL3ST2, MSLN, D2HGDH, and MUC16). We compared CA125 levels in controls by variant and generated variant-defined CA125 cutoffs and then classified cases and controls into functional groups based on their variant profile. We used this variant classification to evaluate the diagnostic performance of CA125 in patients with PDAC. RESULTS: Six variants associated with CA125 levels were used to group controls into one of four groups. Mean CA125 levels in the highest variant group were approximately fourfold higher than in the lowest group. African Americans were more likely to have a variant group associated with low CA125 levels. After setting diagnostic cutoffs by variant group, the diagnostic sensitivity of CA125 for PDAC was 20.2% at 98% specificity (areas under the ROC curve, 0.702), not significantly different from a uniform CA125 diagnostic cutoff (areas under the ROC curve, 0.700). CONCLUSIONS: Gene variants can be used to generate personalized CA125 reference ranges. This approach did not significantly improve CA125's diagnostic performance for pancreatic cancer, but it merits evaluation in other diagnostic settings, such as detecting ovarian cancer. IMPACT: Gene variants can be used to personalize CA125 levels.

Humans↗
PubMed1978

Thin-layer isoelectric focusing of hemoglobin variants: screening and determination of isoelectric points.

The high resolving power of thin-layer isoelectric focusing was applied for screening some hemoglobin variants classified on the basis of their electrophoretic mobility in: electrophoretically slow variants (as Hb A2), electrophoretically slow variants (as Hb S), electrophorectically fast variants (Hbs type J). An analysis of the variant compounds has been performed, and the corresponding pI values were determined in whole hemolysate.

Genetic Variation↗
PubMed2025

Discovery of a MET -driven monogenic cause of steatotic liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction-associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking. APPROACH AND RESULTS: We identified a novel genetic variant in a familial case of metabolic dysfunction-associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant. CONCLUSIONS: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.

Adult↗
PubMed2026

Nonuniform Association of Genetic Risk Scores for Intraocular Pressure.

IMPORTANCE: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. OBJECTIVE: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. EXPOSURES: Ninety-eight genetic variants associated with IOP. MAIN OUTCOMES AND MEASURES: Tests were carried out for 98 genetic variants associated with IOP (P&#x2009;<&#x2009;5.0&#x2009;&#xd7;10-8) to examine (1) dominant or recessive genetic effects, (2) genotype&#x2009;&#xd7;&#x2009;genotype interactions, (3) genotype&#x2009;&#xd7;&#x2009;age interactions, and (4) genotype&#x2009;&#xd7;&#x2009;sex interactions. RESULTS: A total of 98&#x202f;235 participants (mean [SD] age, 58.1 [7.9] years; 52&#x202f;168 female [53.1%]) were included in this analysis. More variants exhibited genotype&#x2009;&#xd7;&#x2009;age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P&#x2009;=&#x2009;3.76&#x2009;&#xd7;10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2&#x2009;=&#x2009;4.05; 95% CI, 3.82-4.31 and interaction model, R2&#x2009;=&#x2009;4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. CONCLUSIONS AND RELEVANCE: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype&#x2009;&#xd7;&#x2009;genotype interactions, and genotype&#x2009;&#xd7;&#x2009;sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype&#x2009;&#xd7;&#x2009;age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.

Humans↗
PubMed1976

Radiation-induced mutations at mouse hemoglobin loci.

In experiments designed to detect new mutations affecting hemoglobin, we irradiated the male or female parent in reciprocal crosses of two mouse strains that differ in alleles at the hemoglobin (Hba, Hbb) loci as well as at five other specific loci. Offspring were analyzed for hemoglobin properties (electrophoretic pattern, solubility, crystal pattern), serum albumin differences, erythrocyte lysis, reticulocyte count, and external appearance. Five hemoglobin variants were found among the mutants. In three, the genetic contribution from the irradiated father was not expressed with regard to the alpha-chain; one carried a tandem deuplication (the first known case in the mouse) involving Hbb; and one probably resulted from double nondisjunction of chromosome 7. The finding that major chromosome aberrations can mimic hemoglobin mutations indicates the need, in similar experiments, to follow F1 screening with thorough cytogenetic analysis. The variants in which there is nonexpression of the alpha chain may be the result of small deficiencies or of faults in transcription or translation. Mutation rates based on these three variants are not out of line with earlier specific-locus results, although confidence limits are still wide.

Anemia↗
PubMed2024

Association analysis of mitochondrial DNA heteroplasmic variants: Methods and application.

We rigorously assessed a comprehensive association testing framework for heteroplasmy, employing both simulated and real-world data. This framework employed a variant allele fraction (VAF) threshold and harnessed multiple gene-based tests for robust identification and association testing of heteroplasmy. Our simulation studies demonstrated that gene-based tests maintained an appropriate type I error rate at &#x3b1;&#x202f;=&#x202f;0.001. Notably, when 5&#x202f;% or more heteroplasmic variants within a target region were linked to an outcome, burden-extension tests (including the adaptive burden test, variable threshold burden test, and z-score weighting burden test) outperformed the sequence kernel association test (SKAT) and the original burden test. Applying this framework, we conducted association analyses on whole-blood derived heteroplasmy in 17,507 individuals of African and European ancestries (31&#x202f;% of African Ancestry, mean age of 62, with 58&#x202f;% women) with whole genome sequencing data. We performed both cohort- and ancestry-specific association analyses, followed by meta-analysis on both pooled samples and within each ancestry group. Our results suggest that mtDNA-encoded genes/regions are likely to exhibit varying rates in somatic aging, with the notably strong associations observed between heteroplasmy in the RNR1 and RNR2 genes (p&#x202f;<&#x202f;0.001) and advance aging by the Original Burden test. In contrast, SKAT identified significant associations (p&#x202f;<&#x202f;0.001) between diabetes and the aggregated effects of heteroplasmy in several protein-coding genes. Further research is warranted to validate these findings. In summary, our proposed statistical framework represents a valuable tool for facilitating association testing of heteroplasmy with disease traits in large human populations.

Humans↗
PubMed2026

MarkerMatch: a proximity-based probe-matching algorithm for joint analysis of copy-number variants from different genotyping arrays.

MOTIVATION: Copy-number variants (CNVs) are a form of genetic structural variation with increasing importance in complex human disorders. Both DNA sequencing and microarray data can be used to detect CNVs, which can be used in genetic association tests. Unlike genotypes, CNV detection in microarrays requires the use of observed intensity signals at each probe, which limits the imputability for analyses that span multiple array types. Thus far, a consensus set of probes (those present on all arrays) has been used to circumvent the problem of differing array-specific sensitivities. This has led to excessive reduction in overall sensitivity since arrays can have an undesirably low probe overlap. To overcome this limitation, we developed MarkerMatch, a proximity-based algorithm that matches probes across different genotyping microarrays to maximize the number of probes considered in the CNV calling algorithm, thereby increasing the resolution and sensitivity while preserving precision. RESULTS: By analyzing CNV calls from 4906 individuals genotyped across three different arrays, we show that the MarkerMatch approach improves sensitivity by increasing the density of probes available for CNV calling while maintaining precision or improving it relative to the current practice (e.g. use of consensus probes only). We further demonstrate that MarkerMatch matches the CNV detection from current practice in terms of F1 score and PPV for larger CNVs. We also optimize MarkerMatch parameters, DMAX and Method, and find an optimal DMAX setting at 10&#x2009;kb, with no clear optimal candidate based on Method, indicating that parameters for this metric should be determined on a use case basis. AVAILABILITY: The R package for MarkerMatch is available at: https://github.com/FranjoIM/MarkerMatch. The code used for analysis and implementation is available at: https://doi.org/10.5281/zenodo.18460979. The live notebook is available at https://fivankovic.notion.site/2026-markermatch.

DNA Copy Number Variations↗
PubMed2025

MarkerMatch: A Proximity-Based Probe-Matching Algorithm for Joint Analysis of Copy-Number Variants from Different Genotyping Arrays.

MOTIVATION: Copy-number variants (CNVs) are a form of genetic structural variation with increasing importance in complex human disorders. Both DNA sequencing and microarray data can be used to call CNVs, which can be used in association tests, such as association between CNV number and disease status. Unlike genotypes, CNV detection in microarrays requires the use of observed intensity signals at each probe, which limits the imputability for analyses that span multiple array types. Thus far, a consensus set of probes (the intersection encompassing the probes that occur in common on all arrays) has been used to circumvent the problem of differing array-specific sensitivities. This has, however, led to excessive reduction in overall sensitivity of CNV calls as arrays can have an undesirably low overlap of probe sets. To overcome this limitation, we developed MarkerMatch, a proximity-based algorithm that matches probes across different genotyping microarrays to maximize the number of probes considered in the CNV calling algorithm, thereby increasing the resolution and sensitivity while preserving precision. RESULTS: By analyzing CNV calls from 4,906 individuals genotyped across three different arrays (Global Screening Array, Omni2.5 array, and Omni Express Exome array), we show that the MarkerMatch approach improves sensitivity by increasing the density of probes available for CNV calling while maintaining precision or improving it relative to the current practice (e.g., use of consensus probes only). We further demonstrate that MarkerMatch exceeds the output from current practice in terms of F1 score, Fowlkes-Mallows index, and Jaccard index. We also optimize MarkerMatch parameters, D MAX and Method, and find an optimal D MAX setting at 10kb, with no clear optimal candidate based on Method, indicating that parameters for this metric should be determined on a use case basis.

Journal Article↗
PubMed1979

Glucose-6-phosphate dehydrogenase deficiency in Sicily. Incidence, biochemical characteristics and clinical implications.

This report deals with the incidence, type and clinical implications of G6PD deficiency in Sicily. Of 3347 male subjects examined, 56 were deficient in G6PD. They were distributed throughout the island. The G6PD levels in RBC were almost zero; in leukocytes, platelets and saliva they were found to be 26%, 18% and 16%, respectively, of controls. The Michaelis constant for NADP and G6PD was lower than for controls. Conversely, the utilization of the analogous Ga16P and 2dG6P was higher. The thermostability of the enzyme was lower and the pH optima (6.5 and 9.5) were different from the controls. An identical electrophoretic pattern was found both in normal and deficient subjects. This pattern is superimposable on that described as Mediterranean variant. The analysis among 270 subjects admitted to our Clinic with hemolysis due to G6PD deficiency demonstrated that the most frequent disease is favism, followed by neonatal jaundice, while hemolysis due to drugs is very rare. Ingestion of fresh fava beans was the most frequent cause of favism, but cases occurred after breast feeding and inhalation of pollen.

Adolescent↗