scholarly journals Point Mutations in Ferroportin Disease: Genotype/Phenotype Correlation

10.5772/34218 ◽  
2012 ◽  
Author(s):  
Riad Akoum
Keyword(s):  
Point Mutations ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation

scholarly journals Detection of Splicing Abnormalities and Genotype-Phenotype Correlation in X-linked Alport Syndrome

2018 ◽  
Vol 29 (8) ◽  
pp. 2244-2254 ◽  
Author(s):  
Tomoko Horinouchi ◽  
Kandai Nozu ◽  
Tomohiko Yamamura ◽  
Shogo Minamikawa ◽  
Takashi Omori ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Alport Syndrome ◽  
Stop Codon ◽  
Consensus Sequence ◽  
Point Mutations ◽  
Premature Stop Codon ◽  
Transcript Level ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
Splicing Patterns

BackgroundX-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS.MethodsWe examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating (n=21, from 14 families) and nontruncating (n=25, from 15 families) mutations at the transcript level.ResultsWe detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns (n=14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations (P=0.001).ConclusionsWe report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

scholarly journals Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction

2016 ◽  
Vol 175 (2) ◽  
pp. 107-116 ◽  
Author(s):  
Daniel F de Carvalho ◽  
Mirela C Miranda ◽  
Larissa G Gomes ◽  
Guiomar Madureira ◽  
José A M Marcondes ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Founder Effect ◽  
Novel Mutation ◽  
Point Mutations ◽  
Carrier Status ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Specific Pcr ◽  
Genotype Phenotype Correlation ◽  
Simple Virilizing

Background Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. Objective To review causal mutations and genotype–phenotype correlation in 480 Brazilian patients. Methods DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3–7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). Results Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3ng/mL was the best cutoff to identify NC-patients carrying severe mutations. Conclusions We identified a good genotype–phenotype correlation in CAH, providing useful data regarding prediction of disease’s severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

scholarly journals Genotype-Phenotype Correlation in Patients with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency in Cuba

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Tania Mayvel Espinosa Reyes ◽  
Teresa Collazo Mesa ◽  
Paulina Arasely Lantigua Cruz ◽  
Adriana Agramonte Machado ◽  
Emma Domínguez Alonso ◽  
...  
Keyword(s):  
Congenital Adrenal Hyperplasia ◽  
Point Mutations ◽  
Clinical Manifestations ◽  
Adrenal Hyperplasia ◽  
Phenotype Correlation ◽  
Hydroxylase Deficiency ◽  
Cyp21a2 Gene ◽  
Genotype Phenotype Correlation ◽  
21 Hydroxylase Deficiency ◽  
Cuban Population

Background. There are several studies that show a good genotype-phenotype correlation in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). However, there is well-documented evidence of inconsistency in some cases. Objectives. To determine if there is a correlation between the identified mutations and the clinical manifestations of 21OHD in the Cuban population. Methods. A cross-sectional descriptive study of all patients referred for a molecular diagnosis of 21OHD in Cuba from January 2000 to December 2018. The clinical manifestations of each patient were identified and classified according to the phenotype. The CYP21A2 gene was analyzed for the presence of 5 point mutations involved in the pathogenesis of 21OHD (intron 2, deletion of 8bp, I172N, P30L, and Q318X); correlation was sought between the phenotypic characteristics and the frequencies of point mutations in the patients using the Spearman test. Results. A total of 55 patients underwent direct analysis of the CYP21A2 gene in order to determine the presence of the 5 point mutations. Point mutations were identified in 31 patients, which corresponded to 56%. A statistically significant genotype-phenotype correlation was found. Conclusions. The correlation between the detected molecular defect and the clinical expression of 21OHD was reasonable in the Cuban population, which could allow phenotypic predictions to be made from the genotype.

scholarly journals CYP21 Gene Mutation Analysis in 198 Patients with 21-Hydroxylase Deficiency in The Netherlands: Six Novel Mutations and a Specific Cluster of Four Mutations

2003 ◽  
Vol 88 (8) ◽  
pp. 3852-3859 ◽  
Author(s):  
Nike M. M. L. Stikkelbroeck ◽  
Lies H. Hoefsloot ◽  
Ilse J. de Wijs ◽  
Barto J. Otten ◽  
Ad R. M. M. Hermus ◽  
...  
Keyword(s):  
The Netherlands ◽  
Point Mutations ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Hydroxylase Deficiency ◽  
Salt Wasting ◽  
Cyp21 Gene ◽  
Genotype Phenotype Correlation ◽  
Single Allele ◽  
21 Hydroxylase Deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. The aim of this study was to assess the frequencies of CYP21 mutations and to study genotype-phenotype correlation in a large population of Dutch 21-hydroxylase deficient patients. From 198 patients with 21-hydroxylase deficiency, 370 unrelated alleles were studied. Gene deletion/conversion was present in 118 of the 370 alleles (31.9%). The most frequent point mutations were I2G (28.1%) and I172N (12.4%). Clustering of pseudogene-derived mutations in exons 7 and 8 (V281L-F306 + 1nt-Q318X-R356W) on a single allele was found in seven unrelated alleles (1.9%). This cluster had been reported before in two other Dutch patients and in two patients in a study from New York, but not in other series worldwide. Six novel mutations were found: 995–996insA, 1123delC, G291R, S301Y, Y376X, and R483Q. Genotype-phenotype correlation (in 87 well documented patients) showed that 28 of 29 (97%) patients with two null mutations and 23 of 24 (96%) patients with mutation I2G (homozygous or heterozygous with a null mutation) had classic salt wasting. Patients with mutation I172N (homozygous or heterozygous with a null or I2G mutation) had salt wasting (2 of 17, 12%), simple virilizing (10 of 17, 59%), or nonclassic CAH (5 of 17, 29%). All six patients with mutation P30L, V281L, or P453S (homozygous or compound heterozygous) had nonclassic CAH. The frequency of CYP21 mutations and the genotype-phenotype correlation in 21-hydroxylase deficient patients in The Netherlands show in general high concordance with previous reports from other Western European countries. However, a cluster of four pseudogene-derived point mutations on exons 7 and 8 on a single allele, observed in almost 2% of the unrelated alleles, seems to be particular for the Dutch population and six novel CYP21 gene mutations were found.

A familial case of osteogenesis imperfecta: study of genotype-phenotype correlation

2013 ◽  
Author(s):  
Ponti Emanuela ◽  
Mihalich Alessandra ◽  
Broggi Francesca ◽  
Maria Di Blasio Anna ◽  
Luisa Bianchi Maria
Keyword(s):  
Osteogenesis Imperfecta ◽  
Familial Case ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation
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