Objectives
To examine the diagnostic yield of trio exome sequencing in fetuses with multiple structural defects with no pathogenic findings in cytogenetic and microarray analyses.
Methods
We ...recruited 51 fetuses with two or more defects, non‐immune fetal hydrops or fetal akinesia deformation syndrome|or fetal akinesia deformation sequence (FADS). Trio exome sequencing was performed on DNA from chorionic villi samples and parental blood. Detection of genomic variation and prioritization of clinically relevant variants was performed according to in‐house standard operating procedures.
Results
Median maternal and gestational age was 32.0 years and 21.0 weeks, respectively. Forty‐three (84.3%) fetuses had two or more affected organ systems. The remaining fetuses had isolated fetal hydrops or FADS. In total, the exome analysis established the genetic cause for the clinical abnormalities in 22 (43.1%, 95% CI 29.4%–57.8%) pregnancies.
Conclusions
In fetuses with multiple defects, hydrops or FADS and normal standard genetic results, trio exome sequencing has the potential to identify genetic anomalies in more than 40% of cases.
Key points
What's already known about this topic?
Genome‐wide sequencing for unspecific heterogeneous syndromic and non‐syndromic congenital conditions increases the diagnostic yield compared with standard genetic testing in both the pre‐ and postnatal settings. The diagnostic yield prenatally varies depending on selection criteria and number of anomalies present.
What does this study add?
Trio exome sequencing should be considered for fetuses with normal cytogenetic and micro‐array analysis and two or more organ defects, fetal hydrops or fetal akinesia syndromes. Selection of cases for exome sequencing should be based on expert prenatal imaging.
Niemann-Pick type C (NPC; OMIM 257219) disease is a neurodegenerative lysosomal storage disorder characterized by accumulation of unesterified cholesterol in the lysosomal/late endosomal system. This ...autosomal recessive disorder occurs in approximately 1/150,000 births. The broad clinical spectrum ranges from a prenatal severe presentation to an adult-onset chronic neurodegenerative disease. Data about prenatal presentation of NPC are limited. A female newborn was born at 34(2) weeks' gestation with a birth weight of 3070 g, and transferred to the Neonatal Intensive Care Unit because of nonimmune hydrops fetalis (NIHF) and respiratory distress. On admission, a physical examination revealed skin edema, mild respiratory distress, and abdominal distention due to massive ascites. Hepatosplenomegaly and cholestasis increased progressively and bleeding diathesis occurred. Results of an abdominal ultrasonography showed hepatosplenomegaly and segmental multicystic dysplastic left kidney. Foamy cells with a lysosomal phospholipid storage pattern compatible with NPC were found in the bone marrow smear. Cultured fibroblasts showed a strongly elevated filipin staining (classical NPC cellular phenotype), establishing the diagnosis of NPC. The infant died on the 52(nd) day of life because of respiratory distress due to lung involvement of NPC, massive ascites, and progressive liver failure. Results of an autopsy showed multiorgan storage disease involving the liver, spleen, lymph nodes, thymus, lungs, and brain. Here, we present a preterm infant with NIHF as a sign of severe prenatal-onset NPC and review the literature.
Inverse associations between selenium status and cancer risk have been observed in animal studies, ecologic studies, and some case-control and prospective studies. Whereas results of some prospective ...studies have suggested an overall inverse relationship between selenium levels and cancer, other prospective studies have failed to confirm this finding. Prospective data on women are particularly limited because fewer women than men have been studied prospectively.
The aim of this study was to prospectively examine the relationship between selenium levels in toenails (previously shown to reflect selenium intake) and incidence of cancer among women.
The Nurses' Health Study cohort began in 1976 with 121,700 female nurses aged 30-55 years living in 11 U.S. states. In 1982, we requested toenail clippings from the members of the cohort, and 62,641 participants with no history of cancer returned these clippings. During 41 months of follow-up, 503 cases of cancer other than breast cancer (results previously reported) or nonmelanoma skin cancer were analyzed. For each case patient, a control subject was chosen from women who remained free of diagnosed cancer, matched by age and by date of nail return.
No inverse association was observed between selenium levels in toenails and cancer risk. The age- and smoking-adjusted relative risk (RR), comparing the highest with the lowest quintile of toenail selenium level, was 1.44 (95% confidence interval CI = 0.97-2.13), and the trend across quintiles was marginally significant (two-sided P = .06). Comparing the highest with the lowest decile, the RR (age- and smoking-adjusted) was 1.77 (95% CI = 1.04-3.02). When these data were combined with the data from 434 breast cancer case patients and their matched control subjects identified in parallel from this same cohort, the RR comparing the highest with the lowest quintile was 1.24 (95% CI = 0.93-1.65). Toenail selenium level was not inversely associated with cancer at any major site, including uterine cancer, colorectal cancer, melanoma, ovarian cancer, or lung cancer (after adjusting for smoking); in fact, nonsignificant positive associations were observed at several sites.
Toenail selenium levels were not inversely associated with cancer risk in this study.
These data, in conjunction with previous findings of no association between toenail selenium status and breast cancer risk, strongly suggest that higher selenium intake within the range consumed by most U.S. women (as reflected by toenail selenium levels) is not protective against overall cancer incidence in women.
Menstrual cycle characteristics and ovulatory infertility were evaluated in relation to breast cancer risk among 116,678 women in the Nurses' Health Study II, a prospective cohort study of female ...registered nurses who were aged 25–42 years and living in 14 US states at enrollment in 1989. During 396,299 person-years of follow-up between return of the baseline questionnaire and June 1993, 251 cases of breast cancer were identified in this cohort. The multivariate relative risk (RR) associated with age at menarche >13 years compared with age ≤12 years was 0.66 (95% confidence interval (CI) 0.44–0.99). Short and long menstrual cycle lengths at ages 18–22 years were associated with reduced risk. Compared with menstrual cycle length 26–31 days, the multivariate relative risks (95% CIs) for more extreme cycle lengths were: <26 days, 0.50 (0.25–0.98); 32–39 days, 0.81 (0.51–1.28); and >39 days or too irregular for estimation of a usual cycle length, 0.41 (0.18–0.94). The multivariate relative risk associated with a history of ovulatory infertility, compared with no such history, was 0.41 (95% CI 0.18–0.93). These results are consistent with the hypothesis that reduced exposure to ovulatory menstrual cycles provides a protective effect against breast cancer. Am J Epidemiol 1998; 147: 636–43.
We evaluated current and past alcohol consumption prospectively in relation to breast cancer risk among 116,671 women ages
25–42 years old at enrollment in 1989. During 6 years of follow-up, 445 ...cases of invasive breast cancer were identified. For
alcohol consumption in the previous year, the multivariate relative risk associated with more than 20 g/day (approximately
10 drinks/week) was 1.23 (95% confidence interval, 0.68–2.21); the P for trend was 0.85. For average lifetime alcohol consumption, the multivariate relative risk associated with consumption
of 10 or more drinks/week was 1.20 (95% confidence interval, 0.69–2.11); the P for trend was 0.18. We examined drinking in several time periods of life; only drinking at ages 23–30 was significantly positively
associated with risk. Although this may represent a chance finding, it merits further study. Because drinking levels in this
population were low, we had limited information on heavier drinking. Our results suggest that there is unlikely to be a large
effect of moderate alcohol consumption on breast cancer risk among young women, although a modest effect cannot be excluded.
The association between alcohol consumption and breast cancer is unlikely to be substantially stronger among premenopausal
women than among postmenopausal women.
We assessed the reproducibility over a 6-year period of 16 trace elements measured in toenails by comparing levels in paired
specimens collected in 1982-1983 and 1988 from 127 women in the United ...States. The Spearman correlation coefficients for the
reproducibility of toenail levels of selenium and arsenic (both known to reflect intake of these elements) were 0.48 and 0.54.
Correlations for other elements ranged from 0.26 (copper) to 0.58 (zinc). In utilizing biomarkers to assess exposure in epidemiological
studies of cancer and other chronic disease, random within-person variability in exposure leads to attenuation of measures
of association between exposure and disease. We demonstrate the effect of such variability on odds ratios from a hypothetical
case-control study. For a true odds ratio of 3.0 (for a comparison of the highest quintile versus the remaining 4 quintiles
of exposure) the odds ratios which would be observed in the presence of the degree of within-person variability demonstrated
in this study were 2.15 for toenail arsenic and 1.67 for toenail copper levels. Toenail concentrations of certain trace elements
are useful biomarkers of exposure in which a single sample is assumed to represent long-term exposure. However, substantial
attenuation in measures of association may occur.
The associations between toenail levels of five trace elements and breast cancer risk were studied among a cohort of 62, 641 US women who provided toenail clippings and were free from diagnosed ...breast cancer in 1982. Among 433 cases of breast cancer identified during 4 years of follow-up and their matched controls, the odds ratios comparing the highest with the lowest quintiles and adjusted for established breast cancer risk factors were as follows: for arsenic, 1.12 (95% confidence interval (CI) 0.66–1.91); for copper, 0.91 (95% CI 0.59–1.42); for chromium, 0.96 (95% Cl 0.61–1.52); for iron, 0.89 (95% CI 0.56–1.40); and for zinc, 1.09 (95% CI 0.70–1.70). Among postmenopausal women, a marginally significant positive association was observed between toenail chromium levels and breast cancer risk (odds ratio = 1.71, 95% Cl 0.87–3.35) (p for trend = 0.07). However, the association between chromium and breast cancer risk was inverse among premenopausal women. Although data on the validity of toenail levels of certain of these elements are limited, these results do not provide evidence for an important effect of arsenic, copper, chromium, iron, or zinc on breast cancer risk. Am J Epidemiol 1996;144:653–60.
A common deletion polymorphism in the gene coding for the glutathione S-transferase class mu (the GSTM1 gene) results in a
decreased ability to detoxify carcinogenic epoxide intermediates and has ...been associated with increased breast cancer risk
in some small studies. We studied the GSTM1 gene deletion polymorphism (conferring the null genotype) in 243 women who had
prevalent breast cancer and 245 women without breast cancer, who were among the 32,826 women in the Nurses' Health Study who
gave a blood sample in 1989-1990. In the prevalent case series, the null genotype was slightly more common among cases (58%)
than among controls (51%; age-adjusted odds ratio = 1.30; 95% confidence interval, 0.91-1.86). Among cases, the prevalence
of the GSTM1 deletion increased with duration of survival 68% for > or = 8 years since diagnosis; 57% for 4-8 years; 51%
for < 4 years; P (trend) = 0.04. In an incident case series of 240 women who were diagnosed with breast cancer following
blood collection and prior to June of 1992 and compared with age-matched controls, the GSTM1 deletion was not associated with
an elevation in risk (relative risk, 1.08; 95% confidence interval, 0.74-1.57). No significant interaction with cigarette
smoking was evident. Thus, there was no significant increase in risk of incident breast cancer associated with the GSTM1 null
genotype; however, the gene deletion polymorphism appeared to confer improved survival. These data suggest that odds ratios
based upon prevalent cases in molecular epidemiologic studies may be biased due to differential survival. Further studies
are required to determine whether this polymorphism is associated with improved breast cancer prognosis.
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