The controlling nutritional status score and clinical outcomes in patients with heart failure: Pool analysis of observational studies.

Background and aims Malnutrition is very common in patients with heart failure (HF) and is associated with a worse clinical outcome. The Controlling Nutritional Status (CONUT) score is an easily derived index for the evaluation of malnutrition. This study aimed to evaluate the association between the CONUT score and the prognosis in patients with HF. Methods and results Electronic databases were searched for potential studies from inception up to February 15, 2022. Observational cohort studies included adult participants with HF, and reported the associations between the CONUT score and the adjusted relative risk (RR) of all-cause mortality, and patients with composite major adverse cardiac outcomes (MACEs) were included. We finally included 18 studies comprising 12,532 participants with HF for analysis. The median age of the patients was 70.5 years old, and 35.4% were women. After a median follow-up duration of 32.5 months, patients with HF with a higher CONUT score were associated with a higher risk of all-cause mortality (per 1 increment of the CONUT score: RR, 1.21, 95% CI, 1.13-1.29, I 2 = 68%, P for heterogeneity = 0.002) and MACEs (per 1 increment of the CONUT score: RR, 1.14, 95% CI, 1.06-1.23, I 2 = 81%, P for heterogeneity <0.0001) after adjusting for other prognostic factors. When the CONUT score was divided into the normal nutritional status and malnourished status, malnourished patients with HF were associated with increased risks of all-cause death (RR, 1.61, 95% CI, 1.40-1.85, I 2 = 17%, P for heterogeneity = 0.29) and MACEs (RR, 2.12, 95% CI, 1.49-3.02, I 2 = 87%, P for heterogeneity <0.0001), compared with those with normal nutritional status. Conclusions The CONUT score is associated with the clinical outcomes in patients with HF, and can be used as a screening tool of nutritional status in HF to improve prognosis

The clinical significance of small copy number variants in neurodevelopmental disorders

Background: Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. Methods: By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1–500 kb in a cohort of 714 patients with undiagnosed NDDs. Results: We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. Conclusions: These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions

The clinical significance of small copy number variants in neurodevelopmental disorders

BACKGROUND Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. METHODS By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in a cohort of 714 patients with undiagnosed NDDs. RESULTS We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. CONCLUSIONS These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions

Cardiovascular risk factors, BMI and mortality in a cohort of Swiss males (1976-2001) with high-sum-assured life insurance cover

BACKGROUND: This long-term study investigates the influence of body mass index, blood pressure, smoking habits, impaired glucose metabolism and history of any disease on the mortality of Swiss males holding life insurance cover with high sums assured. METHODS: In a prospective study (1976-2001) including 22,927 Swiss insured males holding life insurance cover with high sums assured, the prevalence of overweight and obesity was compared with data from the general population. The relationship between BMI and all-cause mortality was assessed using a Cox proportional hazard model adjusted for age and calendar year, thereby controlling for mortality improvement over time. Multivariable models were used to investigate the impact of multiple cardiovascular risk factors on all-cause and cardiovascular mortality. The evolution of hazard ratios was assessed by dividing the observation period into two periods (1976-1985 vs 1986-2001). RESULTS: The prevalence of overweight was 35.7% and of obesity 6.2%. The prevalence of both increased over time. The association between BMI and all-cause mortality showed a 'U'-shaped curve with the nadir at 22.0-23.9 kg/m2. Compared with this optimal range, a relative risk of 1.76 (CI 95%: 1.17-2.67) was found for a BMI in the range of 30.0-31.9 kg/m2, representing the lowest category of obese subjects. In the multivariable model, obese subjects had a hazard ratio of 1.76 (CI 95%: 1.34-2.30) compared against those with normal BMI. The hazard ratios for all-cause mortality associated with prehypertension, stage 1 and stage 2 hypertension were 1.58, 2.28 and 3.14, respectively, all of them being statistically significant. The results for cardiovascular mortality were more pronounced, however, with wider confidence intervals. Comparing the two observational periods, the hazard ratios for obese vs non-obese subjects were 1.57 (CI 95%: 1.08 to 2.28) in period 1 and 2.41 (CI 95%: 1.71-3.39) in period 2. Similarly, the hazard ratio for combined stages 1 and 2 hypertension vs the other categories of JNC7 were 1.52 (CI 95%: 1.15-2.01) and 1.96 (CI 95%: 1.49-2.58) for periods 1 and 2, respectively. CONCLUSIONS: In this cohort of Swiss insured males holding life insurance cover with high sums assured, prevalence trends of elevated BMI are similar to those in the general population. The relative mortality risks associated with cardiovascular risk factors are higher than in the general population and, in the case of elevated BMI and high blood pressure, might exhibit an increase over time

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction

An assessment of teratology training provided by masters level genetic counseling programs

The increasing demand in the clinical genetics setting for information about teratogen exposures has created a need for genetic counselors to have the capabilities to appropriately address patient concerns. In order to assess how training in teratogen counseling is currently being conducted, the GLaRGG Teratogen Subcommittee surveyed all 17 genetic counseling training programs in North America in September 1993. Information was obtained from training programs about coursework, resources, and clinical training. In addition, each training program was asked to provide information about how their teratogen training needs could better be met. While all programs responded that some information in their coursework applicable to teratogen counseling was provided, there was wide variation in the amount of time devoted to this topic. The programs also greatly differed in the provision of clinical training in teratogen counseling. For both coursework and clinical work, genetic counselors were the main trainers in teratogen counseling. In spite of this, fewer than 25% of training programs have a defined teratogen clinical rotation. Data from the survey are discussed and recommendations presented.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44927/1/10897_2005_Article_BF01408075.pd

Noninvasive prenatal testing: more caution in counseling is needed in high risk pregnancies with ultrasound abnormalities

OBJECTIVE Non-invasive prenatal testing (NIPT) is increasingly being used in prenatal aneuploidy screening. The objective of this study was to assess the positive predictive value in our cohort of 68 cases with positive NIPT result. In addition, we wondered if the use of NIPT in cases with ultrasound abnormalities is appropriate, given the limited number of chromosomes investigated. DESIGN We performed confirmative invasive testing using karyotyping, fluorescence in situ hybridization (FISH) and/or high-resolution chromosomal microarray analysis. RESULTS In line with the published data, the positive NIPT result was confirmed in 64.7% of cases. Inconclusive and negative NIPT results followed by cytogenetically pathologic findings were encountered in three and in five cases, respectively. Four of the five fetuses with negative NIPT but pathologic cytogenetic findings were born with several malformations and diagnosed right after birth with severe genetic conditions. Of note, in all of those four cases, NIPT was offered despite the finding of major fetal ultrasound abnormalities and despite the fact that the family would not have opposed invasive testing or pregnancy termination. CONCLUSION More education of health care providers and caution in counseling and interpretation of test results are needed in order to meet the challenges that this new test, which enriches our diagnostic options in prenatal testing, poses

Genome-wide non-invasive prenatal testing in single- and multiple-pregnancies at any risk: Identification of maternal polymorphisms to reduce the number of unnecessary invasive confirmation testing

OBJECTIVE Non-invasive prenatal testing by targeted or genome-wide copy number profiling (cnNIPT) has the potential to outperform standard NIPT targeting the common trisomies 13, 18, and 21, only. Nevertheless, prospective results and outcome data on cnNIPT are still scarce and there is increasing evidence for maternal copy number variants (CNVs) interfering with results of both, standard and cnNIPT. STUDY DESIGN We assessed the performance of cnNIPT in 3053 prospective and 116 retrospective cases with special consideration of maternal CNVs in singleton and multiple gestational pregnancies at any risk, as well as comprehensive follow-up. RESULTS A result was achieved in 2998 (98.2%) of total prospective cases (89.2% analyzed genome-wide). Confirmed fetal chromosomal abnormalities were detected in 45 (1.5%) cases, of which five (11%) would have remained undetected in standard NIPTs. Additionally, we observed 4 likely fetal trisomies without follow-up and a likely phenotype associated placental partial trisomy 16. Moreover, we observed clinically relevant confirmed maternal CNVs in 9 (0.3%) cases and likely maternal clonal hematopoiesis in 3 (0.1%). For common fetal trisomies we prospectively observed a very high sensitivity (100% [95% CI: 91.96-100%]) and specificity (>99.9% [95% CI: 99.8-100%]), and positive predictive value (PPV) (97.8% [95% CI: 86.1-99.7%]), but our retrospective control cases demonstrated that due to cases of fetal restricted mosaicism the true sensitivity of NIPT is lower. After showing that 97.3% of small CNVs prospectively observed in 8.3% of genome-wide tests were mostly benign maternal variants, sensitivity (75.0% [95% CI: 19.4%-99.4%]), specificity (99.7% [99.5%-99.9%]) and PPV (30.0% [14.5%-52.1%]) for relevant fetal CNVs were relatively high, too. Maternal autoimmune disorders and medication, such as dalteparin, seem to impair assay quality. CONCLUSION When maternal CNVs are recognized as such, cnNIPT showed a very high sensitivity, specificity and PPV for common trisomies in single and multiple pregnancies at any risk and very good values genome-wide. We found that the resolution for segmental aberrations is generally comparable to standard karyotyping, and exceeds the latter if the fetal fraction is above 10%, which allows detection of the 2.5 Mb 22q11.2 microdeletion associated with the velocardiofacial syndrome, even if the mother is not a carrier