Category Archives: Eur J Hum Genet

Experiences, considerations and emotions relating to cardiogenetic evaluation in relatives of young sudden cardiac death victims.

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Experiences, considerations and emotions relating to cardiogenetic evaluation in relatives of young sudden cardiac death victims.
Eur J Hum Genet. 2014 Feb;22(2):192-6
Authors: van der Werf C, Onderw… Continue reading

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The Genome of the Netherlands: design, and project goals.

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The Genome of the Netherlands: design, and project goals.
Eur J Hum Genet. 2014 Feb;22(2):221-7
Authors: Boomsma DI, Wijmenga C, Slagboom EP, Swertz MA, Karssen LC, Abdellaoui A, Ye K, Guryev V, Ver… Continue reading

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Recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic).

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Recommendations for reporting results of diagnostic genetic testing (biochemical, cytogenetic and molecular genetic).

Eur J Hum Genet. 2014 Feb;22(2):160-70

Authors: Claustres M, Kožich V, Dequeker E, Fowler B, Hehir-Kwa JY, Miller K, Oosterwijk C, Peterlin B, van Ravenswaaij-Arts C, Zimmermann U, Zuffardi O, Hastings RJ, Barton DE, European Society of Human Genetics

Abstract
Genetic test results can have considerable importance for patients, their parents and more remote family members. Clinical therapy and surveillance, reproductive decisions and genetic diagnostics in family members, including prenatal diagnosis, are based on these results. The genetic test report should therefore provide a clear, concise, accurate, fully interpretative and authoritative answer to the clinical question. The need for harmonizing reporting practice of genetic tests has been recognised by the External Quality Assessment (EQA), providers and laboratories. The ESHG Genetic Services Quality Committee has produced reporting guidelines for the genetic disciplines (biochemical, cytogenetic and molecular genetic). These guidelines give assistance on report content, including the interpretation of results. Selected examples of genetic test reports for all three disciplines are provided in an annexe.

PMID: 23942201 [PubMed – indexed for MEDLINE]

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Reply to Sajantila and Budowle.

Reply to Sajantila and Budowle.

Eur J Hum Genet. 2015 Jan 14;

Authors: Barton DE, Claustres M, Kozich V, Dequeker E, Fowler B, Hehir-Kwa JY, Miller K, Oosterwijk C,…

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Maximising the efficiency of clinical screening programmes: balancing predictive genetic testing with a right not to know.

Maximising the efficiency of clinical screening programmes: balancing predictive genetic testing with a right not to know.
Eur J Hum Genet. 2015 Jan 7;
Authors: Schuurman AG, van der Kolk DM, Verkerk MA, Birnie E, Ra… Continue reading

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Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.

Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.
Eur J Hum Genet. 2014 Nov 26;
Authors: Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, Kant SG, Jones EA, Br… Continue reading

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Further delineation of the KAT6B molecular and phenotypic spectrum.

Further delineation of the KAT6B molecular and phenotypic spectrum.

Eur J Hum Genet. 2014 Nov 26;

Authors: Gannon T, Perveen R, Schlecht H, Ramsden S, Anderson B, Kerr B, Day R, Banka S, Suri M, Berland S, Gabbett M, Ma A, Lyonnet S, Cormier-Daire V, Yilmaz R, Borck G, Wieczorek D, Anderlid BM, Smithson S, Vogt J, Moore-Barton H, Simsek-Kiper PO, Maystadt I, Destrée A, Bucher J, Angle B, Mohammed S, Wakeling E, Price S, Singer A, Sznajer Y, Toutain A, Haye D, Newbury-Ecob R, Fradin M, McGaughran J, Tuysuz B, Tein M, Bouman K, Dabir T, Van den Ende J, Luk HM, Pilz DT, Eason J, Davies S, Reardon W, Garavelli L, Zuffardi O, Devriendt K, Armstrong R, Johnson D, Doco-Fenzy M, Bijlsma E, Unger S, Veenstra-Knol HE, Kohlhase J, Lo IF, DDD study, Smith J, Clayton-Smith J

Abstract
KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.European Journal of Human Genetics advance online publication, 26 November 2014; doi:10.1038/ejhg.2014.248.

PMID: 25424711 [PubMed – as supplied by publisher]

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A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy.

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A 3-base pair deletion, c.9711_9713del, in DMD results in intellectual disability without muscular dystrophy.

Eur J Hum Genet. 2014 Apr;22(4):480-5

Authors: de Brouwer AP, Nabuurs SB, Verhaart IE, Oudakker AR, Hordijk R, Yntema HG, Hordijk-Hos JM, Voesenek K, de Vries BB, van Essen T, Chen W, Hu H, Chelly J, den Dunnen JT, Kalscheuer VM, Aartsma-Rus AM, Hamel BC, van Bokhoven H, Kleefstra T

Abstract
We have identified a deletion of 3 base pairs in the dystrophin gene (DMD), c.9711_9713del, in a family with nonspecific X-linked intellectual disability (ID) by sequencing of the exons of 86 known X-linked ID genes. This in-frame deletion results in the deletion of a single-amino-acid residue, Leu3238, in the brain-specific isoform Dp71 of dystrophin. Linkage analysis supported causality as the mutation was present in the 7.6 cM linkage interval on Xp22.11-Xp21.1 with a maximum positive LOD score of 2.41 (MRX85 locus). Molecular modeling predicts that the p.(Leu3238del) deletion results in the destabilization of the C-terminal domain of dystrophin and hence reduces the ability to interact with β-dystroglycan. Correspondingly, Dp71 protein levels in lymphoblastoid cells from the index patient are 6.7-fold lower than those in control cell lines (P=0.08). Subsequent determination of the creatine kinase levels in blood of the index patient showed a mild but significant elevation in serum creatine kinase, which is in line with impaired dystrophin function. In conclusion, we have identified the first DMD mutation in Dp71 that results in ID without muscular dystrophy.

PMID: 23900271 [PubMed – indexed for MEDLINE]

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Charles Buys (1942-2014).

Charles Buys (1942-2014).
Eur J Hum Genet. 2014 Dec;22(12):1343-1344
Authors: Sijmons RH, Te Meerman GJ, Hofstra RM
PMID: 25393683 [PubMed – as supplied by publisher]

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Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.
Eur J Hum Genet. 2014 Oct 22;
Authors: Wessels MW, Herkert JC, Frohn-Muld… Continue reading

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Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe.

Meckel-Gruber Syndrome: a population-based study on prevalence, prenatal diagnosis, clinical features, and survival in Europe.

Eur J Hum Genet. 2014 Sep 3;

Authors: Barisic I, Boban L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Bergman JE, Braz P, Draper ES, Haeusler M, Khoshnood B, Klungsoyr K, Pierini A, Queisser-Luft A, Rankin J, Rissmann A, Verellen-Dumoulin C

Abstract
Meckel-Gruber Syndrome is a rare autosomal recessive lethal ciliopathy characterized by the triad of cystic renal dysplasia, occipital encephalocele and postaxial polydactyly. We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. The study population consisted of 191 cases of MKS identified between January 1990 and December 2011 in 34 European registries. The mean prevalence was 2.6 per 100 000 births in a subset of registries with good ascertainment. The prevalence was stable over time, but regional differences were observed. There were 145 (75.9%) terminations of pregnancy after prenatal diagnosis, 13 (6.8%) fetal deaths, 33 (17.3%) live births. In addition to cystic kidneys (97.7%), encephalocele (83.8%) and polydactyly (87.3%), frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with post mortem examination) and orofacial clefts (31.8%). Various other anomalies were present in 64 (37%) patients. As nowadays most patients are detected very early in pregnancy when liver or kidney changes may not yet be developed or may be difficult to assess, none of the anomalies should be considered obligatory for the diagnosis. Most cases (90.2%) are diagnosed prenatally at 14.3±2.6 (range 11-36) gestational weeks and pregnancies are mainly terminated, reducing the number of LB to one-fifth of the total prevalence rate. Early diagnosis is important for timely counseling of affected couples regarding the option of pregnancy termination and prenatal genetic testing in future pregnancies.European Journal of Human Genetics advance online publication, 3 September 2014; doi:10.1038/ejhg.2014.174.

PMID: 25182137 [PubMed – as supplied by publisher]

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Evaluation of European coeliac disease risk variants in a north Indian population.

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Evaluation of European coeliac disease risk variants in a north Indian population.

Eur J Hum Genet. 2014 Jul 23;

Authors: Senapati S,…

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Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.

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Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.

Eur J Hum Genet. 2014 Jul 23;

Authors: Verloes A, Di…

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Impact on parents of HLA-DQ2/DQ8 genotyping in healthy children from coeliac families.

Impact on parents of HLA-DQ2/DQ8 genotyping in healthy children from coeliac families.
Eur J Hum Genet. 2014 Jun 11;
Authors: Wessels MM, Vriezinga SL, Koletzko S, Werkstetter K, Castillejo-De Villasante G, Shamir R,… Continue reading

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Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands’

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Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands’

Eur J Hum Genet. 2014 Jun 4;

Authors: Deelen P, Menelaou A, van Leeuwen EM, Kanterakis A, van Dijk F, Medina-Gomez C, Francioli LC, Hottenga JJ, Karssen LC, Estrada K, Kreiner-Møller E, Rivadeneira F, van Setten J, Gutierrez-Achury J, Westra HJ, Franke L, van Enckevort D, Dijkstra M, Byelas H, van Duijn CM, Genome of the Netherlands Consortium, de Bakker PI, Wijmenga C, Swertz MA

Abstract
Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with ‘true’ genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05-0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r(2), increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r(2) improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r(2) increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results.European Journal of Human Genetics advance online publication, 4 June 2014; doi:10.1038/ejhg.2014.19.

PMID: 24896149 [PubMed – as supplied by publisher]

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Clinical utility gene card for: dilated cardiomyopathy (CMD).

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Clinical utility gene card for: dilated cardiomyopathy (CMD).
Eur J Hum Genet. 2013 Oct;21(10)
Authors: Posafalvi A, Herkert JC, Sinke RJ, van den Berg MP, Mogensen J, Jongbloed JD, van Tintelen JP
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Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

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Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

Eur J Hum Genet. 2014 Jan 15;

Authors: Michot C, Le Goff C, Mahaut C, Afenjar A,…

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Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.

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Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe.

Eur J Hum Genet. 2014 Jan 8;

Authors: Barisic I, Odak L, Loane M, Garne E, Wellesley D, Calzolari E, Dolk H, Addor MC, Arriola L, Bergman J, Bianca S, Doray B, Khoshnood B, Klungsoyr K, McDonnell B, Pierini A, Rankin J, Rissmann A, Rounding C, Queisser-Luft A, Scarano G, Tucker D

Abstract
Oculo-auriculo-vertebral spectrum is a complex developmental disorder characterised mainly by anomalies of the ear, hemifacial microsomia, epibulbar dermoids and vertebral anomalies. The aetiology is largely unknown, and the epidemiological data are limited and inconsistent. We present the largest population-based epidemiological study to date, using data provided by the large network of congenital anomalies registries in Europe. The study population included infants diagnosed with oculo-auriculo-vertebral spectrum during the 1990-2009 period from 34 registries active in 16 European countries. Of the 355 infants diagnosed with oculo-auriculo-vertebral spectrum, there were 95.8% (340/355) live born, 0.8% (3/355) fetal deaths, 3.4% (12/355) terminations of pregnancy for fetal anomaly and 1.5% (5/340) neonatal deaths. In 18.9%, there was prenatal detection of anomaly/anomalies associated with oculo-auriculo-vertebral spectrum, 69.7% were diagnosed at birth, 3.9% in the first week of life and 6.1% within 1 year of life. Microtia (88.8%), hemifacial microsomia (49.0%) and ear tags (44.4%) were the most frequent anomalies, followed by atresia/stenosis of external auditory canal (25.1%), diverse vertebral (24.3%) and eye (24.3%) anomalies. There was a high rate (69.5%) of associated anomalies of other organs/systems. The most common were congenital heart defects present in 27.8% of patients. The prevalence of oculo-auriculo-vertebral spectrum, defined as microtia/ear anomalies and at least one major characteristic anomaly, was 3.8 per 100 000 births. Twinning, assisted reproductive techniques and maternal pre-pregnancy diabetes were confirmed as risk factors. The high rate of different associated anomalies points to the need of performing an early ultrasound screening in all infants born with this disorder.European Journal of Human Genetics advance online publication, 8 January 2014; doi:10.1038/ejhg.2013.287.

PMID: 24398798 [PubMed – as supplied by publisher]

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Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC).

Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC).

Eur J Hum Genet. 2013 Jun 5;

Authors: Te Rijdt WP, Jongbloed JD, de Boer RA, Thiene G, Basso…

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Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics.

Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics.

Eur J Hum Genet. 2012 Feb;20(2):161-5

Authors: Hanemaaijer NM,…

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