TY  - JOUR
AB  - Cardiac desmosomes are specialized cell junctions responsible for cardiomyocytes mechanical coupling. Mutation in desmosomal genes cause autosomal dominant and recessive familial arrhythmogenic cardiomyopathy. Motivated by evidence that Mendelian diseases share genetic architecture with common complex traits, we assessed whether common variants in any desmosomal gene were associated with cardiac conduction traits in the general population. We analysed data of N = 4342 Cooperative Health Research in South Tyrol (CHRIS) study participants. We tested associations between genotype imputed variants covering the five desmosomal genes Desmoplakin (DSP), junction plakoglobin (JUP), plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmocollin 2 (DSC2), and P-wave, PR, QRS, and QT electrocardiographic intervals, using linear mixed models. Functional annotation and interrogation of publicly available genome-wide association study resources implicated potential connection with antisense long non-coding RNAs (lncRNAs), DNA methylation sites, and complex traits. Causality was tested via two-sample Mendelian randomization (MR) analysis and validated with functional in vitro follow-up in human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). DSP variant rs2744389 was associated with QRS (P = 3.5 × 10-6), with replication in the Microisolates in South Tyrol (MICROS) study (n = 636; P = 0.010). Observing that rs2744389 was associated with DSP-AS1 antisense lncRNA but not with DSP expression in multiple Genotype-Tissue Expression (GTEx) v8 tissues, we conducted two-sample Mendelian randomization analyses that identified causal effects of DSP-AS1 on DSP expression (P = 6.33 × 10-5; colocalization posterior probability = 0.91) and QRS (P = 0.015). In hiPSC-CMs, DSP-AS1 expression downregulation through a specific GapmerR matching sequence led to significant DSP upregulation at both mRNA and protein levels. The evidence that DSP-AS1 has a regulatory role on DSP opens the venue for further investigations on DSP-AS1's therapeutic potential for conditions caused by reduced desmoplakin production.
AU  - Foco, L.*
AU  - De Bortoli, M.*
AU  - Del Greco M, F.*
AU  - Frommelt, L.S.*
AU  - Volani, C.*
AU  - Riekschnitz, D.A.*
AU  - Motta, B.M.*
AU  - Fuchsberger, C.*
AU  - Delerue, T.
AU  - Völker, U.*
AU  - Huan, T.*
AU  - Gögele, M.*
AU  - Winkelmann, J.
AU  - Dörr, M.*
AU  - Levy, D.*
AU  - Waldenberger, M.
AU  - Teumer, A.*
AU  - Pramstaller, P.P.*
AU  - Rossini, A.*
AU  - Pattaro, C.*
C1  - 75264
C2  - 57896
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Genomic and molecular evidence that the LncRNA DSP-AS1 modulates desmoplakin expression.
JO  - Hum. Genet.
PB  - Springer
PY  - 2025
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.
AU  - Fallerini, C.*
AU  - Picchiotti, N.*
AU  - Baldassarri, M.*
AU  - Zguro, K.*
AU  - Daga, S.*
AU  - Fava, F.*
AU  - Benetti, E.*
AU  - Amitrano, S.*
AU  - Bruttini, M.*
AU  - Palmieri, M.C.*
AU  - Croci, S.*
AU  - Lista, M.*
AU  - Beligni, G.*
AU  - Valentino, F.*
AU  - Meloni, I.*
AU  - Tanfoni, M.*
AU  - Minnai, F.*
AU  - Colombo, F.*
AU  - Cabri, E.*
AU  - Fratelli, M.*
AU  - Gabbi, C.*
AU  - Mantovani, S.*
AU  - Frullanti, E.*
AU  - Gori, M.*
AU  - Crawley, F.P.*
AU  - Butler-Laporte, G.*
AU  - Richards, B.*
AU  - Zeberg, H.*
AU  - Lipcsey, M.*
AU  - Hultström, M.*
AU  - Ludwig, K.U.*
AU  - Schulte, E.C.
AU  - Pairo-Castineira, E.*
AU  - Baillie, J.K.*
AU  - Schmidt, A.*
AU  - Frithiof, R.*
AU  - GEN-COVID Multicenter Study (Protzer, U.)
AU  - Mari, F.*
AU  - Renieri, A.*
AU  - Furini, S.*
C1  - 63783
C2  - 51758
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 147-173
TI  - Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.
JO  - Hum. Genet.
VL  - 141
IS  - 1
PB  - Springer
PY  - 2022
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Mouse mutants are a long-lasting, valuable tool to identify genes underlying eye diseases, because the absence of eyes, very small eyes and severely affected, cataractous eyes are easily to detect without major technical equipment. In mice, actually 145 genes or loci are known for anophthalmia, 269 for microphthalmia, and 180 for cataracts. Approximately, 25% of the loci are not yet characterized; however, some of the ancient lines are extinct and not available for future research. The phenotypes of the mutants represent a continuous spectrum either in anophthalmia and microphthalmia, or in microphthalmia and cataracts. On the other side, mouse models are still missing for some genes, which have been identified in human families to be causative for anophthalmia, microphthalmia, or cataracts. Finally, the mouse offers the possibility to genetically test the roles of modifiers and the role of SNPs; these aspects open new avenues for ophthalmogenetics in the mouse.
AU  - Graw, J.
C1  - 55782
C2  - 46537
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 1007-1018
TI  - Mouse models for microphthalmia, anophthalmia and cataracts.
JO  - Hum. Genet.
VL  - 138
IS  - 8-9
PB  - Springer
PY  - 2019
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Metabolic coherence (MC) is a network-based approach to dimensionality reduction that can be used, for example, to interpret the joint expression of genes linked to human metabolism. Computationally, the derivation of transcriptomic' MC involves mapping of an individual gene expression profile onto a gene-centric network derived beforehand from a metabolic network (currently Recon2), followed by the determination of the connectivity of a particular, profile-specific subnetwork. The biological significance of MC has been exemplified previously in the context of human inflammatory bowel disease, among others, but the genetic architecture of this quantitative cellular trait is still unclear. Therefore, we performed a genome-wide association study (GWAS) of MC in the 1000 Genomes/ GEUVADIS data (n=457) and identified a solitary genome-wide significant association with single nucleotide polymorphisms (SNPs) in the intronic region of the cadherin 18 (CDH18) gene on chromosome 5 (lead SNP: rs11744487, p=1.2x10(-8)). Cadherin 18 is a transmembrane protein involved in human neural development and cell-to-cell signaling. Notably, genetic variation at the CDH18 locus has been associated with metabolic syndrome-related traits before. Replication of our genome-wide significant GWAS result was successful in another population study from the Netherlands (BIOS, n=2661; lead SNP), but failed in two additional studies (KORA, Germany, n=711; GENOA, USA, n=411). Besides sample size issues, we surmise that these discrepant findings may be attributable to technical differences. While 1000 Genomes/GEUVADIS and BIOS gene expression profiles were generated by RNA sequencing, the KORA and GENOA data were microarray-based. In addition to providing first evidence for a link between regional genetic variation and a metabolism-related characteristic of human transcriptomes, our findings highlight the benefit of adopting a systems biology-oriented approach to molecular data analysis.
AU  - Schlicht, K.*
AU  - Nyczka, P.*
AU  - Caliebe, A.*
AU  - Freitag-Wolf, S.*
AU  - Claringbould, A.*
AU  - Franke, L.*
AU  - Võsa, U.*
AU  - Kardia, S.L.R.*
AU  - Smith, J.A.*
AU  - Zhao, W.*
AU  - Gieger, C.
AU  - Peters, A.
AU  - Prokisch, H.
AU  - Strauch, K.
AU  - Baurecht, H.*
AU  - Weidinger, S.*
AU  - Rosenstiel, P.*
AU  - Hütt, M.T.*
AU  - Knecht, C.*
AU  - Szymczak, S.*
AU  - Krawczak, M.*
C1  - 55651
C2  - 46513
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 375–388
TI  - The metabolic network coherence of human transcriptomes is associated with genetic variation at the cadherin 18 locus.
JO  - Hum. Genet.
VL  - 138
IS  - 4
PB  - Springer
PY  - 2019
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the NALCN channelosome, consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variantlocated in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.
AU  - Bramswig, N.C.*
AU  - Bertoli-Avella, A.M.*
AU  - Albrecht, B.*
AU  - Al Aqeel, A.I.*
AU  - Alhashem, A.*
AU  - Al-Sannaa, N.*
AU  - Bah, M.*
AU  - Bröhl, K.*
AU  - Depienne, C.*
AU  - Dorison, N.*
AU  - Doummar, D.*
AU  - Ehmke, N.*
AU  - Elbendary, H.M.*
AU  - Gorokhova, S.*
AU  - Héron, D.*
AU  - Horn, D.*
AU  - James, K.*
AU  - Keren, B.*
AU  - Kuechler, A.*
AU  - Ismail, S.*
AU  - Issa, M.Y.*
AU  - Marey, I.*
AU  - Mayer, M.*
AU  - McEvoy-Venneri, J.*
AU  - Megarbane, A.*
AU  - Mignot, C.*
AU  - Mohamed, S.*
AU  - Nava, C.*
AU  - Philip, N.*
AU  - Ravix, C.*
AU  - Rolfs, A.*
AU  - Sadek, A.A.*
AU  - Segebrecht, L.*
AU  - Stanley, V.*
AU  - Trautman, C.*
AU  - Valence, S.*
AU  - Villard, L.*
AU  - Wieland, T.
AU  - Engels, H.*
AU  - Strom, T.M.
AU  - Zaki, M.S.*
AU  - Gleeson, J.G.*
AU  - Lüdecke, H.J.*
AU  - Bauer, P.*
AU  - Wieczorek, D.*
C1  - 54214
C2  - 45441
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 753-768
TI  - Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).
JO  - Hum. Genet.
VL  - 137
IS  - 9
PB  - Springer
PY  - 2018
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Intellectual disability (ID) has an estimated prevalence of 1.5–2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.
AU  - Fritzen, D.*
AU  - Kuechler, A.*
AU  - Grimmel, M.*
AU  - Becker, J.*
AU  - Peters, S.*
AU  - Sturm, M.*
AU  - Hundertmark, H.*
AU  - Schmidt, A.*
AU  - Kreiss, M.*
AU  - Strom, T.M.
AU  - Wieczorek, D.*
AU  - Haack, T.B.*
AU  - Beck-Woedl, S.*
AU  - Cremer, K.*
AU  - Engels, H.*
C1  - 53645
C2  - 44821
SP  - 401-411
TI  - De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies.
JO  - Hum. Genet.
VL  - 137
IS  - 5
PY  - 2018
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Mutations in the SACS gene have been initially reported in a rare autosomal recessive cerebellar ataxia syndrome featuring prominent cerebellar atrophy, spasticity and peripheral neuropathy as well as retinal abnormalities in some cases (autosomal recessive spastic ataxia of Charlevoix-Saguenay, ARSACS). In the past few years, the phenotypic spectrum has broadened, mainly owing to the availability and application of high-throughput genetic testing methods. We identified nine patients (three sib pairs, three singleton cases) with isolated, non-syndromic hereditary motor and sensory neuropathy (HMSN) who carried pathogenic SACS mutations, either in the homozygous or compound heterozygous state. None of the patients displayed spasticity or pyramidal signs. Ataxia, which was noted in only three patients, was consistent with a sensory ataxia. Nerve conduction and nerve biopsy studies showed mixed demyelinating and axonal neuropathy. Brain MRI scans were either normal or revealed isolated upper vermis atrophy of the cerebellum. Our findings confirm the broad clinical spectrum associated with SACS mutations, including pure polyneuropathy without characteristic clinical and brain imaging manifestations of ARSACS.
AU  - Vill, K.*
AU  - Müller-Felber, W.*
AU  - Gläser, D.*
AU  - Kuhn, M.*
AU  - Teusch, V.*
AU  - Schreiber, H.*
AU  - Weis, J.*
AU  - Klepper, J.*
AU  - Schirmacher, A.*
AU  - Blaschek, A.*
AU  - Wiessner, M.*
AU  - Strom, T.M.
AU  - Dräger, B.*
AU  - Hofmeister-Kiltz, K.*
AU  - Tacke, M.*
AU  - Gerstl, L.*
AU  - Young, P.*
AU  - Horvath, R.*
AU  - Senderek, J.*
C1  - 54779
C2  - 45885
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 911-919
TI  - SACS variants are a relevant cause of autosomal recessive hereditary motor and sensory neuropathy.
JO  - Hum. Genet.
VL  - 137
IS  - 11-12
PB  - Springer
PY  - 2018
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families.
AU  - Wesdorp, M.*
AU  - de Koning Gans, P.A.M.*
AU  - Schraders, M.*
AU  - Oostrik, J.*
AU  - Huynen, M.A.*
AU  - Venselaar, H.*
AU  - Beynon, A.J.*
AU  - van Gaalen, J.*
AU  - Piai, V.*
AU  - Voermans, N.*
AU  - van Rossum, M.M.*
AU  - Hartel, B.P.*
AU  - Lelieveld, S.H.*
AU  - Wiel, L.*
AU  - Verbist, B.*
AU  - Rotteveel, L.J.*
AU  - van Dooren, M.F.*
AU  - Lichtner, P.
AU  - Kunst, H.P.M.*
AU  - Feenstra, I.*
AU  - Admiraal, R.J.C.*
AU  - DOOFNL Consortium*
AU  - Yntema, H.G.*
AU  - Hoefsloot, L.H.*
AU  - Pennings, R.J.E.*
AU  - Kremer, H.*
C1  - 53517
C2  - 44795
SP  - 389-400
TI  - Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction.
JO  - Hum. Genet.
VL  - 137
IS  - 5
PY  - 2018
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.
AU  - Bramswig, N.C.*
AU  - Lüdecke, H.J.*
AU  - Pettersson, M.*
AU  - Albrecht, B.*
AU  - Bernier, R.A.*
AU  - Cremer, K.*
AU  - Eichler, E.E.*
AU  - Falkenstein, D.*
AU  - Gerdts, J.*
AU  - Jansen, S.*
AU  - Kuechler, A.*
AU  - Kvarnung, M.*
AU  - Lindstrand, A.*
AU  - Nilsson, D.*
AU  - Nordgren, A.*
AU  - Pfundt, R.*
AU  - Spruijt, L.*
AU  - Surowy, H.M.*
AU  - de Vries, B.*
AU  - Wieland, T.
AU  - Engels, H.*
AU  - Strom, T.M.
AU  - Kleefstra, T.*
AU  - Wieczorek, D.*
C1  - 50034
C2  - 41985
CY  - New York
SP  - 179-192
TI  - Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.
JO  - Hum. Genet.
VL  - 136
IS  - 2
PB  - Springer
PY  - 2017
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Chromatin remodeling is a complex process shaping the nucleosome landscape, thereby regulating the accessibility of transcription factors to regulatory regions of target genes and ultimately managing gene expression. The SWI/SNF (switch/sucrose nonfermentable) complex remodels the nucleosome landscape in an ATP-dependent manner and is divided into the two major subclasses Brahma-associated factor (BAF) and Polybromo Brahma-associated factor (PBAF) complex. Somatic mutations in subunits of the SWI/SNF complex have been associated with different cancers, while germline mutations have been associated with autism spectrum disorder and the neurodevelopmental disorders Coffin–Siris (CSS) and Nicolaides–Baraitser syndromes (NCBRS). CSS is characterized by intellectual disability (ID), coarsening of the face and hypoplasia or absence of the fifth finger- and/or toenails. So far, variants in five of the SWI/SNF subunit-encoding genes ARID1B, SMARCA4, SMARCB1, ARID1A, and SMARCE1 as well as variants in the transcription factor-encoding gene SOX11 have been identified in CSS-affected individuals. ARID2 is a member of the PBAF subcomplex, which until recently had not been linked to any neurodevelopmental phenotypes. In 2015, mutations in the ARID2 gene were associated with intellectual disability. In this study, we report on two individuals with private de novo ARID2 frameshift mutations. Both individuals present with a CSS-like phenotype including ID, coarsening of facial features, other recognizable facial dysmorphisms and hypoplasia of the fifth toenails. Hence, this study identifies mutations in the ARID2 gene as a novel and rare cause for a CSS-like phenotype and enlarges the list of CSS-like genes.
AU  - Bramswig, N.C.*
AU  - Caluseriu, O.*
AU  - Lüdecke, H.J.*
AU  - Bolduc, F.V.*
AU  - Noel, N.C.L.*
AU  - Wieland, T.
AU  - Surowy, H.M.*
AU  - Christen, H.J.*
AU  - Engels, H.*
AU  - Strom, T.M.
AU  - Wieczorek, D.*
C1  - 50458
C2  - 42474
CY  - New York
SP  - 297-305
TI  - Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin–Siris syndrome-like phenotype.
JO  - Hum. Genet.
VL  - 136
IS  - 3
PB  - Springer
PY  - 2017
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA–protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.
AU  - Bramswig, N.C.*
AU  - Lüdecke, H.J.*
AU  - Hamdan, F.F.*
AU  - Altmüller, J.*
AU  - Beleggia, F.*
AU  - Elcioğlu, N.H.*
AU  - Freyer, C.*
AU  - Gerkes, E.H.*
AU  - Demirkol, Y.K.*
AU  - Knupp, K.G.*
AU  - Kuechler, A.*
AU  - Li, Y.*
AU  - Lowenstein, D.H.*
AU  - Michaud, J.L.*
AU  - Park, K.*
AU  - Stegmann, A.P.A.*
AU  - Veenstra-Knol, H.E.*
AU  - Wieland, T.
AU  - Wollnik, B.*
AU  - Engels, H.*
AU  - Strom, T.M.
AU  - Kleefstra, T.*
AU  - Wieczorek, D.*
C1  - 50930
C2  - 42974
CY  - New York
SP  - 821-834
TI  - Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability.
JO  - Hum. Genet.
VL  - 136
IS  - 7
PB  - Springer
PY  - 2017
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - GATA5 belongs to the GATA family of transcription factors characterized by highly evolutionarily conserved zinc-finger DNA-binding domains. Mouse models have implicated a role of GATA5 during mammalian embryogenesis, including proper heart development and gender-specific regulation of female genitourinary tract formation. Previous studies have found an association of heterozygous missense alterations in GATA5 with a broad variety of heart diseases; however, the clinical relevance of the identified susceptibility variants has remained unclear. Here, we report on a girl with hydrops fetalis, congenital heart defects, clitoromegaly and postnatally increased 17-hydroxyprogesterone levels. By trio whole-exome sequencing, we identified compound heterozygous missense mutations, p.Ser19Trp and p.Arg202Gln, in GATA5 as putative disease-causing alterations. The identified mutations fail to rescue the cardia bifida phenotype in a zebrafish model, mislocalize to subnuclear foci when transiently transfected in HEK293 cells and possess less transcriptional activity. In addition to demonstrating the pathogenicity of identified mutations, our findings show that GATA5 mutations, in addition to heart diseases, can result in congenital abnormalities of the female genitourinary tract in humans.
AU  - Hempel, M.*
AU  - Casar Tena, T.*
AU  - Diehl, T.*
AU  - Burczyk, M.S.*
AU  - Strom, T.M.
AU  - Kubisch, C.*
AU  - Philipp, M.*
AU  - Lessel, D.*
C1  - 50536
C2  - 42506
CY  - New York
SP  - 339-346
TI  - Compound heterozygous GATA5 mutations in a girl with hydrops fetalis, congenital heart defects and genital anomalies.
JO  - Hum. Genet.
VL  - 136
IS  - 3
PB  - Springer
PY  - 2017
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed “transcriptomopathies” that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin–Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders.
AU  - Parenti, I.*
AU  - Teresa-Rodrigo, M.E.*
AU  - Pozojevic, J.*
AU  - Ruiz Gil, S.*
AU  - Bader, I.*
AU  - Braunholz, D.*
AU  - Bramswig, N.C.*
AU  - Gervasini, C.*
AU  - Larizza, L.*
AU  - Pfeiffer, L.*
AU  - Ozkınay, F.*
AU  - Ramos, F.*
AU  - Reiz, B.*
AU  - Rittinger, O.*
AU  - Strom, T.M.
AU  - Watrin, E.*
AU  - Wendt, K.*
AU  - Wieczorek, D.*
AU  - Wollnik, B.*
AU  - Baquero-Montoya, C.*
AU  - Pié, J.*
AU  - Deardorff, M.A.*
AU  - Gillessen-Kaesbach, G.*
AU  - Kaiser, F.J.*
C1  - 50456
C2  - 42472
CY  - New York
SP  - 307-320
TI  - Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.
JO  - Hum. Genet.
VL  - 136
IS  - 3
PB  - Springer
PY  - 2017
SN  - 0340-6717
ER  - 

TY  - JOUR
AU  - Brenner, D.R.*
AU  - Brennan, P.*
AU  - Boffetta, P.*
AU  - Amos, C.I.*
AU  - Spitz, M.R.*
AU  - Chen, C.*
AU  - Goodman, G.*
AU  - Heinrich, J.
AU  - Bickeböller, H.*
AU  - Rosenberger, A.*
AU  - Risch, A.*
AU  - Muley, T.*
AU  - McLaughlin, J.R.*
AU  - Benhamou, S.*
AU  - Bouchardy, C.*
AU  - Lewinger, J.P.*
AU  - Witte, J.S.*
AU  - Chen, G.*
AU  - Bull, S.*
AU  - Hung, R.J.*
C1  - 48764
C2  - 41324
CY  - New York
SP  - 963-963
TI  - Erratum to: Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls.
JO  - Hum. Genet.
VL  - 135
IS  - 8
PB  - Springer
PY  - 2016
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Coffin–Siris syndrome (CSS) and Nicolaides–Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann–Steiner, Kabuki, and Adams–Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers.
AU  - Bramswig, N.C.*
AU  - Lüdecke, H.J.*
AU  - Alanay, Y.*
AU  - Albrecht, B.*
AU  - Barthelmie, A.*
AU  - Boduroglu, K.*
AU  - Braunholz, D.*
AU  - Caliebe, A.*
AU  - Chrzanowska, K.*
AU  - Czeschik, J.C.*
AU  - Endele, S.U.*
AU  - Graf, E.
AU  - Guillén-Navarro, E.*
AU  - Kiper, P.O.S.*
AU  - López-González, V.*
AU  - Parenti, I.*
AU  - Pozojevic, J.*
AU  - Ü̈tine, G.E.*
AU  - Wieland, T.
AU  - Kaiser, F.J.*
AU  - Wollnik, B.*
AU  - Strom, T.M.
AU  - Wieczorek, D.*
C1  - 43792
C2  - 36763
CY  - New York
SP  - 553-568
TI  - Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin–Siris and Nicolaides–Baraitser syndromes.
JO  - Hum. Genet.
VL  - 134
IS  - 6
PB  - Springer
PY  - 2015
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - KCNH1 mutations have recently been described in six individuals with Temple–Baraitser syndrome (TMBTS) and six individuals with Zimmermann–Laband syndrome (ZLS). TMBTS is characterized by intellectual disability (ID), epilepsy, dysmorphic facial features, broad thumbs and great toes with absent/hypoplastic nails. ZLS is characterized by facial dysmorphism including coarsening of the face and a large nose, gingival enlargement, ID, hypoplasia of terminal phalanges and nails and hypertrichosis. In this study, we present four additional unrelated individuals with de novo KCNH1 mutations from ID cohorts. We report on a novel recurrent pathogenic KCNH1 variant in three individuals and add a fourth individual with a previously TMBTS-associated KCNH1 variant. Neither TMBTS nor ZLS was suspected clinically. KCNH1 encodes a voltage-gated potassium channel, which is not only highly expressed in the central nervous system, but also seems to play an important role during development. Clinical evaluation of our mutation-positive individuals revealed that one of the main characteristics of TMBTS/ZLS, namely the pronounced nail hypoplasia of the great toes and thumbs, can be mild and develop over time. Clinical comparison of all published KCNH1 mutation-positive individuals revealed a similar facial but variable limb phenotype. KCNH1 mutation-positive individuals present with severe ID, neonatal hypotonia, hypertelorism, broad nasal tip, wide mouth, nail a/hypoplasia, a proximal implanted and long thumb and long great toes. In summary, we show that the phenotypic variability of individuals with KCNH1 mutations is more pronounced than previously expected, and we discuss whether KCNH1 mutations allow for “lumping” or for “splitting” of TMBTS and ZLS.
AU  - Bramswig, N.C.*
AU  - Ockeloen, C.W.*
AU  - Czeschik, J.C.*
AU  - van Essen, A.J.*
AU  - Pfundt, R.*
AU  - Smeitink, J.*
AU  - Poll-The, B.T.*
AU  - Engels, H.*
AU  - Strom, T.M.
AU  - Wieczorek, D.*
AU  - Kleefstra, T.*
AU  - Lüdecke, H.J.*
C1  - 46675
C2  - 37672
SP  - 1089-1097
TI  - ‘Splitting versus lumping’: Temple–Baraitser and Zimmermann–Laband syndromes.
JO  - Hum. Genet.
VL  - 134
IS  - 10
PY  - 2015
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.
AU  - Kuechler, A.*
AU  - Willemsen, M.H.*
AU  - Albrecht, B.*
AU  - Bacino, C.A.*
AU  - Bartholomew, D.W.*
AU  - van Bokhoven, H.*
AU  - van den Boogaard, M.J.*
AU  - Bramswig, N.*
AU  - Büttner, C.*
AU  - Cremer, K.*
AU  - Czeschik, J.C.*
AU  - Engels, H.*
AU  - van Gassen, K.*
AU  - Graf, E.
AU  - van Haelst, M.M.*
AU  - He, W.*
AU  - Hogue, J.S.*
AU  - Kempers, M.*
AU  - Koolen, D.A.*
AU  - Monroe, G.*
AU  - de Munnik, S.*
AU  - Pastore, M.*
AU  - Reis, A.*
AU  - Reuter, M.S.*
AU  - Tegay, D.H.*
AU  - Veltman, J.A.*
AU  - Visser, G.*
AU  - van Hasselt, P.*
AU  - Smeets, E.E.*
AU  - Vissers, L.E.*
AU  - Wieland, T.
AU  - Wissink, W.*
AU  - Yntema, H.*
AU  - Zink, A.M.*
AU  - Strom, T.M.
AU  - Lüdecke, H.J.*
AU  - Kleefstra, T.*
AU  - Wieczorek, D.*
C1  - 32593
C2  - 35146
CY  - New York
SP  - 97-109
TI  - De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: Expanding the mutational and clinical spectrum.
JO  - Hum. Genet.
VL  - 134
IS  - 1
PB  - Springer
PY  - 2015
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
AU  - Li, Q.*
AU  - Wojciechowski, R.*
AU  - Simpson, C.L.*
AU  - Hysi, P.G.*
AU  - Verhoeven, V.J.*
AU  - Ikram, M.K.*
AU  - Höhn, R.*
AU  - Vitart, V.*
AU  - Hewitt, A.W.*
AU  - Oexle, K.*
AU  - Mäkelä, K.M.*
AU  - MacGregor, S.*
AU  - Pirastu, M.*
AU  - Fan, Q.*
AU  - Cheng, C.Y.*
AU  - St. Pourcain, B.*
AU  - McMahon, G.*
AU  - Kemp, J.P.*
AU  - Northstone, K.*
AU  - Rahi, J.S.*
AU  - Cumberland, P.M.*
AU  - Martin, N.G.*
AU  - Sanfilippo, P.G.*
AU  - Lu, Y.*
AU  - Wang, Y.X.*
AU  - Hayward, C.*
AU  - Polasek, O.*
AU  - Campbell, H.*
AU  - Bencic, G.*
AU  - Wright, A.F.*
AU  - Wedenoja, J.*
AU  - Zeller, T.*
AU  - Schillert, A.*
AU  - Mirshahi, A.*
AU  - Lackner, K.J.*
AU  - Yip, S.P.*
AU  - Yap, M.K.H.*
AU  - Ried, J.S.
AU  - Gieger, C.
AU  - Murgia, F.*
AU  - Wilson, J.F.*
AU  - Fleck, B.*
AU  - Yazar, S.*
AU  - Vingerling, J.R.*
AU  - Hofman, A.*
AU  - Uitterlinden, A.*
AU  - Rivadeneira, F.*
AU  - Amin, N.*
AU  - Karssen, L.C.*
AU  - Oostra, B.A.*
AU  - Zhou, X.*
AU  - Teo, Y.Y.*
AU  - Tai, E.S.*
AU  - Vithana, E.*
AU  - Barathi, V.A.*
AU  - Zheng, Y.*
AU  - Siantar, R.G.*
AU  - Neelam, K.*
AU  - Shin, Y.K.*
AU  - Lam, J.S.Y.*
AU  - Yonova-Doing, E.*
AU  - Venturini, C.*
AU  - Hosseini, S.M.*
AU  - Wong, H.S.*
AU  - Lehtimäki, T.*
AU  - Kähönen, M.*
AU  - Raitakari, O.*
AU  - Timpson, N.J.*
AU  - Evans, D.M*
AU  - Khor, C.C.*
AU  - Aung, T.*
AU  - Young, T.L.*
AU  - Mitchell, P.*
AU  - Klein, B.*
AU  - van Duijn, C.M.*
AU  - Meitinger, T.
AU  - Jonas, J.B.*
AU  - Baird, P.N.*
AU  - Mackey, D.A.*
AU  - Wong, T.Y.*
AU  - Saw, S.M.*
AU  - Pärssinen, O.*
AU  - Stambolian, D.*
AU  - Hammond, C.J.*
AU  - Klaver, C.C.*
AU  - Williams, C.*
AU  - Paterson, A.D.*
AU  - Bailey-Wilson, J.E.*
AU  - Guggenheim, J.A.*
C1  - 34362
C2  - 35233
CY  - New York
SP  - 131-146
TI  - Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: The CREAM consortium.
JO  - Hum. Genet.
VL  - 134
IS  - 2
PB  - Springer
PY  - 2015
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant (p < 5 × 10−8) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic (p = 0.012) and systolic (p = 0.035) BP levels, as well as peripheral vascular resistance (p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease.
AU  - Turpeinen, H.*
AU  - Seppälä, I.J.T.*
AU  - Lyytikäinen, L.-P.*
AU  - Raitoharju, E.*
AU  - Hutri-Kähönen, N.*
AU  - Levula, M.*
AU  - Oksala, N.K.J.*
AU  - Waldenberger, M.
AU  - Klopp, N.
AU  - Illig, T.
AU  - Mononen, N.*
AU  - Laaksonen, R.*
AU  - Raitakari, O.T.*
AU  - Kähönen, M.*
AU  - Lehtimäki, T.*
AU  - Pesu, M.*
C1  - 44095
C2  - 36810
CY  - New York
SP  - 627-636
TI  - A genome-wide expression quantitative trait loci analysis of proprotein convertase subtilisin/kexin enzymes identifies a novel regulatory gene variant for FURIN expression and blood pressure.
JO  - Hum. Genet.
VL  - 134
IS  - 6
PB  - Springer
PY  - 2015
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance (p < 2.2 × 10-6) for four loci in AA, three of which have been reported previously in individuals of European descent (IL6R, p = 2.0 × 10-6; CRP, p = 4.2 × 10-71; APOE, p = 1.6 × 10-6). The fourth significant locus, CD36 (p = 1.6 × 10-6), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding (p = 1.8 × 10-5) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance (p = 1.5 × 10-10). In the race-combined meta-analyses, 13 loci reached significance, including ten (CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one (ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected (RPS6KB1, p = 2.0 × 10-6; CD36, p = 1.4 × 10-6). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent.
AU  - Ellis, J.*
AU  - Lange, E.M.*
AU  - Li, J.*
AU  - Dupuis, J.*
AU  - Baumert, J.J.
AU  - Walston, J.D.*
AU  - Keating, B.J.*
AU  - Durda, P.*
AU  - Fox, E.R.*
AU  - Palmer, C.D.*
AU  - Meng, Y.A.*
AU  - Young, T.*
AU  - Farlow, D.N.*
AU  - Schnabel, R.B.*
AU  - Marzi, C.
AU  - Larkin, E.*
AU  - Martin, L.W.*
AU  - Bis, J.C.*
AU  - Auer, P.*
AU  - Ramachandran, V.S.*
AU  - Gabriel, S.B.*
AU  - Willis, M.S.*
AU  - Pankow, J.S.*
AU  - Papanicolau, G.J.*
AU  - Rotter, J.I.*
AU  - Ballantyne, C.M.*
AU  - Gross, M.D.*
AU  - Lettre, G.*
AU  - Wilson, J.G.*
AU  - Peters, U.*
AU  - Koenig, W.*
AU  - Tracy, R.P.*
AU  - Redline, S.*
AU  - Reiner, A.P.*
AU  - Benjamin, E.J.*
AU  - Lange, L.A.*
C1  - 30926
C2  - 34013
CY  - New York
SP  - 985-995
TI  - Large multiethnic candidate gene study for C-reactive protein levels: Identification of a novel association at CD36 in African Americans.
JO  - Hum. Genet.
VL  - 133
IS  - 8
PB  - Springer
PY  - 2014
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Recent evidence suggests that inflammation plays a pivotal role in the development of lung cancer. In this study, we used a two-stage approach to investigate associations between genetic variants in inflammation pathways and lung cancer risk based on genome-wide association study (GWAS) data. A total of 7,650 sequence variants from 720 genes relevant to inflammation pathways were identified using keyword and pathway searches from Gene Cards and Gene Ontology databases. In Stage 1, six GWAS datasets from the International Lung Cancer Consortium were pooled (4,441 cases and 5,094 controls of European ancestry), and a hierarchical modeling (HM) approach was used to incorporate prior information for each of the variants into the analysis. The prior matrix was constructed using (1) role of genes in the inflammation and immune pathways; (2) physical properties of the variants including the location of the variants, their conservation scores and amino acid coding; (3) LD with other functional variants and (4) measures of heterogeneity across the studies. HM affected the priority ranking of variants particularly among those having low prior weights, imprecise estimates and/or heterogeneity across studies. In Stage 2, we used an independent NCI lung cancer GWAS study (5,699 cases and 5,818 controls) for in silico replication. We identified one novel variant at the level corrected for multiple comparisons (rs2741354 in EPHX2 at 8q21.1 with p value = 7.4 × 10(-6)), and confirmed the associations between TERT (rs2736100) and the HLA region and lung cancer risk. HM allows for prior knowledge such as from bioinformatic sources to be incorporated into the analysis systematically, and it represents a complementary analytical approach to the conventional GWAS analysis.
AU  - Brenner, D.R.*
AU  - Brennan, P.*
AU  - Boffetta, P.*
AU  - Amos, C.I.*
AU  - Spitz, M.R.*
AU  - Chen, C.*
AU  - Goodman, G.*
AU  - Heinrich, J.
AU  - Bickeböller, H.*
AU  - Rosenberger, A.*
AU  - Risch, A.*
AU  - Muley, T.*
AU  - McLaughlin, J.R.*
AU  - Benhamou, S.*
AU  - Bouchardy, C.*
AU  - Lewinger, J.P.*
AU  - Witte, J.S.*
AU  - Chen, G.*
AU  - Bull, S.*
AU  - Hung, R.J.*
C1  - 24382
C2  - 31532
SP  - 579-589
TI  - Hierarchical modeling identifies novel lung cancer susceptibility variants in inflammation pathways among 10,140 cases and 11,012 controls.
JO  - Hum. Genet.
VL  - 132
IS  - 5
PB  - Springer
PY  - 2013
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 x 10(-12) for SNP rs634990 in Caucasians, and 9.65 x 10(-4) for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 x 10(-23) for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 x 10(-2) for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide.
AU  - Verhoeven, V.J.M.*
AU  - Hysi, P.G.*
AU  - Saw, S.-M.*
AU  - Vitart, V.*
AU  - Mirshahi, A.*
AU  - Guggenheim, J.A.*
AU  - Cotch, M.F.*
AU  - Yamashiro, K.*
AU  - Baird, P.N.*
AU  - Mackey, D.A.*
AU  - Wojciechowski, R.*
AU  - Ikram, M.K.*
AU  - Hewitt, A.W.*
AU  - Duggal, P.*
AU  - Janmahasatian, S.*
AU  - Khor, C.-C.*
AU  - Fan, Q.*
AU  - Zhou, X.*
AU  - Young, T.L.*
AU  - Tai, E.-S.*
AU  - Goh, L.-K.*
AU  - Li, Y.-J.*
AU  - Aung, T.*
AU  - Vithana, E.*
AU  - Teo, Y.-Y.*
AU  - Tay, W.*
AU  - Sim, X.*
AU  - Rudan, I.*
AU  - Hayward, C.*
AU  - Wright, A.F.*
AU  - Polasek, O.*
AU  - Campbell, H.*
AU  - Wilson, J.F.*
AU  - Fleck, B.W.*
AU  - Nakata, I.*
AU  - Yoshimura, N.*
AU  - Yamada, R.*
AU  - Matsuda, F.*
AU  - Ohno-Matsui, K.*
AU  - Nag, A.*
AU  - McMahon, G.*
AU  - St Pourcain, B.*
AU  - Lu, Y.*
AU  - Rahi, J.S.*
AU  - Cumberland, P.M.*
AU  - Bhattacharya, S.*
AU  - Simpson, C.L.*
AU  - Atwood, L.D.*
AU  - Li, X.H.*
AU  - Raffel, L.J.*
AU  - Murgia, F.*
AU  - Portas, L.*
AU  - Despriet, D.D.G.*
AU  - van Koolwijk, L.M.E.*
AU  - Wolfram, C.*
AU  - Lackner, K.J.*
AU  - Tönjes, A.*
AU  - Mägi, R.*
AU  - Lehtimäki, T.*
AU  - Kähönen, M.*
AU  - Esko, T.*
AU  - Metspalu, A.*
AU  - Rantanen, T.*
AU  - Pärssinen, O.*
AU  - Klein, B.E.*
AU  - Meitinger, T.
AU  - Spector, T.D.*
AU  - Oostra, B.A.*
AU  - Smith, A.V.*
AU  - de Jong, P.T.V.M.*
AU  - Hofman, A.*
AU  - Amin, N.*
AU  - Karssen, L.C.*
AU  - Rivadeneira, F.*
AU  - Vingerling, J.R.*
AU  - Eiriksdottir, G.*
AU  - Gudnason, V.*
AU  - Döring, A.
AU  - Bettecken, T.*
AU  - Uitterlinden, A.G.*
AU  - Williams, C.*
AU  - Zeller, T.*
AU  - Castagné, R.*
AU  - Oexle, K.*
AU  - van Duijn, C.M.*
AU  - Iyengar, S.K.*
AU  - Mitchell, P.*
AU  - Wang, J.J.*
AU  - Höhn, R.*
AU  - Pfeiffer, N.*
AU  - Bailey-Wilson, J.E.*
AU  - Stambolian, D.*
AU  - Wong, T.-Y.*
AU  - Hammond, C.J.*
AU  - Klaver, C.C.W.*
C1  - 8555
C2  - 30282
SP  - 1467-1480
TI  - Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium.
JO  - Hum. Genet.
VL  - 131
IS  - 9
PB  - Springer
PY  - 2012
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Recently there has been an increased interest in large-scale genomic variation and clinically in the consequences of haploinsufficiency of genomic segments or disruption of normal gene function by chromosome rearrangements. Here, we present an extraordinary case in which both mother and daughter presented with unexpected chromosomal rearrangement complexity, which we characterized with array-CGH, array painting and multicolor large insert clone hybridizations. We found the same 12 breakpoints involving four chromosomes in both mother and daughter. In addition, the daughter inherited a microdeletion from her father. We mapped all breakpoints to the resolution level of breakpoint spanning clones. Genes were found within 7 of the 12 breakpoint regions, some of which were disrupted by the chromosome rearrangement. One of the rearrangements disrupted a locus, which has been discussed as a quantitative trait locus for fetal hemoglobin expression in adults. Interestingly, both mother and daughter show persistent fetal hemoglobin levels. We detail the most complicated familial complex chromosomal rearrangement reported to date and thus an extreme example of inheritance of chromosomal rearrangements without error in meiotic segregation.
AU  - Fauth, C.
AU  - Gribble, S.M.*
AU  - Porter, K.M.*
AU  - Codina-Pascual, M.*
AU  - Ng, B.L.*
AU  - Kraus, J.
AU  - Uhrig, S.*
AU  - Leifheit, J.*
AU  - Haaf, T.*
AU  - Fiegler, H.*
AU  - Carter, N.P.*
C1  - 5087
C2  - 23677
SP  - 145-153
TI  - Micro-array analysis decipher exceptional complex familial chromosomal rearrangement.
JO  - Hum. Genet.
VL  - 119
PY  - 2006
SN  - 0340-6717
ER  - 

TY  - JOUR
AU  - Pfuhl, T.*
AU  - Dürr, T.*
AU  - Spurk, A.*
AU  - Schwalbert, B.*
AU  - Nord, R.*
AU  - Mysliwietz, J.
AU  - Kremmer, E.
AU  - Grässer, F.A.
C1  - 1284
C2  - 23037
SP  - 70-80
TI  - Biochemical charcterisation of the proteins encoded by the Di George critical region 6 (DGCR6).
JO  - Hum. Genet.
VL  - 117
PY  - 2005
SN  - 0340-6717
ER  - 

TY  - JOUR
AU  - Müller, S.*
AU  - Hollatz, M.*
AU  - Wienberg, J.
C1  - 9428
C2  - 21637
SP  - 493-501
TI  - Chromosomal phylogeny and evolution of gibbons (Hylobatidae).
JO  - Hum. Genet.
VL  - 113
PY  - 2003
SN  - 0340-6717
ER  - 

TY  - JOUR
AU  - Lohmann, D.
AU  - Horsthemke, B.
AU  - Gillessen-Kaesbach, G.
AU  - Stefani, F.H.
AU  - Höfler, H.
C1  - 20238
C2  - 13421
SP  - 49-53
TI  - Detection of small RB1 Gene Deletions in Retinoblastoma by Multiplex PCR and High- Resolution Gel Electrophoresis.
JO  - Hum. Genet.
VL  - 89
PY  - 1992
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - It is generally believed that idiopathic haemochromatosis is exclusively a disease of middle age, affecting primarily men. We describe here four cases of idiopathic haemochromatosis having onset of symptoms before or around the age of 20 years. Other similar cases have previously been reported. In this juvenile form, males and females appear to be equally affected. These subjects may have a history of unexplained abdominal pain, present with hypogonadotropic hypogonadism, and, unless proper treatment is started, die early because of cardiac dysfunction. In this regard, their clinical course is very similar to that of well-transfused thalassaemia major. Thus, early diagnosis is even more important in the juvenile form than in the adult form of idiopathic haemochromatosis. We suggest that evaluation of body iron stores should be performed as a screening procedure in young subjects with hypogonadotropic hypogonadism and/or cardiac dysfunction.
AU  - Cazzola, M.*
AU  - ASCARI, E.*
AU  - Barosi, G.*
AU  - Claudiani, G.*
AU  - Daccó, M.*
AU  - Kaltwasser, J.P.*
AU  - Panaiotopoulos, N.*
AU  - Schalk, K.P.*
AU  - Werner, E.E.
C1  - 41748
C2  - 40332
SP  - 149-154
TI  - Juvenile idiopathic haemochromatosis: A life-threatening disorder presenting as hypogonadotropic hypogonadism.
JO  - Hum. Genet.
VL  - 65
IS  - 2
PY  - 1983
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Chromosome analyses were carried out in lymphocytes of ten children with ALL, prior to and during combined therapy with antineoplastic drugs and cranial irradiation. Chromosome preparations from group I (four patients) were analysed by conventional staining. For group II (six patients) the FPG technique (fluorescence plus Giemsa) was applied after BrdU treatment of cultures and cells were scored exclusively in first division. A significant clastogenic effect could not be detected in samples collected during or after chemotherapy for either group. After cranial irradiation of those patients in group II, linear dose-effect relationships for dicentric plus ring chromosomes, and for excess acentrics, could be demonstrated after correction for the relative amount of irradiated volume.
AU  - Rauscher, K.H.
AU  - Bauchinger, M.
C1  - 41469
C2  - 38323
SP  - 73-79
TI  - Chromosome aberrations induced in patients treated with chemotherapeutic drugs and irradiation for acute lymphatic leukemia.
JO  - Hum. Genet.
VL  - 64
IS  - 1
PY  - 1983
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Polycyclic aromatic hydrocarbon-inducible monooxygenase directed toward the substrate benzo(a)pyrene, i.e., 'aryl hydrocarbon hydroxylase', was monitored in cell hybrids formed from mouse RAG cells and several human fibroblasts lines. In RAG cells no aryl hydrocarbon hydroxylase activity was detectable; however, these cells exhibited relatively high levels of NADPH cytochrome C (P-450) reductase (EC. 1.6.2.4). In 12 hybrids lines, induced aryl hydrocarbon hydroxylase segregated with human chromosome 2. The results indicate that the structural gene of the polycyclic aromatic hydrocarbon-inducible monooxygenase or gene(s) involved in the induction of the enzyme is located on human chromosome 2.
AU  - Wiebel, F.J.
AU  - Hlavica, P.
AU  - Grzeschik -, K.H.
C1  - 41423
C2  - 40368
SP  - 277-280
TI  - Expression of aromatic polycyclic hydrocarbon-induced monooxygenase (aryl hydrocarbon hydroxylase) in man x mouse hybrids is associated with human chromosome 2.
JO  - Hum. Genet.
VL  - 59
IS  - 4
PY  - 1981
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - This study was undertaken to get more insight into the previously suggested heterogeneity of the HLA-DW3 cluster. Preliminary evidence of DW3 heterogeneity was derived from results of intrafamilial mixed lymphocyte culture tests (MLC) where cells of apparently homozygous offspring revealed unexpected stimulations of one of the parents' cells. Therefore, 15 different homozygous typing cells (HTCs) of DW3 specificity were tested against 43 HLA-DW3 heterozygous individuals. The response patterns of the 43 HLA-DW3 heterozygous cells toward 13 HTCs lead to the definition of at least three groups of DW3 stimulating cells. According to these patterns, four groups of responding cells could be classified. These results were confirmed by a MLC checkerboard experiment running all DW3-HTCs against each other. Discussing all possible explanations for these observations, the authors conclude that the existence of DW3 subtypes having some properties in common is the most likely interpretation of the results obtained. Family segregation studies will be needed to define the genotypic situation of the DW3 cluster.
AU  - Niese, D.*
AU  - Grosse-Wilde, H.
AU  - Dupont, B.*
AU  - Du Toit, E.D.*
AU  - Johannsen, R.*
AU  - Suciu- Foca, N.M.*
AU  - Stroehmann, I.*
AU  - Rittner, C.K.*
C1  - 42530
C2  - 35741
SP  - 23-30
TI  - Evidence for subtypic determinants in the HLA-DW3 cluster.
JO  - Hum. Genet.
VL  - 43
IS  - 1
PY  - 1978
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Mutagenic damages in female germ, cells of mice have been tested with the dominant, lethal assay and the cytogenetic analysis of unfertilized M II-oocytes. Concluding one can say that from the experimental data presented here do not show any mutagenic effect of INH on oogenesis of different strains of mice can be stated.
AU  - Röhrborn, G.*
AU  - Sezer, V.*
AU  - Adler, I.-D.
AU  - Schmaltz, A.
AU  - Pawlowitzki, I.H.*
AU  - Nautsch, C.*
C1  - 40952
C2  - 38543
SP  - 55-58
TI  - Effects of isoniazid (INH) on the oogenesis of mice.
JO  - Hum. Genet.
VL  - 42
IS  - 1
PY  - 1978
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - The family of an individual was studied who lacks the seventh component of complement in his serum (C7 homozygous deficiency). Both parents are C7 heterozygousdeficient. In this investigation, the following parameters were determined: complement components in functional and immunochemical tests; HLA-A,B antigens, HLA-D (MLC) determinants; the Bf system; glyoxalase I and B cell antigens. No evidence for linkage between the immunogenetic linkage group on chromosome 6 and gene(s) controlling the synthesis of the seventh component of complement was obtained. This is in accordance with the assumption that only genes controlling components of the initiating rather than the membrane attack unit of complement are linked to the HLA region.
AU  - Rittner, C.K.*
AU  - Opferkuch, W.*
AU  - Wellek, B.*
AU  - Grosse-Wilde, H.
AU  - Wernet, P.A.*
C1  - 33096
C2  - 35287
SP  - 137-142
TI  - Lack of linkage between gene(s) controlling the synthesis of the seventh component of complement and the HLA region on chromosome No. 6 in man.
JO  - Hum. Genet.
VL  - 34
IS  - 2
PY  - 1976
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Genetic linkage between the HL-A and Bf loci could be confirmed in 43 families with 168 offspring. In 4 families, 5 recombinants out of 82 informative meiotic divisions were observed (r=6.1%). The localisation of the Bf marker system was studied in 3 families with crossovers between HL-A and MLC. From these data the following map order of human chromosome 6 can be proposed: HL-A (1st locus) -HL-A (2nd locus)-MLC-Bf---PGM3. The fact that important components of the classical and alternate pathway of complement activation are governed by genes closely linked with HL-A and MLC loci leads to the proposition to include the Bf system into the Major Histocompatibility Complex in man.
AU  - Rittner, C.K.*
AU  - Grosse-Wilde, H.
AU  - Rittner, B.*
AU  - Netzel, B.
AU  - Scholz, S.*
AU  - Lorenz, H.*
AU  - Albert, E.D.*
C1  - 41389
C2  - 38104
SP  - 173-183
TI  - Linkage group HL-A-MLC-Bf (properdin factor B) - The site of the Bf locus at the immunogenetic linkage group on chromosome 6.
JO  - Hum. Genet.
VL  - 27
IS  - 3
PY  - 1975
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - The arm ratio of the late replicating X-chromosome was determined in 5 control persons, 5 47,XXY Klinefelter patients, 1 46/47,XX/XXX mosaic and 1 45/46,X/XX mosaic. The analysis of the values obtained shows that the method of defining the arm ratio by means of measuring arm lengths on drawings of highly magnified projected chromosomes proves practicable. The mean values of the arm ratios of the 5 control persons cannot be valued as equal. The total mean value of the arm ratios is significantly smaller (1.487) for the Klinefelter patients than for the normal control persons (1.546). The values of the mosaics XX/XXX (1.557) and XO/XX (1.528) lie in the range of the control values.
AU  - Back, F.
AU  - Pohl, W.
AU  - Olbrich, E.
C1  - 42095
C2  - 37961
SP  - 302-315
TI  - Investigations of defining the arm ratio of the late replicating X-chromosome in man
JO  - Hum. Genet.
VL  - 12
IS  - 4
PY  - 1971
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - Whole-mount preparations and thin sections of human interphase cells and metaphase chromosomes were examined by electron microscopy. Irregularly folded, 250 Å thick fibers, which is the basic substructure of inactive chromatin and mitotic chromosomes, were found to be firmly attached to the annuli of the inner nuclear membrane. At metaphase, fragments of the nuclear membrane were seen to adhere to the chromatids. Single fibers stretching out from the telomeres were observed connecting chromatids of nonhomologous chromosomes. A possible model of DNA replication at the nuclear pore complex is presented.
AU  - Lampert, F.H.
C1  - 33638
C2  - 38057
SP  - 285-295
TI  - Attachment of human chromatin fibers to the nuclear membrane, as seen by electron microscopy.
JO  - Hum. Genet.
VL  - 13
IS  - 4
PY  - 1971
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - A 37 old phenotypically normal male with oligospermia was found to have a balanced form of the translocation (14p+; 15p-) in the peripheral lymphocytes. The two chromosomes involved in the translocation could be verified by means of autoradiography. In the patient's family 5 of 11 pregnancies have been terminated by spontaneous abortions. Possible reasons for this phenomenon are discussed.
AU  - Bauchinger, M.
AU  - Schmid, E.
C1  - 42216
C2  - 37969
SP  - 312-320
TI  - Ein Fall mit balancierter (14p+; 15p-)-Translokation.
JO  - Hum. Genet.
VL  - 8
IS  - 4
PY  - 1970
SN  - 0340-6717
ER  - 

TY  - JOUR
AB  - A 21/2 years old girl with multiple malformations is reported. The cytogenetic and autoradiographic investigations show a trisomy D2(14). In the following symptoms the clinical signs are different from the syndrome of a trisomy D1(13): There are no malformations of the eyes, no inborn deafness, no malformations of the heart and kidneys, no hypoplasia of the thumb. The child does not show any signs of capillary haemangioma and no aplasia of the root of the bony nose. The malformation of the bony pelvis, like a splitted pelvis with very narrow high iliococcygeals is remarkable. The child shows all the mainsymptoms of the other autosomal trisomies: oligophrenia, craniofacial dysmorphia, hypotonia of the muscle tonus and dysplasia of the ears. © 1970 Springer-Verlag.
AU  - Murken, J.D.
AU  - Bauchinger, M.
AU  - Palitzsch, D.
AU  - Pfeifer, H.
AU  - Suschke, J.
AU  - Haendle, H.
C1  - 42524
C2  - 0
SP  - 254-268
TI  - Trisomy D2 in a 21/2 years old girl (47,XX,14+).
JO  - Hum. Genet.
VL  - 10
IS  - 3
PY  - 1970
SN  - 0340-6717
ER  -