Tiled array-based sequencing identifies enrichment of loss-of-function variants in the highly homologous filaggrin gene in African-American children with severe atopic dermatitis.

Filaggrin (FLG) loss-of-function (LOF) variants are a major risk factor for the common inflammatory skin disease, atopic dermatitis (AD) and are often population-specific. African-American (AA) children are disproportionately affected with AD, often later developing asthma and/or allergic rhinitis and comprise an atopy health disparity group for which the role of FLG LOF is not well known. Discovery of FLG LOF using exome sequencing is challenging given the known difficulties for accurate short-read alignment to FLG's high homology repeat variation. Here, we employed an array-based sequencing approach to tile across each FLG repeat and discover FLG LOF in a well-characterized cohort of AA children with moderate-to-severe AD. Five FLG LOF were identified in 23% of our cohort. Two novel FLG LOF singletons, c.488delG and p.S3101*, were discovered as well as p.R501*, p.R826* and p.S3316* previously reported for AD. p.S3316* (rs149484917) is likely an African ancestral FLG LOF, reported in African individuals in ExAC (Exome Aggregation Consortium), Exome Variant Server (ESP), and 4 African 1000G population databases (ESN, MSL, ASW, and ACB). The proportion of FLG LOF (11.5%) among the total FLG alleles in our cohort was significantly higher in comparisons with FLG LOF reported for African individuals in ExAC (2.5%; P = 4.3 × 10-4 ) and ESP (1.7%; P = 3.5 × 10-5 ) suggesting a disease-enrichment effect for FLG LOF. Our results demonstrate the utility of array-based sequencing in discovering FLG LOF, including novel and population-specific, which are of higher prevalence in our AA severe AD group than previously reported.

Analyzing the Genetic Spectrum of Vascular Anomalies with Overgrowth via Cancer Genomics.

Vascular anomalies are variably associated with overgrowth, skeletal anomalies, and abnormalities of the brain, leptomeninges, and eye. We assembled a 16-institution network to determine the range of genetic variants associated with a spectrum of vascular anomalies with overgrowth, ranging from mild to severe. Because of the overlap between cancer-associated variants and previously described somatic variants in vascular overgrowth syndromes, we employed tumor genetic profiling via high-depth next-generation sequencing using a panel to assay affected tissue from a diverse cohort of subjects with vascular anomalies with overgrowth. Seventy-five percent (43/57) harbored pathogenic or likely pathogenic variants in 10 genes. We identified two genes (mTOR, PIK3R1) and several variants previously described in the setting of cancer but that, to our knowledge, have not been described in vascular malformations. All were identified at low variant allele frequency consistent with somatic mosaic etiology. By leveraging somatic variant detection technology typically applied to cancer in a cohort inclusive of broad phenotypic severity, we demonstrated that most vascular anomalies with overgrowth harbor postzygotic gain-of-function mutations in oncogenes. Furthermore, continued interrogation of oncogenes in benign developmental disorders could provide insight into fundamental mechanisms regulating cell growth.

Aquagenic wrinkling of the palms in cystic fibrosis: comparison with controls and genotype-phenotype correlations.

OBJECTIVE: To determine the prevalence of aquagenic wrinkling of the palms (AWP) in patients with cystic fibrosis (CF) compared with control patients, and evaluate for genotype-phenotype correlations. Since its first description over 30 years ago, AWP has frequently been anecdotally associated with CF, but this association has not been confirmed in a rigorous prospective case-control study. DESIGN: Blinded comparison. SETTING: The CF and dermatology clinics at St Louis Children's Hospital. PARTICIPANTS: Forty-four individuals with CF from a CF clinic and 26 controls from a dermatology clinic. Intervention Participants were tested for AWP using 3 minutes of water immersion with room-temperature tap water. Main Outcome Measure The degree of AWP was scored from 0 (no wrinkling) to 4 (severe wrinkling) by 3 blinded physicians. For genotype-phenotype correlations, patients with CF were divided into those homozygous for the DeltaF508 mutation and those with other genotypes. RESULTS: The mean AWP score of the CF group was significantly higher than the mean score of the control group (1.5 vs 0.6; P < .001). Patients with CF who were homozygous for the DeltaF508 mutation (n = 27) had significantly higher scores than patients with CF who were not homozygous for the DeltaF508 mutation (n = 17) (1.7 vs 1.1; P = .02). The 17 patients with CF who were not homozygous for the DeltaF508 mutation still had higher scores than the control group (1.1 vs 0.6; P = .03). There was no correlation between sweat chloride concentrations measured at the time of diagnosis and AWP score. CONCLUSIONS: Our results confirm the association between AWP and CF. Among patients with CF, greater AWP occurs in those who are homozygous for the DeltaF508 mutation.

A prospective assessment of food and nutrient intake in a population of Malawian children at risk for kwashiorkor.

OBJECTIVE: To determine what foods, nutrients, and dietary patterns are associated with development of kwashiorkor in populations of vulnerable 1- to 3-year-old Malawian children. PATIENTS AND METHODS: This was a prospective observational study conducted in 8 rural villages. Upon enrollment, demographic, anthropometric, and dietary intake data were collected. Children were studied every 2 weeks for 10 weeks to determine whether they developed kwashiorkor. Dietary intake was assessed on enrollment using a food frequency questionnaire, which included all possible foods in the child's diet. Food frequency data were used to estimate energy, protein, vitamins C and A, niacin, thiamin, zinc, and iron intake using food composition and serving size data. Dietary diversity was assessed with a 7-point score. Regression modeling was used to determine whether the consumption of any food or nutrient was associated with the development of kwashiorkor. RESULTS: A total of 43 (2.6%) of the 1651 healthy children ages 1 to 3 years enrolled developed kwashiorkor. Children who developed kwashiorkor were younger and had more nutritional wasting than those who did not. Thirty children (70%) who developed kwashiorkor were breast-fed. In the combined regression model no foods or nutrients were found to be associated with the development of kwashiorkor. There were no differences in the dietary diversity between children who developed kwashiorkor and those who did not. CONCLUSIONS: No association between the development of kwashiorkor and the consumption of any food or nutrient was found.

Comparison of home-based therapy with ready-to-use therapeutic food with standard therapy in the treatment of malnourished Malawian children: a controlled, clinical effectiveness trial.

BACKGROUND: Childhood malnutrition is common in Malawi, and the standard treatment, which follows international guidelines, results in poor recovery rates. Higher recovery rates have been seen in pilot studies of home-based therapy with ready-to-use therapeutic food (RUTF). OBJECTIVE: The objective was to compare the recovery rates among children with moderate and severe wasting, kwashiorkor, or both receiving either home-based therapy with RUTF or standard inpatient therapy. DESIGN: A controlled, comparative, clinical effectiveness trial was conducted in southern Malawi with 1178 malnourished children. Children were systematically allocated to either standard therapy (186 children) or home-based therapy with RUTF (992 children) according to a stepped wedge design to control for bias introduced by the season of the year. Recovery, defined as reaching a weight-for-height z score > -2, and relapse or death were the primary outcomes. The rate of weight gain and the prevalence of fever, cough, and diarrhea were the secondary outcomes. RESULTS: Children who received home-based therapy with RUTF were more likely to achieve a weight-for-height z score > -2 than were those who received standard therapy (79% compared with 46%; P < 0.001) and were less likely to relapse or die (8.7% compared with 16.7%; P < 0.001). Children who received home-based therapy with RUTF had greater rates of weight gain (3.5 compared with 2.0 g . kg(-1) . d(-1); difference: 1.5; 95% CI: 1.0, 2.0 g . kg(-1) . d(-1)) and a lower prevalence of fever, cough, and diarrhea than did children who received standard therapy. CONCLUSION: Home-based therapy with RUTF is associated with better outcomes for childhood malnutrition than is standard therapy.