Assessment of genomic instability and proliferation index in cultured lymphocytes of patients with Down syndrome, congenital anomalies and aplastic anaemia

George, Alex; Somasundaram, Venkatesan; Ashok, Narmada; Saraswathy, Radha; Hande, M. Prakash

doi:10.1016/j.mrgentox.2018.06.015

Cited by 15 publications

(5 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, recent studies have suggested that within chromosome 21 there is a “congenital heart defect critical region”. Other potential mechanisms could include genomic instability (George, Venkatesan, Ashok, Saraswathy, & Hande, 2018) or interaction with other genes not localized on chromosome 21 and altered DNA methylation (Gensous, Franceschi, Salvioli, Garagnani, & Bacalini, 2019) that could lead to birth defects in children with trisomy 21.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of structural birth defects among infants with Down syndrome, 2013–2017: A US population‐based study

Heinke

Isenburg

Stallings

et al. 2020

Birth Defects Research

View full text Add to dashboard Cite

BackgroundDown syndrome is the most common chromosomal disorder at birth and is often accompanied by structural birth defects. Current data on major structural defects in this population are limited.MethodsStates and territorial population‐based surveillance programs submitted data on identified cases of Down syndrome and identified structural birth defects during 2013–2017. We estimated prevalence by program type and maternal and infant characteristics. Among programs with active case ascertainment, we estimated the prevalence of birth defects by organ system and for specific defects by maternal age (<35, ≥35) and infant sex.ResultsWe identified 13,376 cases of Down syndrome. Prevalence among all programs was 12.7 per 10,000 live births. Among these children, 75% had at least one reported co‐occurring birth defect diagnosis code. Among 6,210 cases identified by active programs, 66% had a cardiovascular defect with septal defects being the most common: atrial (32.5%), ventricular (20.6%), and atrioventricular (17.4%). Defect prevalence differed by infant sex more frequently than by maternal age. For example, atrioventricular septal defects were more common in female children (20.1% vs. 15.1%) while limb deficiencies were more prevalent in male children (0.4% vs. 0.1%).ConclusionsOur study provides updated prevalence estimates for structural defects, including rare defects, among children with Down syndrome using one of the largest and most recent cohorts to date. These data may aid clinical care and surveillance.

show abstract

Section: Discussionmentioning

confidence: 99%

Prevalence of structural birth defects among infants with Down syndrome, 2013–2017: A US population‐based study

Heinke

Isenburg

Stallings

et al. 2020

Birth Defects Research

View full text Add to dashboard Cite

show abstract

“…Also, a variety of diseases, 11,[22][23][24] including Down syndrome, congenital anomalies, aplastic anemia, and solid cancers (e.g., breast cancers) has been associated with genomic instability. 22,25 Therefore, we evaluated the aforementioned factors to assess the genotoxicity of long-term PPI use, and included only patients with no previous medical or drug history within 2 years. Increased frequencies of MNi, NPBs, and Nbuds, used as markers of carcinogenic events, are associated with an increased risk of cancer.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity in Patients on Long-term Proton Pump Inhibitor Therapy in Korea: A Nested Case-control, Prospective, Pilot Study

Choi

Chung

Park

et al. 2020

Korean J Helicobacter Up Gastrointest Res

View full text Add to dashboard Cite

Background/Aims: Although proton pump inhibitors (PPIs) remain a mainstay for the suppression of gastric acid secretion, long-term PPI use is associated with side effects. However, the genotoxicity associated with long-term PPI use is unclear.Materials and Methods: This prospective observational pilot study enrolled patients who had been on PPIs for >1 year and healthy controls from July 2015 to August 2016. The subjects completed self-report questionnaires pertaining to their drug and medical history, and only those with no medical history and a ≥2-year wash-out period (for drugs other than PPIs) were included. We collected peripheral-blood lymphocytes from long-term PPI users and healthy controls and analyzed the genotoxicity by using the cytokinesis-block micronucleus cytome assay; we also determined the fasting serum levels of pyridoxine, folate, cobalamin, and homocysteine.Results: Ten long-term PPI users and 40 healthy control subjects were enrolled. The median serum pyridoxine, folate, cobalamin, and homocysteine levels were not significantly different between the groups. The median frequencies of micronuclei (MNi), nucleoplasmic bridges (NPBs), and nuclear buds (Nbuds) per 1,000 binucleated cells, in long-term PPI users and healthy controls, were 30.3 and 16.3 (P<0.005), 2.5 and 1.8 (P<0.005), and 9.3 and 5.0 (P<0.005), respectively. Even after adjustment for confounding factors, the OR of the MNi, NPBs, and Nbuds for long-term PPI users compared with healthy control subjects were 14.1 (P<0.001), 2.0 (P=0.001), and 1.3 (P=0.3), respectively.Conclusions: Long-term PPI use was significantly associated with an increased risk of genotoxicity after adjustment for age, sex, body mass index, medical history, drug history, and the serum levels of vitamins.

show abstract

“…Acquired chromosomal instability represents one subset of biomarkers associated with/related to acquired health conditions and aging in the general population [13], but there is a paucity of studies in which spontaneous acquired somatic chromosomal instability frequencies (SCINF) have been evaluated in people with Down syndrome. In the few previous reports, most investigators have observed increased SCINF in the buccal mucosa cells [14,15] or lymphocytes [16][17][18][19] of people with Down syndrome compared to the levels seen in healthy, age-matched controls. However, genetic (e.g., genes that might contribute to an increased propensity to have acquired somatic cell instability) and environmental background differences between the different individuals in the trisomic and control groups have limited the investigators' ability to directly attribute the observed changes to influences reflective of a trisomic imbalance [20].…”

Section: Introductionmentioning

confidence: 91%

Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome

et al. 2021

View full text Add to dashboard Cite

Down syndrome, which results from a trisomic imbalance for chromosome 21, has been associated with 80+ phenotypic traits. However, the cellular changes that arise in somatic cells due to this aneuploid condition are not fully understood. The primary aim of this study was to determine if germline trisomy 21 is associated with an increase in spontaneous somatic cell chromosomal instability frequencies (SCINF). To achieve this aim, we quantified SCINF in people with mosaic Down syndrome using a cytokinesis-blocked micronucleus assay. By comparing values in their isogenic trisomic/disomic cells, we obtained a measure of differences in SCINF that are directly attributable to a trisomy 21 imbalance, since differential effects attributable to “background” genetic factors and environmental exposures could be eliminated. A cross-sectional assessment of 69 people with mosaic Down syndrome (ages 1 to 44; mean age of 12.84 years) showed a significantly higher frequency of micronuclei in their trisomic (0.37 ± 0.35 [mean ± standard deviation]) compared to disomic cells (0.18 ± 0.11)(P <0.0001). The daughter binucleates also showed significantly higher levels of abnormal patterns in the trisomic (1.68 ± 1.21) compared to disomic (0.35 ± 0.45) cells (P <0.0001). Moreover, a significant Age x Cell Type interaction was noted (P = 0.0113), indicating the relationship between age and SCINF differed between the trisomic and disomic cells. Similarly, a longitudinal assessment (mean time interval of 3.9 years; range of 2 to 6 years) of 18 participants showed a mean 1.63-fold increase in SCINF within individuals over time for their trisomic cells (P = 0.0186), compared to a 1.13-fold change in their disomic cells (P = 0.0464). In summary, these results showed a trisomy 21-associated, age-related increase in SCINF. They also underscore the strength of the isogenic mosaic Down syndrome model system for “unmasking” cellular changes arising from a trisomy 21 imbalance.

show abstract

Assessment of genomic instability and proliferation index in cultured lymphocytes of patients with Down syndrome, congenital anomalies and aplastic anaemia

Cited by 15 publications

References 34 publications

Prevalence of structural birth defects among infants with Down syndrome, 2013–2017: A US population‐based study

Prevalence of structural birth defects among infants with Down syndrome, 2013–2017: A US population‐based study

Genotoxicity in Patients on Long-term Proton Pump Inhibitor Therapy in Korea: A Nested Case-control, Prospective, Pilot Study

Trisomy 21-associated increases in chromosomal instability are unmasked by comparing isogenic trisomic/disomic leukocytes from people with mosaic Down syndrome

Contact Info

Product

Resources

About