Children's Memorial Hospital

About: Children's Memorial Hospital is a based out in . It is known for research contribution in the topics: Population & Transplantation. The organization has 5652 authors who have published 8967 publications receiving 283837 citations.

Analysis of select folate pathway genes, PAX3, and human T in a Midwestern neural tube defect population.

Abstract: Neural tube defects (NTDs) are a common birth defect, seen in approximately 1/1,000 births in the United States. NTDs are considered a complex trait where several genes, interacting with environmental factors, create the phenotype. Using a Midwestern NTD population consisting of probands, parents, and siblings from Iowa, Minnesota, and Nebraska, we analyzed a range of candidate genes, including 5,10-methylenetetrahydrofolate reductase (MTHFR), folate receptors-alpha (FOLR1; hereafter abbreviated "FR-alpha") and -beta (FOLR2; hereafter, "FR-beta"), methionine synthase (hereinafter, "MS"), T, the human homolog of the murine Brachyury gene, and the paired-box homeotic gene 3 (PAX3), for association with NTDs. We were unable to demonstrate an association using a previously described Ala-->Val mutation in MTHFR and the majority of our NTD populations. However, we discovered a silent polymorphism in exon 6 of MTHFR which conserved a serine residue and which showed significant association with NTDs in our Iowa population. Analysis of exon 7 of MTHFR then demonstrated an Ala-->Glu mutation which was significantly associated with our Iowa NTD population; however, we could not replicate this result either in a combined Minnesota/ Nebraska or in a California NTD population. Using polymorphic markers for MS, FR-beta, T, and PAX3, we were unable to demonstrate linkage disequilibrium with our NTD populations. A mutation search of FR-alpha revealed one proband with a de novo silent mutation of the stop codon. This work provides a new panel of genetic variants for studies of folate metabolism and supports, in some NTD populations, an association between MTHFR and NTDs.

The Genetic Landscape and Epidemiology of Phenylketonuria

Abstract: Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.