Dataset Information

Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China.

ABSTRACT: Mutations in the gene encoding phenylalanine hydroxylase (PAH) are associated with various degrees of phenylketonuria (PKU). The aim of our study was to define the genotype-phenotype correlations of mutations in the PAH gene that cause phenylketonuria (PKU) among the Chinese mainland population. Mutations in the PAH gene were analysed by next-generation sequencing, and a genotype-phenotype correlation analysis was performed in 1079 patients. Fifteen "null?+?null" genotypes, including four homoallelic and eleven heteroallelic genotypes, were clearly associated with classic PKU. Five functionally hemizygous (p.E280K, p.R252Q, p.E56D, p.S310F and p.T372R) and four compound heterozygous (p.T278I/p.S359L, p.R408W/p.R243Q, p.F161S/p.R243Q and p.F161S/p.R413P) genotypes were clearly associated with classic PKU. Ten functionally hemizygous genotypes, p.G257V, p.R158W, p.L255S, p.G247V, p.F161S, p.R158Q, p.V388M, p.I65T, p.I324N and p.R400K, were frequently associated with classic PKU. Three functionally hemizygous genotypes, p.P147L, p.I95del and p.F331S, and four compound heterozygous genotypes, p.G257V/p.R408Q, p.A434D/p.R413P, p.R243Q/p.A47E and p.R241C/p.G239D, were consistently correlated with mild PKU. Three functionally hemizygous genotypes, p.H107R, p.Q419R and p.F392I, and nine compound heterozygous genotypes (p.G312V/p.R241C, p.R243Q/p.V230I, p.R243Q/p.A403V, p.R243Q/p.Q419R, p.R243Q/p.R53H, p.R243Q/p.H107R, p.R241C/p.R408Q, p.R241C/p.H220P and p.R53H/p.R400K) were consistent with mild hyperphenylalaninaemia (MHP). Our study provides further support for the hypothesis that the PAH genotype is the main factor that determines the phenotype of PKU.

SUBMITTER: Li N

PROVIDER: S-EPMC6062512 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China.

Li Nana N He Chunhua C Li Jing J Tao Jing J Liu Zhen Z Zhang Chunyan C Yuan Yuan Y Jiang Hui H Zhu Jun J Deng Ying Y Guo Yixiong Y Li Qintong Q Yu Ping P Wang Yanping Y

Scientific reports 20180726 1

Mutations in the gene encoding phenylalanine hydroxylase (PAH) are associated with various degrees of phenylketonuria (PKU). The aim of our study was to define the genotype-phenotype correlations of mutations in the PAH gene that cause phenylketonuria (PKU) among the Chinese mainland population. Mutations in the PAH gene were analysed by next-generation sequencing, and a genotype-phenotype correlation analysis was performed in 1079 patients. Fifteen "null + null" genotypes, including four homoal ...[more]

PMID: 30050108

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Project description:BackgroundHereditary hemochromatosis (HH) is widely recognized and clinical manifestations of hemochromatosis-related (HFE-related) HH is well studied in European populations. Less is known about the clinical and laboratory characteristics of non-HFE related HH in Asian population. We aimed to explore the relationship between genotype and clinical phenotype in Chinese patients with non-HFE related hereditary hemochromatosis.MethodsPeripheral blood samples and clinical data of patients with primary iron overload were collected from the China Registry of Genetic/Metabolic Liver Diseases. Sanger sequencing was performed in cases with primary iron overload, for 5 known HH related genes (HFE, HJV, HAMP, TFR2 and SLC40A1) and 2 novel iron homeostasis-related genes (DENND3 and SUGP2). The correlation of genotype and clinical phenotype in these patients was analyzed.ResultsOf the 32 patients with primary iron overload (23 were males and 9 were females), non-HFE variants were detected in 31 (31/32, 97%), including 8 pathogenic variants in HJV, 7 pathogenic variants in SLC40A1, 8 likely pathogenic variants in SUGP2 and 5 likely pathogenic variants in DENND3 cases. Among these 31 cases, 4 cases harbored homozygous variants, 2 cases harbored homozygous + heterozygous variants, 19 cases harbored heterozygous or combined heterozygous variants, and 6 cases harbored no any damaging variants. None of investigated cases carried damaging HAMP and TFR2 variants were found. 8 cases were classified as type 2A HH and 6 cases as type 4 HH, 10 cases as non-classical genotype, and 6 cases had no pathogenic variants from 31 cases. During the statistical analysis, we excluded one case (SLC40A1 IVS3 + 10delGTT + SUGP2 p. R639Q(homo)) with difficulty in grouping due to combined damaging variants. Cases with type 2A HH have an earlier age at diagnosis (p = 0.007). The iron index of cases in type 2A HH and type 4 HH was higher than that in other groups (p = 0.01). Arthropathy was relatively rare in all groups. None of cases with type 2A HH developed cirrhosis. Cirrhosis and diabetes are more prevalent in type 4 HH. The incidence of cirrhosis (p = 0.011), cardiac involvement (p = 0.042), diabetes (p = 0.035) and hypogonadism (p = 0.020) was statistically significant in the four groups. However, due to the limited sample size, the pairwise comparison showed no significant difference.ConclusionsThis is the first comprehensive analysis about the gene variant spectrum and phenotypic aspects of non-HFE HH in China. The results will be useful to the identification, diagnosis and management of HH in China.

Dataset Information

Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China.

Publications

Analysis of the genotype-phenotype correlation in patients with phenylketonuria in mainland China.

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