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Russo S.,Human Molecular Genetics Laboratory | Calzari L.,Human Molecular Genetics Laboratory | Mussa A.,University of Turin | Mainini E.,Human Molecular Genetics Laboratory | And 19 more authors.
Clinical Epigenetics

Background: Multiple (epi)genetic defects affecting the expression of the imprinted genes within the 11p15.5 chromosomal region underlie Silver–Russell (SRS) and Beckwith–Wiedemann (BWS) syndromes. The molecular diagnosis of these opposite growth disorders requires a multi-approach flowchart to disclose known primary and secondary (epi)genetic alterations; however, up to 20 and 30 % of clinically diagnosed BWS and SRS cases remain without molecular diagnosis. The complex structure of the 11p15 region with variable CpG methylation and low-rate mosaicism may account for missed diagnoses. Here, we demonstrate the relevance of complementary techniques for the assessment of different CpGs and the importance of testing multiple tissues to increase the SRS and BWS detection rate. Results: Molecular testing of 147 and 450 clinically diagnosed SRS and BWS cases provided diagnosis in 34 SRS and 185 BWS patients, with 9 SRS and 21 BWS cases remaining undiagnosed and herein referred to as “borderline.” A flowchart including complementary techniques and, when applicable, the analysis of buccal swabs, allowed confirmation of the molecular diagnosis in all borderline cases. Comparison of methylation levels by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) in borderline and control cases defined an interval of H19/IGF2:IG-DMR loss of methylation that was distinct between “easy to diagnose” and “borderline” cases, which were characterized by values ≤mean −3 standard deviations (SDs) compared to controls. Values ≥mean +1 SD at H19/IGF2: IG-DMR were assigned to borderline hypermethylated BWS cases and those ≤mean −2 SD at KCNQ1OT1: TSS-DMR to hypomethylated BWS cases; these were supported by quantitative pyrosequencing or Southern blot analysis. Six BWS cases suspected to carry mosaic paternal uniparental disomy of chromosome 11 were confirmed by SNP array, which detected mosaicism till 10 %. Regarding the clinical presentation, borderline SRS were representative of the syndromic phenotype, with exception of one patient, whereas BWS cases showed low frequency of the most common features except hemihyperplasia. Conclusions: A conclusive molecular diagnosis was reached in borderline methylation cases, increasing the detection rate by 6 % for SRS and 5 % for BWS cases. The introduction of complementary techniques and additional tissue analyses into routine diagnostic work-up should facilitate the identification of cases undiagnosed because of mosaicism, a distinctive feature of epigenetic disorders. © 2016, Russo et al. Source

Shi M.,U.S. National Institutes of Health | Murray J.C.,University of Iowa | Marazita M.L.,University of Pittsburgh | Munger R.G.,Utah State University | And 23 more authors.
American Journal of Medical Genetics, Part A

We performed a genome wide association analysis of maternally-mediated genetic effects and parent-of-origin (POO) effects on risk of orofacial clefting (OC) using over 2,000 case-parent triads collected through an international cleft consortium. We used log-linear regression models to test individual SNPs. For SNPs with a P-value <10 -5 for maternal genotypic effects, we also applied a haplotype-based method, TRIMM, to extract potential information from clusters of correlated SNPs. None of the SNPs were significant at the genome wide level. Our results suggest neither maternal genome nor POO effects play major roles in the etiology of OC in our sample. This finding is consistent with previous genetic studies and recent population-based cohort studies in Norway and Denmark, which showed no apparent difference between mother-to-offspring and father-to-offspring recurrence of clefting. We, however, cannot completely rule out maternal genome or POO effects as risk factors because very small effects might not be detectable with our sample size, they may influence risk through interactions with environmental exposures or may act through a more complex network of interacting genes. Thus, the most promising SNPs identified by this study may still be worth further investigation. Published 2012 Wiley Periodicals, Inc. This article is a U.S. Government work and is in the public domain in the USA. Source

Chang M.-Y.,Chang Gung University | Kuok C.-M.,Chang Gung University | Chen Y.-C.,Chang Gung University | Ryu S.-J.,Stroke Center | And 4 more authors.
Nephron - Clinical Practice

Background/Aims: Subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) are two subtypes of hemorrhagic stroke that may cause severe complications in patients with autosomal-dominant polycystic kidney disease (ADPKD). The differences in clinical features between SAH and ICH associated with ADPKD are not known. Methods: Among 647 ADPKD patients hospitalized between 1997 and 2007 in our hospital, 11 with ICH (1.7%) and 6 with SAH (0.9%) were identified. Results: Patients with SAH were significantly younger than patients with ICH (39 ± 6 vs. 57 ± 15 years, p = 0.013). The systolic blood pressure on admission was significantly higher in patients with ICH (194 ± 26 vs. 145 ± 18 mm Hg, p = 0.001). Two patients (18.2%) with ICH died after a first episode, 6 had a second episode, and 2 had a third episode. Two patients (33.3%) with SAH died after a first episode but the survivors had no recurrence during follow-up. The 30-day survival curves comparing patients with ICH and SAH were not significantly different. Patients with a Glasgow Coma Score less than 9 on arrival had a significantly worse outcome. Conclusion: Clinical features differed between ICH and SAH associated with ADPKD. Nevertheless, blood pressure control and early recognition of hemorrhagic stroke are important in ADPKD patients. Copyright © 2009 S. Karger AG. Source

Said M.B.,Targets for Diagnosis and Therapy Unit | Hmani-Aifa M.,Targets for Diagnosis and Therapy Unit | Amar I.,Targets for Diagnosis and Therapy Unit | Amar I.,University of Science and Technology Houari Boumediene | And 12 more authors.
Genetic Testing and Molecular Biomarkers

Founder mutations, particularly 35delG in the GJB2 gene, have to a large extent contributed to the high frequency of autosomal recessive nonsyndromic hearing loss (ARNSHL). Mutations in transmembrane channel-like gene 1 (TMC1) cause ARNSHL. The p.R34X mutation is the most frequent known mutation in the TMC1 gene. To study the origin of this mutation and determine whether it arose in a common ancestor, we analyzed 21 polymorphic markers spanning the TMC1 gene in 11 unrelated individuals from Algeria, Iran, Iraq, Lebanon, Pakistan, Tunisia, and Turkey who carry this mutation. In nine individuals, we observed significant linkage disequilibrium between p.R34X and five polymorphic markers within a 220kb interval, suggesting that p.R34X arose from a common founder. We estimated the age of this mutation to be between 1075 and 1900 years, perhaps spreading along the third Hadramaout population movements during the seventh century. A second founder effect was observed in Turkish and Lebanese individuals with markers in a 920kb interval. Screening for the TMC1 p.R34X mutation is indicated in the genetic evaluation of persons with ARNSHL from North African and Southwest Asia. © Copyright 2010, Mary Ann Liebert, Inc. 2010. Source

Huang C.-L.,Saint Pauls Hospital | Wu-Chou Y.-H.,Human Molecular Genetics Laboratory | Wu-Chou Y.-H.,Neuroscience Research Center | Lai S.-C.,Chang Gung Memorial Hospital | And 7 more authors.
European Journal of Neurology

Background and purpose: The association between glucocerebrosidase (GBA) mutations and Parkinson's disease (PD) is attracting increased attention worldwide. In patients of Chinese ethnicity, other than the common L444P mutation, a few mutations have been reported. However, the contribution of GBA to PD can be answered only by a thorough investigation of its mutations in a unique large population. Methods: We enrolled 1747 participants: 967 PD patients and 780 healthy individuals. We screened entire GBA coding regions and exon-intron boundaries in 30 randomly chosen PD patients, followed by testing five variants (L444P, D409H, R120W, L174P, and Q497R) in all participants. The G2385R and R1628P in LRRK2 had been previously studied in almost all participants. Results: In total, 36 patients (3.72%) carried a heterozygous mutant GBA allele (27 L444P, 7 RecNciI, and 2 D409H). Only two controls (0.26%) carried heterozygous GBA mutation (1 L444P and 1 RecNciI). In PD group, the mean age at onset in carriers was younger than in non-carriers. The difference in percentage of mutation frequencies between patients and controls was highly significant for the L444P mutation (P<0.0001). One L444P carrier was also associated with LRRK2 G2385R variant, but no atypical Parkinsonism was observed. Conclusions: The present study ascertains that L444P mutation in GBA gene may contribute to an earlier onset of development of PD in Han/Chinese population. Following LRRK2 variants, GBA is the second most frequent mutations indicated for sporadic PD development in the Han/Chinese population. These GBA carriers are associated with an earlier onset of Parkinsonism. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS. Source

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