scholarly journals Molecular screening of PROKR2 gene in girls with idiopathic central precocious puberty

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) to identify possible alterations in PROKR2. Methods We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5 IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD). Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD). Conclusions As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Molecular Screening of PROKR2 Gene in Girls with Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Precocious Puberty ◽  
Rare Variants ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Fisher Exact Test ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Exact Test ◽  
First Case

Abstract Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been describedas cause of hypogonadotropic hypogonadism. In 2017, a first case of central precocious puberty(CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5 years-oldgirl. No other cases have been reported yet. This study performs a molecular screening ingirls with early onset CPP (breast budding before 6 years of age) to identify possiblealterations in PROKR2.Methods: We analysed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels >0.3IU/L or peak-LH>5IU/L after stimulation, without any MKRN3 mutations. The Fisher exact test was used to compare polymorphism allele frequency to corresponding ones in genome aggregation database (gnomAD).Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency (MAF) similar to that reported in literature. rs3746682 presented a MAF higher than that described in the gnomAD (0.84 in our cohort vs 0.25 from gnomAD).Conclusions: As for other G protein-coupled receptors (i.e. GPR54), mutations in PROKR2 donot seem to be a frequent cause of CPP in girls.

scholarly journals Molecular Screening of PROKR2 Gene in Girls with Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Precocious Puberty ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Minor Allele ◽  
Fisher Exact Test ◽  
Molecular Screening ◽  
First Case ◽  
A Minor

Abstract Background: Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017 a first case of central precocious puberty (CPP) caused by PROKR2 heterozygous gain of function mutation was described in a 3.5-year-old girl. No other cases have been reported yet. This study performs a molecular screening in girls with early onset CPP (breast budding before 6 years of age) in order to identify possible alterations in PROKR2. Methods: We analyzed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels >0.3 IU/L or peak-LH>5IU/L after stimulation, negative for MKRN3 mutations. The Fisher exact test was used to compare allele frequency of polymorphism found to genome aggregation database (gnomAD).Results: No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency similar to that reported in literature. rs3746682 presented a minor allele frequency higher than described in the gnomAD (0.84 in our population vs 0.25 from gnomAD). Conclusions: As for other G-protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Molecular Screening of PROKR2 Gene in Girls with very early Idiopathic Central Precocious Puberty.

2020 ◽  
Author(s):  
Francesca Aiello ◽  
Grazia Cirillo ◽  
Alessandra Cassio ◽  
Raffaella Di Mase ◽  
Gianluca Tornese ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Precocious Puberty ◽  
Central Precocious Puberty ◽  
Minor Allele ◽  
Fisher Exact Test ◽  
Molecular Screening ◽  
First Case ◽  
Exome Aggregation Consortium ◽  
A Minor

Abstract Background Prokineticin receptor 2 (PROKR2) loss of function mutations have been described as cause of hypogonadotropic hypogonadism. In 2017 a first case of central precocious puberty (CPP) caused by heterozygous gain of function mutation in PROKR2 was described in a 3.5-year‐old girl. No other cases have been reported yet. This study performs a molecular screening in girls with “early” onset CPP (breast budding before 6 years of age) in order to identify possible alterations in PROKR2.Methods We analyzed DNA of 31 girls with idiopathic CPP diagnosed via basal LH levels > 0.3 IU/L or peak-LH > 5UI/L after stimulation, negative for MKRN3 mutations. The Fisher exact test was used to compare allele frequency of polymorphism found to Exome Aggregation Consortium (ExAC) dataset.Results No rare variants were identified. Five polymorphisms were found (rs6076809, rs8116897, rS3746684, rs3746682, rs3746683). All except one (i.e. rs3746682) had a minor allele frequency similar to that reported in literature. rs3746682 presented a minor allele frequency higher than described in The Exome Aggregation Consortium (ExAC) (0.84 in our population vs 0.25 from ExAC).Conclusions As for other G-protein-coupled receptors (i.e. GPR54), mutations in PROKR2 do not seem to be a frequent cause of CPP in girls.

scholarly journals Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders

2012 ◽  
Vol 56 (9) ◽  
pp. 646-652 ◽  
Author(s):  
Cintia Tusset ◽  
Sekoni D. Noel ◽  
Ericka B. Trarbach ◽  
Letícia F. G. Silveira ◽  
Alexander A. L. Jorge ◽  
...  
Keyword(s):  
Genomic Dna ◽  
Rare Variants ◽  
Mutational Analysis ◽  
Pubertal Development ◽  
Hypogonadotropic Hypogonadism ◽  
Central Precocious Puberty ◽  
Control Group ◽  
Loss Of Function ◽  
Coding Region ◽  
Constitutional Delay

OBJECTIVE: To investigate the presence of variants in the TAC3 and TACR3 genes, which encode NKB and its receptor (NK3R), respectively, in a large cohort of patients with idiopathic central pubertal disorders. SUBJECTS AND METHODS: Two hundred and thirty seven patients were studied: 114 with central precocious puberty (CPP), 73 with normosmic isolated hypogonadotropic hypogonadism (IHH), and 50 with constitutional delay of growth and puberty (CDGP). The control group consisted of 150 Brazilian individuals with normal pubertal development. Genomic DNA was extracted from peripheral blood and the entire coding region of both TAC3 and TACR3 genes were amplified and automatically sequenced. RESULTS: We identified one variant (p.A63P) in NKB and four variants, p.G18D, p.L58L (c.172C>T), p.W275* and p.A449S in NK3R, which were absent in the control group. The p.A63P variant was identified in a girl with CPP, and p.A449S in a girl with CDGP. The known p.G18D, p.L58L, and p.W275* variants were identified in three unrelated males with normosmic IHH. CONCLUSION: Rare variants in the TAC3 and TACR3 genes were identified in patients with central pubertal disorders. Loss-of-function variants of TACR3 were associated with the normosmic IHH phenotype. Arq Bras Endocrinol Metab. 2012;56(9):646-52

scholarly journals Genetic Analysis of TREM2 Variants in Tunisian Patients with Alzheimer's Disease

2018 ◽  
Vol 27 (4) ◽  
pp. 317-322 ◽  
Author(s):  
Zied Landoulsi ◽  
Mouna Ben Djebara ◽  
Imen Kacem ◽  
Youssef Sidhom ◽  
Rym Kefi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rare Variants ◽  
Late Onset ◽  
Tunisian Population ◽  
Fisher Exact Test ◽  
Exon 2 ◽  
Exact Test ◽  
Tunisian Patients ◽  
Synonymous Variant

Objective: Rare variants in the TREM2 gene have been reported to significantly increase the risk of Alzheimer’s disease in Caucasian populations. Hitherto, this association was not studied in North African populations. In this work, we aimed to study the association between TREM2 exon 2 variants and the risk of late-onset Alzheimer’s disease (LOAD) in a Tunisian population. Subjects and Methods: We sequenced exon 2 of TREM2 in a Tunisian cohort of 172 LOAD patients and 158 control subjects. We used the Fisher exact test to compare the distribution of allelic frequencies between the two groups. Results: We identified 4 previously reported nonsynonymous variants (p.Asp39Glu, p.Arg62His, p.Thr96Lys, and p.Val126Gly) and 1 novel synonymous variant (p.Gln109Gln), none of which was significantly associated with the risk of Alzheimer’s disease. Moreover, the rare TREM2 variant (p.Arg47His), which was considered to be a risk factor for Alzheimer’s disease in European descent populations, was not detected in our cohort. Conclusion: These findings do not support a major role for TREM2 in the pathogenesis of LOAD in the Tunisian population.

scholarly journals Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children’s Oncology Group

2020 ◽  
pp. 1187-1195
Author(s):  
Brandon J. Diessner ◽  
Nathan Pankratz ◽  
Anthony J. Hooten ◽  
Lisa Mirabello ◽  
Aaron L. Sarver ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Rare Variants ◽  
De Novo ◽  
Phase 1 ◽  
Control Measures ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Whole Exome ◽  
History Of ◽  
De Novo Variant

PURPOSE To ascertain the prevalence of recurrent de novo variants among 240 pediatric patients with osteosarcoma (OS; age < 20 years) unselected for family history of cancer. METHODS The identification of de novo variants was implemented in 2 phases. In the first, we identified genes with a rare (minor allele frequency < 0.01) de novo variant in > 1 of the 95 case-parent trios examined by whole-exome sequencing (WES) who passed quality control measures. In phase 2, 145 additional patients with OS were evaluated by targeted sequencing to identify rare de novo variants in genes nominated from phase 1. Recurrent rare variants identified from phase 1 and 2 were verified as either de novo or inherited by Sanger sequencing of affected patients and their parents. Categorical and continuous data were analyzed using Fisher exact test and t tests, respectively. RESULTS Among 95 case-parent trios who underwent WES, we observed 61 de novo variants in 60 genes among 47 patients, with TP53 identified as the only gene with a pathogenic or likely pathogenic (P/LP) de novo variant in more than one case-parent trio. Among all 240 patients with OS, 13 (5.4%) harbored a P/LP TP53 germline variant, of which 6 (46.2%) were confirmed to be de novo. CONCLUSION Apart from TP53, we did not observe any other recurrent de novo P/LP variants in the case-parent trios, suggesting that new mutations in other genes are not a frequent cause of pediatric OS. That nearly half of P/LP TP53 variants in our sample were de novo suggests universal screening for germline TP53 P/LP variants among pediatric patients with OS should be considered.

scholarly journals Transcript-Specific Loss-of-Function Variants in VPS16 Are Enriched in Patients With Dystonia

2021 ◽  
Vol 8 (1) ◽  
pp. e644
Author(s):  
Joohyun Park ◽  
Annemarie Reilaender ◽  
Jan N. Petry-Schmelzer ◽  
Petra Stöbe ◽  
Isabell Cordts ◽  
...  
Keyword(s):  
Fisher Exact Test ◽  
Data Sets ◽  
Variant Interpretation ◽  
Loss Of Function ◽  
Splice Isoforms ◽  
Exact Test ◽  
Expression Levels ◽  
Genome Data ◽  
Statistical Measures ◽  
Clinical Description

Background and ObjectivesOur objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare VPS16 variants observed in patients with dystonia and patients without dystonia, elaborate on our interpretation of VPS16 variants affecting different transcripts, and provide detailed clinical description of the movement disorder caused by VPS16 variants.MethodsIn-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in VPS16. Using pext (proportion expressed across transcripts) values from the Genome Aggregation Database (gnomAD), we differentiated variants affecting weakly and highly expressed exons/transcripts and applied statistical measures to systematically identify disease-associated genetic variation among patients with dystonia (n = 280).ResultsSix different heterozygous pLoFs in VPS16 transcripts were identified in 13 individuals. Three of these pLoFs occurred in 9 individuals with different phenotypes, and 3 pLoFs were identified in 4 unrelated individuals with early-onset dystonia. Although pLoFs were enriched in the dystonia cohort (n = 280; p = 2.04 × 10−4; 4/280 cases vs 9/11,259 controls; Fisher exact test), it was not exome-wide significant. According to the pext values in gnomAD, all 3 pLoFs observed in the patients with dystonia were located in the highly expressed canonical transcript ENST00000380445.3, whereas 2 of 3 pLoFs detected in 8 individuals without dystonia were located in the first exon of the noncanonical transcript ENST00000380443.3 that is weakly expressed across all tissues. Taking these biological implications into account, pLoFs involving the canonical transcript were exome-wide significantly enriched in patients with dystonia (p = 1.67 × 10−6; 4/280 cases vs 1/11,259 controls; Fisher exact test). All VPS16 patients showed mild progressive dystonia with writer's cramp as the presenting symptom between age 7 and 34 years (mean 20 years) that often progressed to generalized dystonia and was even accompanied by hyperkinetic movements and myoclonus in 1 patient.DiscussionOur data provide strong evidence for VPS16 pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.

scholarly journals Genotype-phenotype correlations in central precocious puberty caused by MKRN3 mutations

2020 ◽  
Author(s):  
Carlos Eduardo Seraphim ◽  
Ana Pinheiro Machado Canton ◽  
Luciana Montenegro ◽  
Maiara Ribeiro Piovesan ◽  
Delanie B Macedo ◽  
...  
Keyword(s):  
Precocious Puberty ◽  
Genetic Defect ◽  
Ring Finger ◽  
Central Precocious Puberty ◽  
Bone Age ◽  
Control Group ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Reproductive Axis ◽  
Time Of Presentation

Abstract Context Loss-of-function mutations of makorin RING finger protein 3 (MKRN3) are the most common monogenic cause of familial central precocious puberty (CPP). Objective To describe the clinical and hormonal features of a large cohort of patients with CPP due to MKRN3 mutations and compare the characteristics of different types of genetic defects. Patients/methods Multiethnic cohort of 716 patients with familial or idiopathic CPP screened for MKRN3 mutations using Sanger sequencing. A group of 156 Brazilian girls with idiopathic CPP (ICPP) was used as control group. Results Seventy-one patients (45 girls and 26 boys from 36 families) had 18 different loss-of-function MKRN3 mutations. Eight mutations were classified as severe (70% of patients). Among the 71 patients, first pubertal signs occurred at 6.2 ± 1.2 years in girls and 7.1 ± 1.5 years in boys. Girls with MKRN3 mutations had a shorter delay between puberty onset and first evaluation and higher FSH levels compared to ICPP. Patients with severe MKRN3 mutations had a greater bone age advancement compared to patients with missense mutations (2·3 ± 1·6 vs. 1·6 ± 1·4 years, p = 0.048), and had higher basal LH levels (2·2 ± 1·8 vs. 1·1 ± 1·1 UI/L, p=0.018) at the time of presentation. Computational protein modeling revealed that 60% of the missense mutations were predicted to cause protein destabilization. Conclusions Inherited premature activation of the reproductive axis caused by loss-of-function mutations of MKRN3 is clinically indistinct from ICPP. However, the type of genetic defect may affect bone age maturation and gonadotropin levels.

scholarly journals A Novel Loss-of-Function MKRN3 Variant in a Chinese Patient With Familial Precocious Puberty: A Case Report and Functional Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Xueling Yin ◽  
Junqi Wang ◽  
Tianting Han ◽  
Zhang Tingting ◽  
Yuhong Li ◽  
...  
Keyword(s):  
Case Report ◽  
Precocious Puberty ◽  
Transcriptional Activity ◽  
Central Precocious Puberty ◽  
Chinese Patient ◽  
Functional Study ◽  
Loss Of Function ◽  
Pediatric Endocrinology ◽  
Functional Studies ◽  
Clinical Pediatric

Background: Central precocious puberty (CPP) is one of the most common and complex problems in clinical pediatric endocrinology practice. Mutation of the MKRN3 gene can cause familial CPP.Methods and Results: Here we reported a Chinese patient bearing a novel MKRN3 mutation (c.G277A/p.Gly93Ser) and showing the CPP phenotype. Functional studies found that this mutation of MKRN3 attenuated its autoubiquitination, degradation, and inhibition on the transcriptional activity of GNRH1, KISS1, and TAC3 promoters.Conclusion: MKRN3 (Gly93Ser) is a loss-of-function mutation, which attenuates the inhibition on GnRH1-related signaling, suggesting that this mutant can lead to central precocious puberty.

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