Dataset Information

Hyperphenylalaninaemias in Estonia: Genotype-Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening.

ABSTRACT: The present study provides a retrospective overview of the cohort of phenylketonuria (PKU) patients in Estonia. Based on the available data, the patients clearly cluster into two distinct groups: the patients with late diagnosis and start of therapy (N = 46), who were born before 1993 when the national newborn screening programme was launched, and the screened babies (N = 48) getting their diagnoses at least in a couple of weeks after birth.Altogether 153 independent phenylalanine hydroxylase (PAH) alleles from 92 patients were analysed in the study, wherein 80% of them were carrying the p.Arg408Trp variation, making the relative frequency of this particular variation one of the highest known. Additionally, 15 other different variations in the PAH gene were identified, each with very low incidence, providing ground for phenotypic variability and potential response to BH4 therapy. Genealogical analysis revealed some "hotspots" of the origin of the p.Arg408Trp variation, with especially high density in South-East Estonia. According to our data, the incidence of PKU in Estonia is estimated as 1 in 6,700 newborns.

SUBMITTER: Lillevali H

PROVIDER: S-EPMC6122019 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Hyperphenylalaninaemias in Estonia: Genotype-Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening.

Lilleväli Hardo H Reinson Karit K Muru Kai K Simenson Kristi K Murumets Ülle Ü Möls Tõnu T Õunap Katrin K

JIMD reports 20170928

The present study provides a retrospective overview of the cohort of phenylketonuria (PKU) patients in Estonia. Based on the available data, the patients clearly cluster into two distinct groups: the patients with late diagnosis and start of therapy (N = 46), who were born before 1993 when the national newborn screening programme was launched, and the screened babies (N = 48) getting their diagnoses at least in a couple of weeks after birth.Altogether 153 independent phenylalanine hydroxylase (P ...[more]

PMID: 28956315

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Project description:PURPOSE: To screen a cohort of corneal dystrophy patients from North India for mutations in the transforming growth factor beta induced (TGFBI) gene, to correlate genotypes to phenotypes, to describe structural implications of various mutations on protein function, and to discuss the implications for diagnosis. METHODS: Eighty affected individuals from 61 unrelated families, who were diagnosed with autosomal dominant granular and/or lattice corneal dystrophy, were recruited for the study. Detailed clinical evaluation was undertaken for these patients to establish their corneal phenotypes. Genomic DNA was isolated from peripheral blood samples and all exons of TGFBI were screened for mutations by polymerase chain reaction (PCR) and direct DNA sequencing. Protein molecular dynamics (MD) simulations were performed for the mutations detected to assess the changes in protein structure. RESULTS: The most common mutations seen were Arg555Trp and Arg124Cys. Two novel mutations, Ser516Arg (c.DNA1548C>G), with a phenotype similar to granular corneal dystrophy I (GCDI), and Leu559Val (c.DNA1675T>G), with an atypical phenotype closely resembling epithelial basement membrane dystrophy/map dot fingerprint dystrophy, were identified. Protein modeling studies involving wild type and mutant protein indicated that the Leu559Val is a destabilizing mutation and that Ser516Arg could adversely affect the specific binding of Fas1 domain 4 with other proteins. In addition, two single-nucleotide polymorphisms, rs4669 and rs11331170, were also identified. Mutations were not identified in 8 affected individuals, 6 of whom were diagnosed with bowman layer dystrophy and 2 with lattice corneal dystrophy. CONCLUSIONS: This is the first comprehensive report of TGFBI mutations covering a large part of North India. Identification of novel mutations, the presence of phenotypic variability, and the genetic heterogeneity seen in our cases stress the need for mandatory screening of TGFBI for precise diagnosis and classification of corneal dystrophies.

Dataset Information

Hyperphenylalaninaemias in Estonia: Genotype-Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening.

Publications

Hyperphenylalaninaemias in Estonia: Genotype-Phenotype Correlation and Comparative Overview of the Patient Cohort Before and After Nation-Wide Neonatal Screening.

Similar Datasets

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