Category Archives: Eur J Hum Genet

Sexual dimorphism in the genetic influence on human childlessness.

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Sexual dimorphism in the genetic influence on human childlessness.
Eur J Hum Genet. 2017 Sep;25(9):1067-1074
Authors: Verweij RM, Mills MC, Tropf FC, Veenstra R, Nyman A, Snieder H
Abstract
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Online genetic counseling from the providers’ perspective: counselors’ evaluations and a time and cost analysis.

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Online genetic counseling from the providers’ perspective: counselors’ evaluations and a time and cost analysis.
Eur J Hum Genet. 2016 Jan 20;
Authors: Otten E, Birnie E, Ranchor AV, van Langen IM
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Preferences for prenatal tests for Down syndrome: an international comparison of the views of pregnant women and health professionals.

Preferences for prenatal tests for Down syndrome: an international comparison of the views of pregnant women and health professionals.

Eur J Hum Genet. 2015 Nov 18;

Authors: Hill M, Johnson JA, Langlois S, Lee H, Winsor S, Dineley B, Horniachek M, Lalatta F, Ronzoni L, Barrett AN, Advani HV, Choolani M, Rabinowitz R, Pajkrt E, van Schendel RV, Henneman L, Rommers W, Bilardo CM, Rendeiro P, Ribeiro MJ, Rocha J, Bay Lund IC, Petersen OB, Becher N, Vogel I, Stefánsdottir V, Ingvarsdottir S, Gottfredsdottir H, Morris S, Chitty LS

Abstract
Non-invasive prenatal testing is increasingly available worldwide and stakeholder viewpoints are essential to guide implementation. Here we compare the preferences of women and health professionals from nine different countries towards attributes of non-invasive and invasive prenatal tests for Down syndrome. A discrete choice experiment was used to obtain participants’ stated preference for prenatal tests that varied according to four attributes: accuracy, time of test, risk of miscarriage, and type of information. Pregnant women and health professionals were recruited from Canada, Denmark, Iceland, Israel, Italy, the Netherlands, Portugal, Singapore, and the United Kingdom. A total of 2666 women’s and 1245 health professionals’ questionnaires were included in the analysis. Differences in preferences were seen between women and health professionals within and between countries. Overall, women placed greater emphasis on test safety and comprehensive information than health professionals, who emphasised accuracy and early testing. Differences between women’s and health professionals’ preferences are marked between countries. Varied approaches to implementation and service delivery are therefore needed and individual countries should develop guidelines appropriate for their own social and screening contexts.European Journal of Human Genetics advance online publication, 18 November 2015; doi:10.1038/ejhg.2015.249.

PMID: 26577044 [PubMed – as supplied by publisher]

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Genome-wide association studies identify genetic loci for low von Willebrand factor levels.

Genome-wide association studies identify genetic loci for low von Willebrand factor levels.

Eur J Hum Genet. 2015 Oct 21;

Authors: van Loon J, Dehghan A, Weihong T,…

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RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling.

RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling.
Eur J Hum Genet. 2015 Sep 23;
Authors: Widowati T, Melhem S, Patria SY, de Graaf… Continue reading

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The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.

The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant.

Eur J Hum Genet. 2015 Aug 26;

Authors: Koolen DA, Pfundt R, Linda K, Beunders G, Veenstra-Knol HE, Conta JH, Fortuna AM, Gillessen-Kaesbach G, Dugan S, Halbach S, Abdul-Rahman OA, Winesett HM, Chung WK, Dalton M, Dimova PS, Mattina T, Prescott K, Zhang HZ, Saal HM, Hehir-Kwa JY, Willemsen MH, Ockeloen CW, Jongmans MC, Van der Aa N, Failla P, Barone C, Avola E, Brooks AS, Kant SG, Gerkes EH, Firth HV, Õunap K, Bird LM, Masser-Frye D, Friedman JR, Sokunbi MA, Dixit A, Splitt M, DDD Study, Kukolich MK, McGaughran J, Coe BP, Flórez J, Nadif Kasri N, Brunner HG, Thompson EM, Gecz J, Romano C, Eichler EE, de Vries BB

Abstract
The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.European Journal of Human Genetics advance online publication, 26 August 2015; doi:10.1038/ejhg.2015.178.

PMID: 26306646 [PubMed – as supplied by publisher]

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Telegenetics use in presymptomatic genetic counselling: patient evaluations on satisfaction and quality of care.

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Telegenetics use in presymptomatic genetic counselling: patient evaluations on satisfaction and quality of care.
Eur J Hum Genet. 2015 Jul 15;
Authors: Otten E, Birnie E, Ranchor AV, van Langen IM
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Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells.

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Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells.

Eur J Hum Genet. 2015 Jul 15;

Authors: Seco CZ, Giese AP, Shafique S, Schraders M, Oonk AM, Grossheim M, Oostrik J, Strom T, Hegde R, van Wijk E, Frolenkov GI, Azam M, Yntema HG, Free RH, Riazuddin S, Verheij JB, Admiraal RJ, Qamar R, Ahmed ZM, Kremer H

Abstract
Variants in CIB2 can underlie either Usher syndrome type I (USH1J) or nonsyndromic hearing impairment (NSHI) (DFNB48). Here, a novel homozygous missense variant c.196C>T and compound heterozygous variants, c.[97C>T];[196C>T], were found, respectively, in two unrelated families of Dutch origin. Besides, the previously reported c.272 T>C functional missense variant in CIB2 was identified in two families of Pakistani origin. The missense variants are demonstrated not to affect subcellular localization of CIB2 in vestibular hair cells in ex vivo expression experiments. Furthermore, these variants do not affect the ATP-induced calcium responses in COS-7 cells. However, based on the residues affected, the variants are suggested to alter αIIβ integrin binding. HI was nonsyndromic in all four families. However, deafness segregating with the c.272T>C variant in one Pakistani family is remarkably less severe than that in all other families with this mutation. Our results contribute to the insight in genotype-phenotype correlations of CIB2 mutations.European Journal of Human Genetics advance online publication, 15 July 2015; doi:10.1038/ejhg.2015.157.

PMID: 26173970 [PubMed – as supplied by publisher]

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SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.

Eur J Hum Genet. 2015 Jun 3;

Authors: Bissay V, Van Malderen SC, Keymolen K, Lissens W, Peeters U, Daneels D, Jansen AC, Pappaert G, Brugada P, De Keyser J, Van Dooren S

Abstract
SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.European Journal of Human Genetics advance online publication, 3 June 2015; doi:10.1038/ejhg.2015.125.

PMID: 26036855 [PubMed – as supplied by publisher]

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Towards a European consensus for reporting incidental findings during clinical NGS testing.

Towards a European consensus for reporting incidental findings during clinical NGS testing.
Eur J Hum Genet. 2015 Jun 3;
Authors: Hehir-Kwa JY, Claustres M, Hastings RJ, van Ravenswaaij-Arts C, Christenhusz G, Genuar… Continue reading

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Clinical utility gene card for: Proximal spinal muscular atrophy (SMA) – update 2015.

Clinical utility gene card for: Proximal spinal muscular atrophy (SMA) – update 2015.

Eur J Hum Genet. 2015 May 20;

Authors: Rudnik-Schöneborn S, Eggermann T, Kress W, Lemmink HH, Cobben JM, Zerres K

PMID: 25990799 [PubMed – as supplied by publisher]

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Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes.

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Association analysis of copy numbers of FC-gamma receptor genes for rheumatoid arthritis and other immune-mediated phenotypes.

Eur J Hum Genet. 2015 May 13;

Authors: Franke L, El Bannoudi H, Jansen DT, Kok K, Trynka G, Diogo D, Swertz M, Fransen K, Knevel R, Gutierrez-Achury J, Ärlestig L, Greenberg JD, Kremer J, Pappas DA, Kanterakis A, Weersma RK, van der Helm-van Mil AH, Guryev V, Rantapää-Dahlqvist S, Gregersen PK, Plenge RM, Wijmenga C, Huizinga TW, Ioan-Facsinay A, Toes RE, Zhernakova A

Abstract
Segmental duplications (SDs) comprise about 5% of the human genome and are enriched for immune genes. SD loci often show copy numbers variations (CNV), which are difficult to tag with genotyping methods. CNV in the Fcγ receptor region (FCGR) has been suggested to be associated with rheumatic diseases. The objective of this study was to delineate association of FCGR-CNV with rheumatoid arthritis (RA), coeliac disease and Inflammatory bowel disease incidence. We developed a method to accurately quantify CNV in SD loci based on the intensity values from the Immunochip platform and applied it to the FCGR locus. We determined the method’s validity using three independent assays: segregation analysis in families, arrayCGH, and whole genome sequencing. Our data showed the presence of two separate CNVs in the FCGR locus. The first region encodes FCGR2A, FCGR3A and part of FCGR2C gene, the second encodes another part of FCGR2C, FCGR3B and FCGR2B. Analysis of CNV status in 4578 individuals with RA and 5457 controls indicated association of duplications in the FCGR3B gene in antibody-negative RA (P=0.002, OR=1.43). Deletion in FCGR3B was associated with increased risk of antibody-positive RA, consistently with previous reports (P=0.023, OR=1.23). A clear genotype-phenotype relationship was observed: CNV polymorphisms of the FCGR3A gene correlated to CD16A expression (encoded by FCGR3A) on CD8 T-cells. In conclusion, our method allows determining the CNV status of the FCGR locus, we identified association of CNV in FCGR3B to RA and showed a functional relationship between CNV in the FCGR3A gene and CD16A expression.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.95.

PMID: 25966632 [PubMed – as supplied by publisher]

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Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci.

Eur J Hum Genet. 2015 Apr 29;

Authors: Coleman C, Quinn EM, Ryan AW, Conroy J, Trimble V, Mahmud N, Kennedy N, Corvin AP, Morris DW, Donohoe G, O’Morain C, MacMathuna P, Byrnes V, Kiat C, Trynka G, Wijmenga C, Kelleher D, Ennis S, Anney RJ, McManus R

Abstract
Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12 014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case-control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10(-16)). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10(-75)). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10(-18)). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42.European Journal of Human Genetics advance online publication, 29 April 2015; doi:10.1038/ejhg.2015.87.

PMID: 25920553 [PubMed – as supplied by publisher]

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Telemedicine uptake among Genetics Professionals in Europe: room for expansion.

Telemedicine uptake among Genetics Professionals in Europe: room for expansion.

Eur J Hum Genet. 2015 Apr 22;

Authors: Otten E, Birnie E, Lucassen AM, Ranchor AV, Van…

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New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.

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New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update.

Eur J Hum Genet. 2014 Aug;22(8):1002-11

Authors: Navarro CL, Esteves-Vieira V, Courrier S, Boyer A, Duong Nguyen T, Huong le TT, Meinke P, Schröder W, Cormier-Daire V, Sznajer Y, Amor DJ, Lagerstedt K, Biervliet M, van den Akker PC, Cau P, Roll P, Lévy N, Badens C, Wehnert M, De Sandre-Giovannoli A

Abstract
Restrictive dermopathy (RD) is a rare and extremely severe congenital genodermatosis, characterized by a tight rigid skin with erosions at flexure sites, multiple joint contractures, low bone density and pulmonary insufficiency generally leading to death in the perinatal period. RD is caused in most patients by compound heterozygous or homozygous ZMPSTE24 null mutations. This gene encodes a metalloprotease specifically involved in lamin A post-translational processing. Here, we report a total of 16 families for whom diagnosis and molecular defects were clearly established. Among them, we report seven new ZMPSTE24 mutations, identified in classical RD or Mandibulo-acral dysplasia (MAD) affected patients. We also report nine families with one or two affected children carrying the common, homozygous thymine insertion in exon 9 and demonstrate the lack of a founder effect. In addition, we describe several new ZMPSTE24 variants identified in unaffected controls or in patients affected with non-classical progeroid syndromes. In addition, this mutation update includes a comprehensive search of the literature on previously described ZMPSTE24 mutations and associated phenotypes. Our comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.

PMID: 24169522 [PubMed – indexed for MEDLINE]

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Guidelines for cytogenetic investigations in tumours.

Guidelines for cytogenetic investigations in tumours.
Eur J Hum Genet. 2015 Mar 25;
Authors: Hastings RJ, Bown N, Tibiletti MG, Debiec-Rychter M, Vanni R, Espinet B, van Roy N, Roberts P, van den Berg-de-Ruiter E, Be… Continue reading

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Clinical utility gene card for: CHARGE syndrome – update 2015.

Clinical utility gene card for: CHARGE syndrome – update 2015.
Eur J Hum Genet. 2015 Feb 18;
Authors: van Ravenswaaij-Arts CM, Blake K, Hoefsloot L, Verloes A
PMID: 25689928 [PubMed – as supplied by publisher… Continue reading

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CHARGE syndrome: a review of the immunological aspects.

CHARGE syndrome: a review of the immunological aspects.

Eur J Hum Genet. 2015 Feb 18;

Authors: Wong MT, Schölvinck EH, Lambeck AJ, van Ravenswaaij-Arts CM

Abstract
CHARGE syndrome is caused by a dominant variant in the CHD7 gene. Multiple organ systems can be affected because of haploinsufficiency of CHD7 during embryonic development. CHARGE syndrome shares many clinical features with the 22q11.2 deletion syndrome. Immunological abnormalities have been described, but are generally given little attention in studies on CHARGE syndrome. However, structured information on immunological abnormalities in CHARGE patients is necessary to develop optimal guidelines for diagnosis, treatment and follow-up in these patients. Here, we provide an overview of the current literature on immunological abnormalities in CHARGE syndrome. We also explore immunological abnormalities in comparable multiple congenital anomaly syndromes to identify common immunological phenotypes and genetic pathways that might regulate the immune system. Finally, we aim to identify gaps in our knowledge on the immunological aspects in CHARGE syndrome that need further study.European Journal of Human Genetics advance online publication, 18 February 2015; doi:10.1038/ejhg.2015.7.

PMID: 25689927 [PubMed – as supplied by publisher]

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A group approach to genetic counselling of cardiomyopathy patients: satisfaction and psychological outcomes sufficient for further implementation.

A group approach to genetic counselling of cardiomyopathy patients: satisfaction and psychological outcomes sufficient for further implementation.
Eur J Hum Genet. 2015 Feb 4;
Authors: Otten E, Birnie E, Ranchor AV, … Continue reading

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Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects.

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Next-generation sequencing-based genome diagnostics across clinical genetics centers: implementation choices and their effects.

Eur J Hum Genet. 2015 Jan…

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