European Journal of HumanGenetics (EUR J HUM GENET)

Publications in this journal

• Article: Heterochromatin variants of human chromosome 9 and the reproduction failure

  Šípek Antonín jr, Panczak Aleš, Mihalová Romana, Celbová Lenka, Janashia Mimoza, Kohoutová Milada
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  ABSTRACT: Pericentric inversion of chromosome 9 - inv(9) - is considered to be clinically insignificant heterochromatin variant of human karyotype. However, various author repeatedly mention possible association of inv(9) and selected pathologies, especially with reproduction failure. This can cause some consultation dilemma, especially when inv(9) is identified in potential gamete donor. Some authors also suggest the same role for other variants of the heterochromatin region of the human chromosome 9 (like 9qh+ or 9qh) as well. Using the data from our cytogenetic laboratory - we analyzed the clinical indications among 383 patients with heterochromatin variant of chromosome 9 and we have found the reproduction failure to be the most common diagnose (more then 43 %). That was far more, then was the incidence of reproduction failure in our control group of patients with normal karyotype. This difference was also statistically significant. We have confirmed heterochromatin variants of chromosome 9 as relatively common finding, this time in population in the Czech Republic. The clinical significance, however, remains subject of discussion. Possible association of heterochromatin variants of human chromosome 9 with reproduction failure had quite low statistical significance and will require further investigation.
  European Journal of HumanGenetics 06/2012; Suppl. 1(20):374.
• Source

  Available from: PubMed Central

  Article: 19q13.11 cryptic deletion: description of two new cases and indication for a role of WTIP haploinsufficiency in hypospadiasEJHGOpen

  Simone Gana, Pierangelo Veggiotti, Giusy Sciacca, Cristina Fedeli, Anna Bersano, Giuseppe Micieli, Mohamad Maghnie, Roberto Ciccone, Elena Rossi, Katie Plunkett, Weimin Bi, Vernon R Sutton, Orsetta Zuffardi
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  ABSTRACT: Developmental delay/intellectual disabilities, speech disturbance, pre- and postnatal growth retardation, microcephaly, signs of ectodermal dysplasia, and genital malformations in males (hypospadias) represent the phenotypic core of the recent emerging 19q13.11 deletion syndrome. Using array-CGH for genome-wide screening we detected an interstitial deletion of chromosome band 19q13.11 in two patients exhibiting the recognizable pattern of malformations as described in other instances of this submicroscopic genomic imbalance. The deletion detected in our patients has been compared with previously reported cases leading to the refinement of the minimal overlapping region (MOR) for this microdeletion syndrome to 324 kb. This region encompasses five genes: four zinc finger (ZNF) genes belonging to the KRAB-ZNF subfamily (ZNF302, ZNF181, ZNF599, and ZNF30) and LOC400685. On the basis of our male patient 1 and on further six male cases of the literature, we also highlighted that larger 19q13.11 deletions including the Wilms tumor interacting protein (WTIP) gene, proximal to the MOR, results in hypospadias making this gene a possible candidate for this genital abnormality due to its well-known interaction with WT1. Although the mechanism underlying the phenotypic effects of copy number alterations involving KRAB-ZNF genes at 19q13.11 has not clearly been established, we suggest their haploinsufficiency as the most likely candidate for the phenotypic core of the 19q13.11 deletion syndrome. In addition, we hypothesized WTIP gene haploinsufficiency as responsible for hypospadias.Keywords: array-CGH; chromosome 19q13.11 deletion syndrome; KRAB-ZNF genes; WTIP gene; sex disorders
  European Journal of HumanGenetics 02/2012; 20(8):852-856.
• Article: C4ST-1 / CHST1-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome

  Klüppel, Samavarchi-Tehrani, Liu, Wrana, Hinek
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  ABSTRACT: Costello syndrome is a pediatric genetic disorder linked to oncogenic germline mutations in the HRAS gene. The disease is characterized by multiple developmental abnormalities, as well as predisposition to malignancies. Our recent observation that heart tissue from patients with Costello syndrome showed a loss of the glycosaminoglycan chondroitin-4-sulfate (C4S) inspired our present study aimed to explore a functional involvement of the chondroitin sulfate (CS) biosynthesis gene Carbohydrate sulfotransferase 11/Chondroitin-4-sulfotransferase-1 (CHST11/C4ST-1), as well as an impaired chondroitin sulfation balance, as a downstream mediator of oncogenic HRAS in Costello syndrome. Here we demonstrate a loss of C4S, as well as a reduction in C4ST-1 mRNA and protein expression, in primary fibroblasts from Costello syndrome patients. We go on to show that expression of oncogenic HRAS in normal fibroblasts can repress C4ST-1 expression, whereas interference with oncogenic HRAS signaling in Costello syndrome fibroblasts elevated C4ST-1 expression, thus identifying C4ST-1 as a negatively regulated target gene of HRAS signaling. Importantly, we show that forced expression of C4ST-1 in Costello fibroblasts could rescue the proliferation and elastogenesis defects associated with oncogenic HRAS signaling in these cells. Our results indicate reduced C4ST-1 expression and chondroitin sulfation imbalance mediating the effects of oncogenic HRAS signaling in the pathogenesis of Costello syndrome. Thus, our work identifies C4ST-1-dependent chondroitin sulfation as a downstream vulnerability in oncogenic RAS signaling, which might be pharmacologically exploited in future treatments of not only Costello syndrome and other RASopathies, but also human cancers associated with activating RAS mutations.
  European Journal of HumanGenetics 02/2012;
• Article: No evidence of association between complement factor I genetic variant rs10033900 and age-related macular degeneration

  Valentina Cipriani, Baljinder K Matharu, Jane C Khan, Humma Shahid, Caroline Hayward, Alan F Wright, Ana Maria Armbrecht, Baljean Dhillon, Simon P Harding, Paul N Bishop, Catey Bunce, David G Clayton, Anthony T Moore, John RW Yates
  European Journal of HumanGenetics 10/2011; 20(1):1-2.
• Article: Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

  Jos|[eacute]| Miguel Laffita-Mesa, Luis C Vel|[aacute]|zquez-P|[eacute]|rez, Nieves Santos Falc|[oacute]|n, Tania Cruz-Mari|[ntilde]|o, Yanetza Gonz|[aacute]|lez Zald|[iacute]|var, Yaimee V|[aacute]|zquez Mojena, Dennis Almaguer-Gotay, Luis Enrique Almaguer Mederos, Roberto Rodr|[iacute]|guez Labrada
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  ABSTRACT: The role of short, large or intermediate normal alleles (ANs) of the ataxin-2 gene in generating expanded alleles (EAs) causing spinocerebellar ataxia type 2 (SCA2) is poorly understood. It has been postulated that SCA2 prevalence is related to the frequency of large ANs. SCA2 shows the highest worldwide prevalence in Cuban population, which is therefore a unique source for studying the relationship between the frequency of large and intermediate alleles and the frequency of SCA2 mutation. Through genetic polymorphism analyses in a comprehensive sample (~3000 chromosomes), we show that the frequency of large ANs in the ataxin-2 gene is the highest worldwide, although short ANs are also frequent. This highly polymorphic population displayed also high variability in the CAG sequence, featured by loss of the anchor CAA interruption(s). In addition, large ANs showed germinal and somatic instability. Our study also includes related genotypic, genealogical and haplotypic data and provides substantial evidence with regard to the role of large and intermediate alleles in the generation of pathological EAs.Keywords: SCA2; genetic polymorphisms; ataxin-2; Cuba
  European Journal of HumanGenetics 09/2011; 20(1):41-49.
• Article: Evidence of linkage to chromosomes 10p15.3–p15.1, 14q24.3–q31.1 and 9q33.3–q34.3 in non-syndromic colorectal cancer families

  Ian W Saunders, Jason Ross, Finlay Macrae, Graeme P Young, Ignacio Blanco, Jesper Brohede, Glenn Brown, Diana Brookes, Trevor Lockett, Peter L Molloy, Victor Moreno, Gabriel Capella, Garry N Hannan
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  ABSTRACT: Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC. We used single-nucleotide polymorphism arrays to genotype 98 concordant affected relative pairs that were informative for linkage analyses. We tested for genome-wide significance (GWS) for linkage to CRC using a quantile statistic method, and we found that GWS was achieved at the 5% level. Independently, using the PSEUDO gene-dropping algorithm, we also found that GWS for linkage to CRC was achieved (P=0.02). Merlin non-parametric linkage analysis revealed significant linkage to CRC for chromosomal region 10p15.3–p15.1 and suggestive linkage to CRC for regions on 14q and 9q. The 10p15.3–p15.1 has not been reported to be linked to hereditary CRC in previous linkage studies, but this region does harbour the Kruppel-like factor 6 (KLF6) gene that is known to be altered in common CRC. Further studies aimed at localising the responsible genes, and characterising their function will give insight into the factors responsible for susceptibility in such families, and perhaps shed further light on the mechanisms of CRC development.Keywords: colorectal cancer; linkage; 10p; 14q; 9q
  European Journal of HumanGenetics 08/2011; 20(1):91-96.
• Article: Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimensEJHGOpen

  Elaine A Sugarman, Narasimhan Nagan, Hui Zhu, Viatcheslav R Akmaev, Zhaoqing Zhou, Elizabeth M Rohlfs, Kerry Flynn, Brant C Hendrickson, Thomas Scholl, Deborah Alexa Sirko-Osadsa, Bernice A Allitto
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  ABSTRACT: Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10 000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n=72 453) and prenatal diagnosis (n=121) for this condition. Our analysis of large-scale population carrier screening data (n=68 471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11 000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA.Keywords: spinal muscular atrophy (SMA); pan-ethnic; carrier screening; SMN1
  European Journal of HumanGenetics 08/2011; 20(1):27-32.
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  Available from: peer.ccsd.cnrs.fr

  Article: Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families

  Maxime Hebrard, Ga|[euml]|l Manes, B|[eacute]|atrice Bocquet, Isabelle Meunier, Delphine Coustes-Chazalette, Emilie H|[eacute]|rald, Audrey S|[eacute]|n|[eacute]|chal, Anne Bolland-Aug|[eacute, Diana Zelenika, Christian P Hamel
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  ABSTRACT: Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.Keywords: retinitis pigmentosa; gene mapping; autosomal recessive inheritance; non-consanguineous families; phenotype characterization
  European Journal of HumanGenetics 07/2011; 19(12):1256-1263.