Genes

Cytogenetic studies represent a critical component of prenatal genetic testing. Prenatal diagnostic testing of amniotic fluid, chorionic villus sampling, or more rarely, fetal cord blood, is recommended following a positive or unreportable NIPT, maternal serum screen, abnormal ultrasound or increased genetic risk based on family history. While chromosomal microarray is the recommended first-tier prenatal diagnostic test for the detection of sub-microscopic copy number variants, in practice, mult...

PurposeGenome sequencing (GS) is potentially the most suitable diagnostic tools for fetal CNS structural anomalies. However, its efficacy hasnt been proved in large cohort of fetal CNS structural anomalies. MethodsPatients were enrolled by a multiple-level referral system when fetal CNS structure anomalies were found by ultrasonography. Samples from fetuses were subjected to GS. ResultsData of 162 fetuses with 11 frequent types of CNS anomalies was collected. The overall diagnosis yield of GS ...

ObjectiveThis study evaluates the diagnostic utility of low-pass whole genome sequencing (LP-WGS) for the detection of chromosomal abnormalities in Amniotic fluid samples (AFS), Chorionic villi samples (CVS) and Product of conception (POC) samples from India. MethodsA total of 1508 prenatal samples including - AFS, CVS and POC were analyzed using LP-WGS at either low-resolution ([~]0.5-1X) or high-resolution ([~]5X). CNV analysis was performed using StrandNGS v4.2 and Variant Intelligence Appli...

ObjectiveTo clinically validate a cell-based noninvasive prenatal genetic test using sequence-based copy number analysis of single trophoblasts from maternal blood. MethodsBlood was obtained from 401 individuals (8-22 weeks) and shipped overnight. Red blood cells were lysed, and nucleated cells stained for cytokeratin (CK) and CD45 using fluorescent antibodies and enriched for positive CK staining. Automated microscopic scanning was used to identify and pick single CK+/CD45- trophoblasts which ...

BackgroundSickle cell disease (SCD) and beta thalassemia ({beta}-thalassemia) are among the most common and severe genetically inherited disorders in the world. Although the maternal carrier status of these beta hemoglobinopathies is screened as a part of routine prenatal care in the US, the paternal carrier status is usually unavailable. Under this current screening paradigm, identification of the majority of SCD and beta thalassemia cases could therefore be delayed until newborn screening resu...

The purpose of this study was to explore the copy number variations (CNVs) associated with miscarriage. A total of 662 specimens of aborted embryonic tissue and 54 samples from peripheral blood were collected. Next generation sequencing for CNV analysis was performed to determine the type and clinical significance of possible CNVs, and relevant medical records were collected. Autosomal trisomy, both single and multiple, was the most common abnormality (207 cases, 63.5% of abnormalities). Trisomy...

BackgroundIdentification and confirmation of copy number variation is an important aspect of genetic testing for several prenatal scenarios, such as abnormal maternal serum screening, abnormal ultrasound findings, high risk results on non-invasive prenatal screening as well as postnatal settings such as developmental delay, intellectual disabilities, congenital anomalies and dysmorphism as well as in couples with recurrent miscarriages. Low pass whole genome sequencing (lpWGS) followed by copy n...

Optical genome mapping (OGM) is an emerging technology with great potential for prenatal diagnosis. OGM can identify and resolve all types of balanced and unbalanced cytogenomic abnormalities in a single test, which are typically assessed by multiple standard of care (SOC) methods including karyotyping, fluorescence in situ hybridization and chromosomal microarray. To assess OGMs viability as an alternative to conventional SOC testing, a comprehensive clinical research study was conducted acros...

Non-invasive prenatal diagnosis for single-gene disorders (SGD-NIPD) has been widely adopted by patients, but is mostly limited to the exclusion of paternal or de novo mutations. Indeed, it is still difficult to infer the inheritance of maternal allele from cell free DNA (cfDNA) analysis. Based on the study of maternal haplotypes imbalance in cfDNA, relative haplotype dosage (RHDO) was developed to address this challenge. Although RHDO has proven to be reliable, robust control of statistical err...

A major challenge for cell-based non-invasive prenatal testing (NIPT) is to distinguish individual presumptive fetal cells from maternal cells in female pregnancies. We have sought a rapid, robust, versatile, and low-cost next-generation sequencing method to facilitate this process. Toward this goal, single isolated cells underwent whole genome amplification prior to genotyping. Multiple highly polymorphic genomic regions (including HLA-A and HLA-B) with 10-20 very informative single nucleotide ...

Patients with Lynch syndrome (LS) are prone to cancer due to heterozygous germline pathogenic variants in genes encoding DNA mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. LS cancer cells exhibit deficient DNA mismatch repair and microsatellite instability due somatic inactivation of the second copy of the affected gene. To study microsatellite characteristics in non-neoplastic cells in LS we determined CAG repeat size in the huntingtin gene (HTT) microsatellite in lymphocyte DNA from LS pa...

PurposeMolecular mechanisms underlying COVID-19 susceptibility and severity are still poorly understood. The presence of genetic risk factors associated with ethnic background has been suggested, highlighting non-European ancestry as a risk factor for hospitalization in the United States. However, the representation of non-European populations in genomic case-control and cohort studies remains insufficient, and Latin American populations have been significantly understudied. Addressing this gap,...

Chromosomal aneuploidy, a condition characterized by an abnormal number of chromosomes, is a major genetic disorder affecting human reproduction, leading to infertility, pregnancy loss, and developmental disabilities. Trisomies of chromosomes 13, 18, and 21 result in Patau, Edwards, and Down syndromes, respectively. While conventional methods like karyotyping and QF-PCR facilitate aneuploidy detection, they are often time-consuming and limited by genetic polymorphism variability. This study intr...

PurposeThe percentage of a maternal cell-free DNA (cfDNA) sample that is fetal-derived (the fetal fraction; FF) is a key driver of the sensitivity and specificity of noninvasive prenatal screening (NIPS). On certain NIPS platforms, >20% of women with high body-mass index (and >5% overall) receive a test failure due to low FF (<4%). MethodsA scalable fetal-fraction amplification (FFA) technology was analytically validated on 1,264 samples undergoing whole-genome sequencing (WGS)-based NIPS. All ...

Genetic diseases encompass a spectrum of disorders resulting from DNA variations. Preimplantation genetic testing (PGT) is a critical strategy for preventing recurrent miscarriage, foetal malformations, and the birth of children affected by chromosomal abnormalities and monogenic disorders. Traditional PGT techniques necessitate comprehensive pedigree genetic data for haplotype linkage analysis, whereas PGT employing third-generation sequencing (TGS) has distinct advantages, particularly in case...

BackgroundCopy number variants platforms, as critical supports for genetic diagnosis, have been well implemented in prenatal diagnosis. However, numerous severe conditions with underlying single-gene defects are not included in current invasive prenatal screening. To bridge this gap, an expanded chromosomal microarray analysis was developed, employing a meticulous designed single nucleotide polymorphism chip. This chip incorporated additional probes to augment its efficacy in screening for spina...

IntroductionSome Polymorphisms of the CYP2C19 gene are associated with a decrease in the activity of the enzyme they encode, being the case of CYP2C19*2 in causing a lower generation of active metabolite of clopidogrel and therefore a low or null antiplatelet action depending on the genotype present. Antiplatelet therapy, mainly clopidogrel, is considered essential treatment in the management of acute coronary syndromes (ACS). TargetThe frequency of the CYPC19*2 polymorphism, identified as rele...

ObjectivesTo investigate the incidence of chromosomal abnormalities in the products of conception (POC) of patients with spontaneous miscarriages (SM) and with recurrent pregnancy losses (RPL), and to determine biological mechanisms contributing to RPL. DesignRetrospective cohort study. SettingUniversity-affiliated medical center. PatientsDuring a 20-years period, 12,096 POC samples underwent classical chromosome analysis as a part of standard clinical care. InterventionsCytogenetic findings...

PMS2, a Lynch Syndrome gene, presents challenges in genetic testing due to the existence of multiple pseudogenes. This study aims to describe a series of cases harboring a rare LoF variant in the PMS2CL pseudogene that has been incorrectly assigned to PMS2 with different nomenclatures. We reviewed data from 647 Brazilian patients who underwent multigene genetic testing at a single center to identify those harboring the PMS2 V1:c.2186_2187delTC or V2:c.2182_2184delACTinsG variants, allegedly loca...

Traditionally, preimplantation genetic testing (PGT) for in vitro fertilization (IVF) requires invasive trophectoderm (TE) biopsy, which might be detrimental to the embryo. Recently proposed non-invasive PGT (ni-PGT) utilizing cell-free DNA from spent embryo culture medium (SCM) also faces serious challenges in accuracy, especially for monogenic diseases (niPGT-M), due to trace DNA content, maternal cell contamination, and high Allele Drop-Out (ADO) rates. In this study, an improved linear singl...