Journal of Medical Genetics (J Med Genet)

Publications in this journal

• Article: No evidence for locus heterogeneity in Knobloch syndrome.

  Mohammed A Aldahmesh, Arif O Khan, Jawahir Y Mohamed, Alex V Levin, Wadakarn Wuthisiri, Sally Lynch, K McCreery, Fowzan S Alkuraya
  Journal of Medical Genetics 05/2013;
• Article: An X chromosome-wide association analysis identifies variants in GPR174 as a risk factor for Graves' disease.

  Xun Chu, Min Shen, Fang Xie, Xiao-Jing Miao, Wei-Hua Shou, Lin Liu, Peng-Peng Yang, Ya-Nan Bai, Kai-Yue Zhang, Lin Yang, Qi Hua, Wen-Dong Liu, Yan Dong, Hai-Feng Wang, Jin-Xiu Shi, Yi Wang, Huai-Dong Song, Sai-Juan Chen, Zhu Chen, Wei Huang
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  ABSTRACT: BACKGROUND: Graves' disease is a female preponderant autoimmune illness and the contribution of the X chromosome to its risk has long been appreciated. However, no X-linked susceptibility loci have been indentified from recent genome-wide association studies (GWAS). METHODS: We re-examined the X chromosome data from our recent GWAS for Graves' disease by including males that were previously excluded from the X chromosome analyses. The data were analysed using logistic regression analysis including sex as a covariate, and an additive method assuming X chromosome inactivation, implemented in snpMatrix. RESULTS: A cluster of single nucleotide polymorphism (SNPs) at Xq21.1 was found showing association with genome-wide significance, among which rs3827440 was a non-synonymous SNP of GPR174 (Plogistic regression= 9.52×10(-8); PsnpMatrix=4.60×10(-9); OR=1.76, 95% CI 1.45 to 2.13). The association was reproduced in an independent sample collection set including 4564 Graves' disease cases and 3968 sex matched controls (combined Plogistic regression=5.53×10(-21); combined PsnpMatrix=4.26×10(-22); OR=1.69, 95% CI 1.53 to 1.86). Notably, GPR174 was widely expressed in immune related tissues and rs3827440 genotypes were associated with distinct mRNA levels (p=0.002). GPR174 did not show sex biased gene expression in our expression analysis. Resequencing study suggested the contribution of some rare variants in the GPR174 gene region to disease risk with a collapsing p value of 1.16×10(-3). CONCLUSIONS: The finding of an X-linked risk locus for Graves' disease expands our understanding of the role of the X chromosome in disease susceptibility.
  Journal of Medical Genetics 05/2013;
• Article: Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

  J M van de Kamp, O T Betsalel, S Mercimek-Mahmutoglu, L Abulhoul, S Grünewald, I Anselm, H Azzouz, D Bratkovic, A de Brouwer, B Hamel, [......], V Valayannopoulos, H Van Esch, S Waltz, M M C Wamelink, P J W Pouwels, A Errami, M S van der Knaap, C Jakobs, G M Mancini, G S Salomons
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  ABSTRACT: BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype-genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.
  Journal of Medical Genetics 05/2013;
• Article: Upregulation of RCAN1 causes Down syndrome-like immune dysfunction.

  Katherine R Martin, Daniel Layton, Natalie Seach, Alicia Corlett, Maria Jose Barallobre, Maria L Arbonés, Richard L Boyd, Bernadette Scott, Melanie A Pritchard
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  ABSTRACT: BACKGROUND: People with Down syndrome (DS) are more susceptible to infections and autoimmune disease, but the molecular genetic basis for these immune defects remains undetermined. In this study, we tested whether increased expression of the chromosome 21 gene RCAN1 contributes to immune dysregulation. METHODS: We investigated the immune phenotype of a mouse model that overexpresses RCAN1. RCAN1 transgenic (TG) mice exhibit T cell abnormalities that bear a striking similarity to the abnormalities described in individuals with DS. RESULTS: RCAN1-TG mice display T cell developmental defects in the thymus and peripheral immune tissues. Thymic cellularity is reduced by substantial losses of mature CD4 and CD8 thymocytes and medullary epithelium. In peripheral immune organs T lymphocytes are reduced in number and exhibit reduced proliferative capacity and aberrant cytokine production. These T cell defects are stem cell intrinsic in that transfer of wild type bone marrow into RCAN1-TG recipients restored medullary thymic epithelium and T cell numbers in the thymus, spleen and lymph nodes. However, bone marrow transplantation failed to improve T cell function, suggesting an additional role for RCAN1 in the non-haemopoietic compartment. CONCLUSIONS: RCAN1 therefore facilitates T cell development and function, and when overexpressed, may contribute to immune dysfunction in DS.
  Journal of Medical Genetics 05/2013;
• Article: A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT.

  Malin Kvarnung, Daniel Nilsson, Anna Lindstrand, G Christoph Korenke, Samuel C C Chiang, Elisabeth Blennow, Markus Bergmann, Tommy Stödberg, Outi Mäkitie, Britt-Marie Anderlid, Yenan T Bryceson, Magnus Nordenskjöld, Ann Nordgren
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  ABSTRACT: PURPOSE: To delineate the molecular basis for a novel autosomal recessive syndrome, characterised by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings. METHODS: We examined four patients from a consanguineous kindred with a strikingly similar phenotype, by using whole exome sequencing (WES). Functional validation of the initial results were performed by flow cytometry determining surface expression of glycosylphosphatidylinositol (GPI) and GPI anchored proteins and, in addition, by in vivo assays on zebrafish embryos. RESULTS: The results from WES identified a homozygous mutation, c.547A>C (p.Thr183Pro), in PIGT; Sanger sequencing of additional family members confirmed segregation with the disease. PIGT encodes phosphatidylinositol-glycan biosynthesis class T (PIG-T) protein, which is a subunit of the transamidase complex that catalyses the attachment of proteins to GPI. By flow cytometry, we found that granulocytes from the patients had reduced levels of the GPI anchored protein CD16b, supporting pathogenicity of the mutation. Further functional in vivo validation via morpholino mediated knockdown of the PIGT ortholog in zebrafish (pigt) showed that, unlike human wild-type PIGT mRNA, the p.Thr183Pro encoding mRNA failed to rescue gastrulation defects induced by the suppression of pigt. CONCLUSIONS: We identified mutations in PIGT as the cause of a novel autosomal recessive intellectual disability syndrome. Our results demonstrate a new pathogenic mechanism in the GPI anchor pathway and expand the clinical spectrum of disorders belonging to the group of GPI anchor deficiencies.
  Journal of Medical Genetics 05/2013;
• Article: Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus.

  Anas M Alazami, Hadia Hijazi, Mohammed S Al-Dosari, Ranad Shaheen, Amal Hashem, Mohammed A Aldahmesh, Jawahir Y Mohamed, Amal Kentab, Mustafa A Salih, Ali Awaji, Tariq A Masoodi, Fowzan S Alkuraya
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  ABSTRACT: BACKGROUND: Intellectual disability (ID) is one of the most common forms of disability worldwide, displaying a wide range of aetiologies and affecting nearly 2% of the global population. OBJECTIVE: To describe a novel autosomal recessive form of ID with strabismus and its underlying aetiology. MATERIALS AND METHODS: Autozygosity mapping, linkage analysis and exome sequencing were performed in a large multiplex consanguineous family that segregates ID and strabismus. Exome sequencing was independently performed in three other consanguineous families segregating the same disease. Direct sequencing of the resulting candidate gene was performed in four additional families with the same phenotype. RESULTS: A single missense mutation was identified in ADAT3 in all studied families on an ancient ancestral haplotype. This gene encodes one of two eukaryotic proteins that are necessary for the deamination of adenosine at position 34 to inosine in t-RNA. Our results show the first human mutation in the t-RNA editing machinery and expand the landscape of pathways involved in the pathogenesis of ID.
  Journal of Medical Genetics 04/2013;
• Article: A novel syndrome of hypohidrosis and intellectual disability is linked to COG6 deficiency.

  Ranad Shaheen, Shinu Ansari, Muneera J Alshammari, Hisham Alkhalidi, Hadeel Alrukban, Wafaa Eyaid, Fowzan S Alkuraya
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  ABSTRACT: BACKGROUND: Numerous syndromic forms of intellectual disability have been described including those with abnormal sweating pattern. PURPOSE: To describe the clinical and molecular analysis of a large multiplex consanguineous Saudi family with an unusual constellation of severe intellectual disability, hypohidrosis, abnormal teeth, and acquired microcephaly. METHODS: Clinical evaluation, autozygosity mapping, exome sequencing, and expression analysis. RESULTS: Autozygosity mapping revealed a single critical locus corresponding to chr13:39 338 062-40 857 430. Exome sequencing uncovered a deep intronic (NM_020751.2:c.1167-24A>G) variant in COG6 that largely replaces the consensus acceptor site, resulting in pronounced reduction of the normal transcript and consequent deficiency of COG6 protein. Patient cells also exhibited pronounced deficiency of STX6, consistent with the established stabilising effect of COG6 on STX6. Four additional patients representing two families of the same tribal origin as the original family were found to have the same mutation, confirming a founder effect. Remarkably, none of the patients displayed any detectable abnormality in the glycosylation pattern of transferrin, which contradicts a previously published report of a patient whose abnormal glycosylation pattern was presumed to be caused by a missense variant in COG6. CONCLUSIONS: Our data implicate COG6 in the pathogenesis of a novel hypohidrotic disorder in humans that is distinct from congenital disorders of glycosylation.
  Journal of Medical Genetics 04/2013;
• Article: TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension.

  Wilhelmina S Kerstjens-Frederikse, Ernie M H F Bongers, Marcus T R Roofthooft, Edward M Leter, J Menno Douwes, Arie Van Dijk, Anton Vonk-Noordegraaf, Krista K Dijk-Bos, Lies H Hoefsloot, Elke S Hoendermis, Johan J P Gille, Birgit Sikkema-Raddatz, Robert M W Hofstra, Rolf M F Berger
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  ABSTRACT: BACKGROUND: Childhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene, BMPR2, were reported to cause PAH in only 10-16% of childhood-onset patients. We aimed to identify more genes associated with childhood-onset PAH. METHODS: We studied 20 consecutive cases with idiopathic or heritable PAH. In patients with accompanying MR/DF (n=6) array-comparative genomic hybridisation analysis was performed, with the aim of finding common deletion regions containing candidate genes for PAH. Three patients had overlapping deletions of 17q23.2. TBX2 and TBX4 were selected from this area as candidate genes and sequenced in all 20 children. After identifying TBX4 mutations in these children, we subsequently sequenced TBX4 in a cohort of 49 adults with PAH. Because TBX4 mutations are known to cause small patella syndrome (SPS), all patients with newly detected TBX4 mutations were screened for features of SPS. We also screened a third cohort of 23 patients with SPS for PAH. RESULTS: TBX4 mutations (n=3) or TBX4-containing deletions (n=3) were detected in 6 out of 20 children with PAH (30%). All living patients and two parents with TBX4 mutations appeared to have previously unrecognised SPS. In the adult PAH-cohort, one TBX4 mutation (2%) was detected. Screening in the cohort of (predominantly adult) SPS patients revealed no PAH. CONCLUSIONS: These data indicate that TBX4 mutations are associated with childhood-onset PAH, but that the prevalence of PAH in adult TBX4 mutation carriers is low.
  Journal of Medical Genetics 04/2013;
• Article: Risk of thyroid cancer in first-degree relatives of patients with non-medullary thyroid cancer by histology type and age at diagnosis: a joint study from five Nordic countries.

  Mahdi Fallah, Eero Pukkala, Laufey Tryggvadottir, Jörgen H Olsen, Steinar Tretli, Kristina Sundquist, Kari Hemminki
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  ABSTRACT: BACKGROUND: We aimed to estimate lifetime cumulative risk of thyroid cancer (CRTC) in first-degree relatives of patients with non-medullary thyroid cancers (NMTC), including papillary (PTC)/follicular/oxyphilic/anaplastic thyroid carcinoma, by histology and age at diagnosis in patients and their relatives. DESIGN: A population-based cohort of 63 495 first-degree relatives of 11 206 NMTC patients diagnosed in 1955-2009 in Nordic countries was followed for cancer incidence. Standardised incidence ratios (SIRs) were calculated using histology-specific, age-specific, sex-specific, period-specific and country-specific incidence rates as reference. RESULTS: The 0-84-year CRTC in female relatives of a patient with PTC was 2%, representing a threefold increase over the general population risk (SIR=2.9, 95% CI 2.4 to 3.4; Men: CRTC=1%, SIR=2.5, 95% CI 1.9 to 3.3). When there were ≥2 PTC patients diagnosed at age <60 years in a family, CRTC for female relatives was 10% (male 24%). Twins had a 23-fold increased risk of concordant PTC. Family history of follicular/oxyphilic/anaplastic carcinoma increased CRTC in relatives to about 1-2%. Although no familial case of concordant oxyphilic/anaplastic carcinoma was found, familial risks of discordant histology types of NMTC were interchangeably high for most of the types, for example, higher risk of PTC when a first-degree relative had follicular (SIR=3.0, 95%CI 1.7 to 4.9) or anaplastic (SIR=3.6, 95% CI 1.2 to 8.4) carcinoma. The earlier a patient was diagnosed with PTC in a family, the higher was the SIR in his/her younger relatives. There was a tendency towards concordant age at diagnosis of thyroid cancer among relatives of PTC patients. CONCLUSIONS: This study provides clinically relevant risk estimates for family members of NMTC patients.
  Journal of Medical Genetics 04/2013;
• Article: Meta-analysis of genome-wide studies identifies MEF2C SNPs associated with bone mineral density at forearm.

  Hou-Feng Zheng, Emma L Duncan, Laura M Yerges-Armstrong, Joel Eriksson, Ulrica Bergström, Paul J Leo, William D Leslie, David Goltzman, John Blangero, David A Hanley, Melanie A Carless, Elizabeth A Streeten, Mattias Lorentzon, Matthew A Brown, Tim D Spector, Ulrika Pettersson-Kymmer, Claes Ohlsson, Braxton D Mitchell, J Brent Richards
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  ABSTRACT: BACKGROUND: Forearm fractures affect 1.7 million individuals worldwide each year and most occur earlier in life than hip fractures. While the heritability of forearm bone mineral density (BMD) and fracture is high, their genetic determinants are largely unknown. AIM: To identify genetic variants associated with forearm BMD and forearm fractures. METHODS: BMD at distal radius, measured by dual-energy x-ray absorptiometry, was tested for association with common genetic variants. We conducted a meta-analysis of genome-wide association studies for BMD in 5866 subjects of European descent and then selected the variants for replication in 715 Mexican American samples. Gene-based association was carried out to supplement the single-nucleotide polymorphism (SNP) association test. We then tested the BMD-associated SNPs for association with forearm fracture in 2023 cases and 3740 controls. RESULTS: We found that five SNPs in the introns of MEF2C were associated with forearm BMD at a genome-wide significance level (p<5×10(-8)) in meta-analysis (lead SNP, rs11951031[T] -0.20 SDs per allele, p=9.01×10(-9)). The gene-based association test suggested an association between MEF2C and forearm BMD (p=0.003). The association between MEF2C variants and risk of fracture did not achieve statistical significance (SNP rs12521522[A]: OR=1.14 (95% CI 0.92 to 1.35), p=0.14). Meta-analysis also revealed two genome-wide suggestive loci at CTNNA2 and 6q23.2. CONCLUSIONS: These findings demonstrate that variants at MEF2C were associated with forearm BMD, implicating this gene in the determination of BMD at forearm.
  Journal of Medical Genetics 04/2013;
• Article: Troponin activator augments muscle force in nemaline myopathy patients with nebulin mutations.

  Josine Marieke de Winter, Danielle Buck, Carlos Hidalgo, Jeffrey R Jasper, Fady I Malik, Nigel F Clarke, Ger J M Stienen, Michael W Lawlor, Alan H Beggs, Coen A C Ottenheijm, Henk Granzier
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  ABSTRACT: BACKGROUND: Nemaline myopathy-the most common non-dystrophic congenital myopathy-is caused by mutations in thin filament genes, of which the nebulin gene is the most frequently affected one. The nebulin gene codes for the giant sarcomeric protein nebulin, which plays a crucial role in skeletal muscle contractile performance. Muscle weakness is a hallmark feature of nemaline myopathy patients with nebulin mutations, and is caused by changes in contractile protein function, including a lower calcium-sensitivity of force generation. To date no therapy exists to treat muscle weakness in nemaline myopathy. Here, we studied the ability of the novel fast skeletal muscle troponin activator, CK-2066260, to augment force generation at submaximal calcium levels in muscle cells from nemaline myopathy patients with nebulin mutations. METHODS: Contractile protein function was determined in permeabilised muscle cells isolated from frozen patient biopsies. The effect of 5 μM CK-2066260 on force production was assessed. RESULTS: Nebulin protein concentrations were severely reduced in muscle cells from these patients compared to controls, while myofibrillar ultrastructure was largely preserved. Both maximal active tension and the calcium-sensitivity of force generation were lower in patients compared to controls. Importantly, CK-2066260 greatly increased the calcium-sensitivity of force generation-without affecting the cooperativity of activation-in patients to levels that exceed those observed in untreated control muscle. CONCLUSIONS: Fast skeletal troponin activation is a therapeutic mechanism to augment contractile protein function in nemaline myopathy patients with nebulin mutations and with other neuromuscular diseases.
  Journal of Medical Genetics 04/2013;
• Article: Rhizomelic chondrodysplasia punctata and cardiac pathology.

  Irene C Huffnagel, Sally-Ann B Clur, Annemieke M Bams-Mengerink, Nico A Blom, Ronald J A Wanders, Hans R Waterham, Bwee Tien Poll-The
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  ABSTRACT: BACKGROUND: Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive peroxisomal disorder characterised by rhizomelia, contractures, congenital cataracts, facial dysmorphia, severe psychomotor defects and growth retardation. Biochemically, the levels of plasmalogens (major constituents of cellular membranes) are low due to a genetic defect in their biosynthesis. Cardiac muscle contains high concentrations of plasmalogens. Recently cardiac dysfunction was found in a mouse model for RCDP with undetectable plasmalogen levels in all tissues including the heart. This suggests the importance of plasmalogens in normal cardiac development and function. Congenital heart disease (CHD), however, has not been recognised as a major characteristic of RCDP. AIMS: We aimed to determine the prevalence of CHD found in RCDP patients as well as to describe genetic, biochemical and cardiac correlations. METHODS: We included 23 patients with genetically proven RCDP. The genetic, biochemical and physical data were evaluated. Echocardiograms were reviewed. RESULTS: Cardiac data were available for 18 patients. 12 (52%) had CHD. All twelve had type 1 RCDP and 11 (92%) had the PEX 7:c.875T>A mutation, of whom seven were homozygous (58%). Plasmalogen levels were significantly lower in the patients with CHD. Cardiac lesions included: septal defects (80% atrial), patent ductus arteriosus, pulmonary artery hypoplasia, tetralogy of Fallot and mitral valve prolapse (mostly older patients). CONCLUSIONS: The CHD prevalence among RCDP patients was at least 52%, significantly higher than among the normal population. Plasmalogen levels were significantly lower in patients with CHD. Routine cardiac evaluation should be included in the clinical management of RCDP patients.
  Journal of Medical Genetics 04/2013;
• Article: A new seipin-associated neurodegenerative syndrome.

  Encarna Guillén-Navarro, Sofía Sánchez-Iglesias, Rosario Domingo-Jiménez, Berta Victoria, Alejandro Ruiz-Riquelme, Alberto Rábano, Lourdes Loidi, Andrés Beiras, Blanca González-Méndez, Adriana Ramos, Vanesa López-González, María Juliana Ballesta-Martínez, Miguel Garrido-Pumar, Pablo Aguiar, Alvaro Ruibal, Jesús R Requena, David Araújo-Vilar
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  ABSTRACT: BACKGROUND: Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied. METHODS: Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting. RESULTS: Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus. CONCLUSIONS: Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.
  Journal of Medical Genetics 04/2013;
• Article: Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.

  Christine Fischer, Karoline Kuchenbäcker, Christoph Engel, Silke Zachariae, Kerstin Rhiem, Alfons Meindl, Nils Rahner, Nicola Dikow, Hansjörg Plendl, Irmgard Debatin, [......], Judit Horvath, Evelin Schröck, Friedrich Stock, Dieter Schäfer, Ira Schwaab, Christiana Kartsonaki, Nasim Mavaddat, Brigitte Schlegelberger, Antonis C Antoniou, Rita Schmutzler
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  ABSTRACT: BACKGROUND: Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. PATIENTS AND METHODS: Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. RESULTS: BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. CONCLUSIONS: Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.
  Journal of Medical Genetics 04/2013;
• Article: Impact of direct-to-consumer genomic testing at long term follow-up.

  Cinnamon S Bloss, Nathan E Wineinger, Burcu F Darst, Nicholas J Schork, Eric J Topol
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  ABSTRACT: BACKGROUND: There are few empirical data to inform the debate surrounding the use and regulation of direct-to-consumer (DTC) genome-wide disease risk tests. This study aimed to determine the long term psychological, behavioural, and clinical impacts of genomic risk testing for common disease. METHODS: The Scripps Genomic Health Initiative is a prospective longitudinal cohort study of adults who purchased the Navigenics Health Compass, a commercially available genomic test. Web based assessments were administered at baseline, short (3 months), and long term (1 year) follow-up. RESULTS: 2240 participants completed either or both follow-ups and a subset of 1325 completed long term follow-up. There were no significant differences from baseline in anxiety (p=0.50), fat intake (p=0.34), or exercise (p=0.39) at long term follow-up, and 96.8% of the sample had no test related distress. Longitudinal linear mixed model analyses were consistent with results of cross-sectional analyses. Screening test completion was associated with sharing genomic test results with a physician (36.0% shared; p<0.001) and perceived utility of the test (61.5% high perceived utility; p=0.002), but was not associated with the genomic risk estimate values themselves. CONCLUSIONS: Over a third of DTC genomic test recipients shared their results with their own physician during an approximate 1 year follow-up period, and this sharing was associated with higher screening test completion. Genomic testing was not associated with long term psychological risks, and most participants reportedly perceived the test to be of high personal utility.
  Journal of Medical Genetics 04/2013;
• Article: Identification of chromosome 3q28 and ALPK1 as susceptibility loci for chronic kidney disease in Japanese individuals by a genome-wide association study.

  Yoshiji Yamada, Tamotsu Nishida, Sahoko Ichihara, Kimihiko Kato, Tetsuo Fujimaki, Mitsutoshi Oguri, Hideki Horibe, Tetsuro Yoshida, Sachiro Watanabe, Kei Satoh, Yukitoshi Aoyagi, Michio Fukuda, Motoji Sawabe
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  ABSTRACT: BACKGROUND: Although genome-wide association studies (GWASs) have implicated several genes in the predisposition to chronic kidney disease (CKD) in Caucasian or African American populations, the genes that confer susceptibility to CKD in Asian populations remain to be identified definitively. We performed a GWAS to identify genetic variants that confer susceptibility to CKD in Japanese individuals. METHODS: 3851 Japanese individuals from three independent subject panels were examined. Subject panels A, B, and C comprised 252, 910, and 190 individuals with CKD and 249, 838, and 1412 controls, respectively. A GWAS for CKD was performed in subject panel A. RESULTS: Five single nucleotide polymorphisms (SNPs) at chromosome 3q28, ALPK1, FAM78B, and UMODL1 were significantly (false discovery rate<0.05) associated with CKD by the GWAS. The relation of these five SNPs and of an additional 22 SNPs at these loci to CKD was examined in subject panel B, revealing that rs9846911 at 3q28 was significantly associated with CKD in all individuals and that rs2074381 and rs2074380 in ALPK1 were associated with CKD in individuals with diabetes mellitus. These three SNPs were further examined in subject panel C, revealing that rs2074381 and rs2074380 were significantly associated with CKD. For subject panels B and C combined, rs9846911 was significantly associated with CKD in all individuals and rs2074381 and rs2074380 were associated with CKD in diabetic individuals. CONCLUSIONS: Chromosome 3q28 may be a susceptibility locus for CKD in Japanese individuals, and ALPK1 may be a susceptibility gene for CKD in such individuals with diabetes mellitus.
  Journal of Medical Genetics 03/2013;
• Article: Inheritance of autoinflammatory diseases: shifting paradigms and nomenclature.

  Isabelle Touitou
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  ABSTRACT: Over 15 years have passed since the discovery of the first autoinflammatory gene, MEFV, responsible for familial Mediterranean fever. The identification of another gene, TNFRSF1A, in 1999 led to the concept of autoinflammation which characterises rheumatological conditions triggered by a defective innate immunity. Substantive progress has been made since then with the identification of 18 autoinflammatory genes accounting for up to 24 disease entities showing overlapping symptoms. The accumulation of studies reporting patients with missing or excess mutations as compared with expected numbers favours the hypothesis that these diseases are distributed along a continuum ranging from monogenic to multifactorial conditions, rather than featuring only classical modes of inheritance. Moreover, the probable interactions of environmental and epigenetic factors further obscure our understanding of the mechanisms underlying the phenotypic expression of patients. This review explores the history of autoinflammatory gene discovery, discusses the nosological disparities stemming from the clinical versus pathophysiological definition of autoinflammatory diseases and summarises various inheritance patterns. This review calls for a consistent disease nomenclature and presents a reconciling hypothesis which places different sequence variants within the autoinflammatory disease continuum. Integrating these new concepts should help to facilitate communication between health professionals and promote personalised patient care.
  Journal of Medical Genetics 03/2013;
• Article: Recent advances in the genetics of sarcoidosis.

  Paolo Spagnolo, Johan Grunewald
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  ABSTRACT: Sarcoidosis is a heterogeneous inflammatory disorder of unknown origin that may affect virtually any organ, although intrathoracic engagement is almost universal. Sarcoidosis may present rather dramatically as an acute disease, which usually resolves either spontaneously or with treatment, while other patients have an insidious onset and a chronic/progressive disease course. The different clinical phenotypes have led to the suggestion that sarcoidosis may consist of several separate entities. Yet, the characteristic immune response eventually leading to granuloma formation indicates that a number of features are common to all subgroups of the disease. Through a classical candidate gene approach, several genes of importance for sarcoidosis have been identified, and in some cases such gene variants associate with distinct clinical phenotypes. More recently, another approach to the search for sarcoidosis-associated genes has been applied, that is, through genome-wide association studies (GWAS). GWAS have led to the identification of a number of new genetic associations, although several of them need to be validated. Conversely, some of the previously identified human leucocyte antigen (HLA) associations with sarcoidosis have already been replicated in different cohorts and found to be quite strong, particularly in specific patient subgroups. In highly specialised centres such HLA associations already represent a useful aid in clinic practice for improving patient management. For the future, there is an urgent need for a better understanding, in particular, of gene-gene as well as gene-environmental interactions, both likely to be of importance for developing sarcoidosis.
  Journal of Medical Genetics 03/2013;