H H Ropers

Max Planck Institute for Molecular Genetics, Berlín, Berlin, Germany

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Publications (286)1999.62 Total impact

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    ABSTRACT: Sample-tagging is designed for identification of accidental sample mix-up, which is a major issue in re-sequencing studies. In this work, we develop a model to measure the information content of SNPs, so that we can optimize a panel of SNPs that approach the maximal information for discrimination. The analysis shows that as low as 60 optimized SNPs can differentiate the individuals in a population as large as the present world, and only 30 optimized SNPs are in practice sufficient in labeling up to 100 thousand individuals. In the simulated populations of 100 thousand individuals, the average Hamming distances, generated by the optimized set of 30 SNPs are larger than 18, and the duality frequency, is lower than 1 in 10 thousand. This strategy of sample discrimination is proved robust in large sample size and different datasets. The optimized sets of SNPs are designed for Whole Exome Sequencing, and a program is provided for SNP selection, allowing for customized SNP numbers and interested genes. The sample-tagging plan based on this framework will improve re-sequencing projects in terms of reliability and cost-effectiveness.
    Scientific Reports 05/2015; 5:10247. DOI:10.1038/srep10247
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    ABSTRACT: Despite twin and family studies having demonstrated a substantial heritability of individual differences in intelligence, no genetic variants have been robustly associated with normal-range intelligence to date. This is largely ascribed to the high polygenicity of intelligence, i.e., to its being subject to the effects of a large number of genes of individually small effect. Intellectual disability, on the other hand, frequently involves large effects of single genetic mutations, many of which have been identified. The present paper aims to 1) introduce the reader to the current state of genetic intelligence research, including next-generation sequencing and the analysis of rare genetic variants, and 2) examine the possible effects of known disability genes on normal-range intelligence. The rationale for the latter rests on the fact that genetic variants affecting continuous, polygenic traits are often concentrated in the same areas of the genome as those underlying related monogenic phenotypes. Using an existing pool of known intellectual disability genes, we constructed a set of 168 candidate genes for normal-range intelligence, and tested their association with intelligence in 191 individuals (aged 5–18) sampled from the high and low ends of the IQ distribution. In particular, we 1) employed exon sequencing to examine the possible effects of rare genetic variants in the 168 genes, and 2) used polygenic prediction to examine the overall effect of common genetic variants in the candidate gene set in a larger sample (N = 2125, mean age 20.4, SD = 14.1). No significant association between the candidate gene set and intelligence was detected.
    Intelligence 04/2015; 49. DOI:10.1016/j.intell.2014.12.001
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    ABSTRACT: Knowledge of the genes responsible for intellectual disability, particularly autosomal recessive forms, is rapidly expanding. Increasing numbers of the gene show great heterogeneity and supports the hypothesis that human genome may contain over 2000 causative genes with a critical role in brain development. Since 2004, we have applied genome-wide SNP genotyping and next-generation sequencing in large consanguineous Iranian families with intellectual disability, to identify the genes harboring disease-causing mutations. The current study paved the way for identification of responsible genes in two unrelated Iranian families. We found two novel nonsense mutations, p.C77* and p.Q115*, in the calpain catalytic domain of CAPN10, which is a cysteine protease known to be involved in pathogenesis of noninsulin-dependent diabetes mellitus. Another different mutation in this gene (p.S138_R139ins5) has previously been reported in an Iranian family. All of these patients have common clinical features in spite of specific brain structural abnormalities on MRI. Different mutations in CAPN10 have already been found in three independent Iranian families. These results have strongly supported the possible role of CAPN10 in human brain development. Altogether, we proposed CAPN10 as a promising candidate gene for intellectual disability, which should be considered in diagnostic gene panels.
    Archives of Iranian medicine 03/2015; 18(3):179-84.
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    ABSTRACT: Multiple inquiries into the genetic etiology of human traits indicated an overlap between genes underlying monogenic disorders (eg, skeletal growth defects) and those affecting continuous variability of related quantitative traits (eg, height). Extending the idea of a shared genetic basis between a Mendelian disorder and a classic polygenic trait, we performed an association study to examine the effect of 43 genes implicated in autosomal recessive cognitive disorders on intelligence in an unselected Dutch population (N=1316). Using both single-nucleotide polymorphism (SNP)- and gene-based association testing, we detected an association between intelligence and the genes of interest, with genes ELP2, TMEM135, PRMT10, and RGS7 showing the strongest associations. This is a demonstration of the relevance of genes implicated in monogenic disorders of intelligence to normal-range intelligence, and a corroboration of the utility of employing knowledge on monogenic disorders in identifying the genetic variability underlying complex traits.European Journal of Human Genetics advance online publication, 25 February 2015; doi:10.1038/ejhg.2015.3.
    European journal of human genetics: EJHG 02/2015; DOI:10.1038/ejhg.2015.3
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    ABSTRACT: We report on Dutch and Iranian families with affected individuals who present with moderate to severe intellectual disability and additional phenotypes including progressive tremor, speech impairment, and behavioral problems in certain individuals. A combination of exome sequencing and homozygosity mapping revealed homozygous mutations c.484G>A (p.Gly162Arg) and c.1898C>G (p.Pro633Arg) in SLC6A17. SLC6A17 is predominantly expressed in the brain, encodes a synaptic vesicular transporter of neutral amino acids and glutamate, and plays an important role in the regulation of glutamatergic synapses. Prediction programs and 3D modeling suggest that the identified mutations are deleterious to protein function. To directly test the functional consequences, we investigated the neuronal subcellular localization of overexpressed wild-type and mutant variants in mouse primary hippocampal neuronal cells. Wild-type protein was present in soma, axons, dendrites, and dendritic spines. p.Pro633Arg altered SLC6A17 was found in soma and proximal dendrites but did not reach spines. p.Gly162Arg altered SLC6A17 showed a normal subcellular distribution but was associated with an abnormal neuronal morphology mainly characterized by the loss of dendritic spines. In summary, our genetic findings implicate homozygous SLC6A17 mutations in autosomal-recessive intellectual disability, and their pathogenic role is strengthened by genetic evidence and in silico and in vitro functional analyses. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 02/2015; 96(3). DOI:10.1016/j.ajhg.2015.01.010
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    ABSTRACT: X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4-/- mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.Molecular Psychiatry advance online publication, 3 February 2015; doi:10.1038/mp.2014.193.
    Molecular Psychiatry 02/2015; advance online publication. DOI:10.1038/mp.2014.193
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    ABSTRACT: Next-generation sequencing has greatly accelerated the search for disease-causing defects, but even for experts the data analysis can be a major challenge. To facilitate the data processing in a clinical setting, we have developed a novel Medical Re-sequencing Analysis Pipeline (MERAP). MERAP assesses the quality of sequencing, and has optimized capacity for calling variants, including Single Nucleotide Variants, insertions and deletions, Copy Number Variation, and other structural variants. MERAP identifies polymorphic and known causal variants by filtering against public-domain databases, and flags non-synonymous and splice-site changes. MERAP uses a logistic model to estimate the causal likelihood of a given missense variant. MERAP considers the relevant information such as phenotype and interaction with known disease-causing genes. MERAP compares favorably with GATK, one of the widely used tools, because of its higher sensitivity for detecting indels, its easy installation, and its economical use of computational resources. Upon testing more than 1200 individuals with mutations in known and novel disease genes, MERAP proved highly reliable, as illustrated here for 5 families with disease-causing variants. We believe that the clinical implementation of MERAP will expedite the diagnostic process of many disease-causing defects.This article is protected by copyright. All rights reserved
    Human Mutation 12/2014; 35(12). DOI:10.1002/humu.22695
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    ABSTRACT: Variants in CUL4B are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from eleven families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all non-truncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development, ventriculomegaly and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.
    Human Mutation 11/2014; DOI:10.1002/humu.22718
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    ABSTRACT: In the context of a comprehensive research project, investigating novel autosomal recessive intellectual disability (ARID) genes, linkage analysis based on autozygosity mapping helped identify an intellectual disability locus on Chr.12q24, in an Iranian family (LOD score=3.7). Next-generation sequencing (NGS) following exon enrichment in this novel interval, detected a nonsense mutation (p.Q1010*) in the CLIP1 gene. CLIP1 encodes a member of microtubule (MT) plus-end tracking proteins, which specifically associates with the ends of growing MTs. These proteins regulate MT dynamic behavior and are important for MT-mediated transport over the length of axons and dendrites. As such, CLIP1 may have a role in neuronal development. We studied lymphoblastoid and skin fibroblast cell lines established from healthy and affected patients. RT-PCR and western blot analyses showed the absence of CLIP1 transcript and protein in lymphoblastoid cells derived from affected patients. Furthermore, immunofluorescence analyses showed MT plus-end staining only in fibroblasts containing the wild-type (and not the mutant) CLIP1 protein. Collectively, our data suggest that defects in CLIP1 may lead to ARID.European Journal of Human Genetics advance online publication, 26 February 2014; doi:10.1038/ejhg.2014.13.
    European journal of human genetics: EJHG 02/2014; 23(3). DOI:10.1038/ejhg.2014.13
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    ABSTRACT: X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (-83% in gray and -79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (-50% to -33% in gray and -45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.
    11/2013; DOI:10.1007/8904_2013_261
  • Luciana Musante, H Hilger Ropers
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    ABSTRACT: Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elucidation has lagged behind. Here we review recent progress in this field, show that ARID is not rare even in outbred Western populations, and discuss the prospects for improving its diagnosis and prevention.
    Trends in Genetics 10/2013; 30(1). DOI:10.1016/j.tig.2013.09.008
  • 2013 International Meeting for Autism Research; 05/2013
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    ABSTRACT: BACKGROUND: Molecular diagnostics can resolve locus heterogeneity underlying clinical phenotypes that may otherwise be co-assigned as a specific syndrome based on shared clinical features, as well as associate phenotypically diverse diseases to a single locus through allelic affinity. Here we describe a novel syndrome, likely caused by de novo truncating mutations in ASXL3, which shares characteristics with Bohring-Opitz syndrome, a disease associated with de novo truncating mutations in ASXL1. METHODS: We used whole genome and whole exome sequencing to interrogate the genomes of 4 subjects with an undiagnosed syndrome. RESULTS: Using genome wide sequencing we identified heterozygous, de novo truncating mutations in ASXL3, a transcriptional repressor related to ASXL1, in four unrelated probands. We found that these probands shared similar phenotypes including severe feeding difficulties, failure-to-thrive and neurologic abnormalities with significant developmental delay. Further, they showed less phenotypic overlap with patients who had de novo truncating mutations in ASXL1. CONCLUSION: We have identified truncating mutations in ASXL3 as the likely cause of a novel syndrome with phenotypic overlap with Bohring-Opitz syndrome.
    Genome Medicine 02/2013; 5(2):11. DOI:10.1186/gm415
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    ABSTRACT: With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(∗)] and c.1114C>T [p.Gln372(∗)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(∗)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development.
    The American Journal of Human Genetics 04/2012; 90(5):847-55. DOI:10.1016/j.ajhg.2012.03.021
  • Clinical Genetics 04/2012; DOI:10.1111/j.1399-0004.2012.01880.x
  • American Journal of Medical Genetics 03/2012;
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    ABSTRACT: During the past years, significant advances have been made in our understanding of the development of the human brain, and much of this knowledge comes from genetic studies of disorders associated with abnormal brain development. We employed array-comparative genomic hybridization (CGH) to investigate copy number variants (CNVs) in a cohort of 169 patients with various structural brain malformations including lissencephaly, polymicrogyria, focal cortical dysplasia, and corpus callosum agenesis. The majority of the patients had intellectual disabilities (ID) and suffered from symptomatic epilepsy. We detected at least one rare CNV in 38 patients (22.5%). All genes located within the rare CNVs were subjected to enrichment analysis for specific Gene Ontology Terms or Kyoto Encyclopedia of Genes and Genomes pathways and to protein-protein network analysis. Based on these analyses, we propose that genes involved in "axonal transport," "cation transmembrane transporter activity," and the "c-Jun N-terminal kinase (JNK) cascade" play a significant role in the etiology of brain malformations. This is to the best of our knowledge the first systematic study of CNVs in patients with structural brain malformations and our data show that CNVs play an important role in the etiology of these malformations, either as direct causes or as genetic risk factors.
    Human Mutation 12/2011; 32(12):1427-35. DOI:10.1002/humu.21585
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    ABSTRACT: Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.
    Nature 09/2011; 478(7367):57-63. DOI:10.1038/nature10423
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    ABSTRACT: The genetic variants leading to impairment of intellectual performance are highly diverse and are still poorly understood. ST3GAL3 encodes the Golgi enzyme β-galactoside-α2,3-sialyltransferase-III that in humans predominantly forms the sialyl Lewis a epitope on proteins. ST3GAL3 resides on chromosome 1 within the MRT4 locus previously identified to associate with nonsyndromic autosomal recessive intellectual disability. We searched for the disease-causing mutations in the MRT4 family and a second independent consanguineous Iranian family by using a combination of chromosome sorting and next-generation sequencing. Two different missense changes in ST3GAL3 cosegregate with the disease but were absent in more than 1000 control chromosomes. In cellular and biochemical test systems, these mutations were shown to cause ER retention of the Golgi enzyme and drastically impair ST3Gal-III functionality. Our data provide conclusive evidence that glycotopes formed by ST3Gal-III are prerequisite for attaining and/or maintaining higher cognitive functions.
    The American Journal of Human Genetics 09/2011; 89(3):407-14. DOI:10.1016/j.ajhg.2011.08.008
  • The American Journal of Human Genetics 08/2011; 89(2). DOI:10.1016/j.ajhg.2011.07.019

Publication Stats

11k Citations
1,999.62 Total Impact Points

Institutions

  • 1996–2015
    • Max Planck Institute for Molecular Genetics
      • Department of Human Molecular Genetics
      Berlín, Berlin, Germany
    • Uppsala University
      Uppsala, Uppsala, Sweden
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2007
    • Max Planck Institute for Informatics
      Saarbrücken, Saarland, Germany
  • 2003
    • Catholic University of Louvain
      Лувен-ла-Нев, Walloon, Belgium
  • 1990–1999
    • Radboud University Medical Centre (Radboudumc)
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
    • Royal Adelaide Hospital
      • Department of Cytogenetics and Molecular Genetics
      Tarndarnya, South Australia, Australia
  • 1988–1997
    • The John F. Kennedy Institute, Denmark
      Glostrup, Capital Region, Denmark
  • 1993
    • University of Mississippi
      • Department of Pediatrics
      Mississippi, United States
    • Princeton University
      Princeton, New Jersey, United States
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1992
    • University of Ruhuna
      Матара, Southern, Sri Lanka
  • 1987–1990
    • Radboud University Nijmegen
      • Department of Human Genetics
      Nymegen, Gelderland, Netherlands
  • 1989
    • The University of Western Ontario
      London, Ontario, Canada
  • 1985–1988
    • University of Oxford
      Oxford, England, United Kingdom
  • 1986
    • ITH Nijmegen
      Nymegen, Gelderland, Netherlands
  • 1976–1985
    • University of Freiburg
      • Institute of Human Genetics
      Freiburg, Baden-Württemberg, Germany
  • 1982–1984
    • Center for Human Genetics Freiburg
      Freiburg, Baden-Württemberg, Germany
  • 1983
    • University of Washington Seattle
      • Department of Medicine
      Seattle, Washington, United States