Ian D Krantz

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (158)958.96 Total impact

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    ABSTRACT: Individuals with Cornelia de Lange Syndrome (CdLS) display diverse developmental deficits, including slow growth, multiple limb and organ abnormalities, and intellectual disabilities. Severely-affected individuals most often have dominant loss-of-function mutations in the Nipped-B-Like (NIPBL) gene, and milder cases often have missense or in-frame deletion mutations in genes encoding subunits of the cohesin complex. Cohesin mediates sister chromatid cohesion to facilitate accurate chromosome segregation, and NIPBL is required for cohesin to bind to chromosomes. Individuals with CdLS, however, do not display overt cohesion or segregation defects. Rather, studies in human cells and model organisms indicate that modest decreases in NIPBL and cohesin activity alter the transcription of many genes that regulate growth and development. Sister chromatid cohesion factors, including the Nipped-B ortholog of NIPBL, are also critical for gene expression and development in Drosophila melanogaster. Here we describe how a modest reduction in Nipped-B activity alters growth and neurological function in Drosophila. These studies reveal that Nipped-B heterozygous mutant Drosophila show reduced growth, learning, and memory, and altered circadian rhythms. Importantly, the growth deficits are not caused by changes in systemic growth controls, but reductions in cell number and size attributable in part to reduced expression of myc (diminutive) and other growth control genes. The learning, memory and circadian deficits are accompanied by morphological abnormalities in brain structure. These studies confirm that Drosophila Nipped-B mutants provide a useful model for understanding CdLS, and provide new insights into the origins of birth defects.
    PLoS Genetics 11/2015; 11(11):e1005655. DOI:10.1371/journal.pgen.1005655 · 7.53 Impact Factor
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    ABSTRACT: Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease.
    Molecular cell 09/2015; 59(6). DOI:10.1016/j.molcel.2015.07.033 · 14.02 Impact Factor
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    ABSTRACT: Maternal uniparental disomy of chromosome 20 (UPD(20)mat) has been reported in only four patients, three of whom also had mosaicism for complete or partial trisomy of chromosome 20. We sought to evaluate the clinical significance of isolated UPD(20)mat in eight individuals. We evaluated phenotypic and genomic findings of a series of eight new patients with UPD(20)mat. All eight individuals with UPD(20)mat had intrauterine growth restriction, short stature, and prominent feeding difficulties with failure to thrive. As a common feature, they often required gastric tube feeds. Genomic data in most patients are indicative of UPD as a result of trisomy rescue after meiosis II nondisjunction. We describe the first natural history of the disorder and the results of therapeutic interventions, including the frequent requirement of direct gastric feedings only during the first few years of life, and propose that growth hormone supplementation is probably safe and effective for this condition. We suggest that UPD(20)mat can be regarded as a new imprinting disorder and its identification requires specialized molecular testing, which should be performed in patients with early-onset idiopathic isolated growth failure.Genet Med advance online publication 06 August 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.103.
    Genetics in medicine: official journal of the American College of Medical Genetics 08/2015; DOI:10.1038/gim.2015.103 · 7.33 Impact Factor
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    ABSTRACT: Background: Conditions associated with sudden cardiac arrest/death (SCA/D) in youth often have a genetic etiology. While SCA/D is uncommon, a pro-active family screening approach may identify these inherited structural and electrical abnormalities prior to symptomatic events and allow appropriate surveillance and treatment. This study investigated the diagnostic utility of exome sequencing (ES) by evaluating the capture and coverage of genes related to SCA/D. Methods: Samples from 102 individuals (13 with known molecular etiologies for SCA/D, 30 individuals without known molecular etiologies for SCA/D and 59 with other conditions) were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter. An additional 100 random variants within the targeted genes associated with SCA/D were also selected and evaluated for depth of sequencing and coverage. Although the primary objective was to evaluate the adequacy of depth of sequencing and coverage of targeted SCA/D genes and not for primary diagnosis, all patients who had SCA/D (known or unknown molecular etiologies) were evaluated with the project's variant analysis pipeline to determine if the molecular etiologies could be successfully identified. Results: The majority of exons (97.6 %) were captured and fully covered on average at minimum of 20x sequencing depth. The proportion of unique genomic positions reported within poorly covered exons remained small (4 %). Exonic regions with less coverage reflect the need to enrich these areas to improve coverage. Despite limitations in coverage, we identified 100 % of cases with a prior known molecular etiology for SCA/D, and analysis of an additional 30 individuals with SCA/D but no known molecular etiology revealed a diagnostic answer in 5/30 (17 %). We also demonstrated 95 % of 100 randomly selected reported variants within our targeted genes would have been picked up on ES based on our coverage analysis. Conclusions: ES is a helpful clinical diagnostic tool for SCA/D given its potential to successfully identify a molecular diagnosis, but clinicians should be aware of limitations of available platforms from technical and diagnostic perspectives.
    Human genomics 07/2015; 9(1):15. DOI:10.1186/s40246-015-0038-y · 2.15 Impact Factor
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    ABSTRACT: Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.European Journal of Human Genetics advance online publication, 6 May 2015; doi:10.1038/ejhg.2015.71.
    European journal of human genetics: EJHG 05/2015; 23(11). DOI:10.1038/ejhg.2015.71 · 4.35 Impact Factor
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    ABSTRACT: Pallister-Killian syndrome (PKS) is a multi-system developmental disorder caused by tetrasomy 12p that exhibits tissue-limited mosaicism. Probands with PKS often demonstrate a unique growth profile consisting of macrosomia at birth with deceleration of growth postnatally. We have previously demonstrated that cultured skin fibroblasts from PKS probands have significantly elevated expression of insulin-like growth factor binding protein-2 (IGFBP2). To further evaluate the role of IGFBP2 in PKS, the amount of IGFBP2 secreted from cultured skin fibroblast cell lines and serum IGFBP2 levels were measured in probands with PKS. Approximately 60% of PKS fibroblast cell lines secreted higher levels of IGFBP2 compared to control fibroblasts, although the remaining 40% of PKS samples produced comparable level of IGFBP2 to that of control fibroblasts. Serum IGFBP2 levels were also measured in PKS probands and were elevated in 40% of PKS probands. PKS probands with elevated IGFBP2 manifested with severe postnatal growth retardation. IGFBPs are the family of related proteins that bind IGFs with high affinity and are typically thought to attenuate IGF action. We suggest that elevated IGFBP2 levels might play a role in the growth retardation phenotype of PKS. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; 167(6). DOI:10.1002/ajmg.a.36976 · 2.16 Impact Factor
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    ABSTRACT: Cornelia de Lange Syndrome (CdLS) is the most common example of disorders of the cohesin complex, or cohesinopathies. There are a myriad of clinical issues facing individuals with CdLS, particularly in the neurodevelopmental system, which also have implications for the parents and caretakers, involved professionals, therapists, and schools. Basic research in developmental and cell biology on cohesin is showing significant progress, with improved understanding of the mechanisms and the possibility of potential therapeutics. The following abstracts are presentations from the 6th Cornelia de Lange Syndrome Scientific and Educational Symposium, which took place on June 25-26, 2014, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting in Costa Mesa, CA. The Research Committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts, and subsequently disseminates the information to the families through members of the Clinical Advisory Board. In addition to the scientific and clinical discussions, there were educationally focused talks related to practical aspects of behavior and development. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; 167(6). DOI:10.1002/ajmg.a.37056 · 2.16 Impact Factor
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    ABSTRACT: Biliary atresia (BA) is a pediatric cholangiopathy with unknown etiology occurring in isolated and syndromic forms. Laterality defects affecting the cardiovascular and gastrointestinal systems are the most common features present in syndromic BA. Most cases are sporadic, although reports of familial cases have led to the hypothesis of genetic susceptibility in some patients. We identified a child with BA, malrotation, and interrupted inferior vena cava whose father presented with situs inversus, polysplenia, panhypopituitarism, and mildly dysmorphic facial features. Chromosomal microarray analysis demonstrated a 277kb heterozygous deletion on chromosome 20 which included a single gene, FOXA2, in the proband and her father. This deletion was confirmed to be de novo in the father. The proband and her father share a common diagnosis of heterotaxy, but they also each presented with a variety of other issues. Further genetic screening revealed that the proband carried an additional protein-altering polymorphism (rs1904589; p.His165Arg) in the NODAL gene that is not present in the father, and this variant has been shown to decrease expression of the gene. As FOXA2 can be a regulator of NODAL expression, we propose that haploinsufficiency for FOXA2 combined with a decreased expression of NODAL is the likely cause for syndromic BA in this proband. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Human Mutation 03/2015; 36(6). DOI:10.1002/humu.22786 · 5.14 Impact Factor
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    ABSTRACT: Transcriptional elongation is critical for gene expression regulation during embryogenesis. The super elongation complex (SEC) governs this process by mobilizing paused RNA polymerase II (RNAP2). Using exome sequencing, we discovered missense mutations in AFF4, a core component of the SEC, in three unrelated probands with a new syndrome that phenotypically overlaps Cornelia de Lange syndrome (CdLS) that we have named CHOPS syndrome (C for cognitive impairment and coarse facies, H for heart defects, O for obesity, P for pulmonary involvement and S for short stature and skeletal dysplasia). Transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated similar alterations of genome-wide binding of AFF4, cohesin and RNAP2 in CdLS and CHOPS syndrome. Direct molecular interaction of the SEC, cohesin and RNAP2 was demonstrated. These data support a common molecular pathogenesis for CHOPS syndrome and CdLS caused by disturbance of transcriptional elongation due to alterations in genome-wide binding of AFF4 and cohesin.
    Nature Genetics 03/2015; 47(4). DOI:10.1038/ng.3229 · 29.35 Impact Factor

  • American Journal of Medical Genetics Part A 03/2015; 167(4). DOI:10.1002/ajmg.a.36946 · 2.16 Impact Factor
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is characterized by facial dysmorphism, growth failure, intellectual disability, limb malformations and multiple organ involvement. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), account for at least 70% of patients with CdLS or CdLS-like phenotypes. To date, only the clinical features from a single CdLS patient with SMC3 mutation has been published. Here, we report the efforts of an international research and clinical collaboration to provide clinical comparison of sixteen patients with CdLS-like features caused by mutations in SMC3. Modelling of the mutation effects on protein structure suggests a dominant-negative effect on the multimeric cohesin complex. When compared to typical CdLS, many SMC3-associated phenotypes are also characterized by postnatal microcephaly but with a less distinctive craniofacial appearance, a milder prenatal growth retardation that worsens in childhood, few congenital heart defects and an absence of limb deficiencies. While most mutations are unique, two unrelated affected individuals shared the same mutation but presented with different phenotypes. This work confirms that de novo SMC3 mutations account for ∼1-2% of CdLS-like phenotypes. This article is protected by copyright. All rights reserved.
    Human Mutation 02/2015; DOI:10.1002/humu.22761 · 5.14 Impact Factor
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    ABSTRACT: The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
    European journal of human genetics: EJHG 12/2014; 23(10). DOI:10.1038/ejhg.2014.270 · 4.35 Impact Factor
  • Kosuke Izumi · Ian D Krantz ·
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    ABSTRACT: Pallister-Killian syndrome (PKS) is characterized by craniofacial dysmorphism, pigmentary skin anomalies, congenital heart defects, congenital diaphragmatic hernia, hypotonia, intellectual disability, and epilepsy. PKS is caused by extra copies of chromosome 12p, most characteristically a marker isochromosome 12p that demonstrates tissue-limited mosaicism. The cytogenetic diagnosis of PKS is often cumbersome due to the absence of the isochromosome in lymphocytes requiring sampling of other tissues. The mechanism by which the isochromosome 12p results in the constellation of multiple congenital anomalies remains largely unknown. In this review, we summarize the background of, and recent advances in, the clinical and molecular understanding of PKS. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 12/2014; 166(4). DOI:10.1002/ajmg.c.31423 · 3.91 Impact Factor
  • Ian D. Krantz · John M. Opitz ·

    American Journal of Medical Genetics Part C Seminars in Medical Genetics 12/2014; 166(4). DOI:10.1002/ajmg.c.31422 · 3.91 Impact Factor
  • Ian D Krantz ·
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    ABSTRACT: A new study identifies homozygous missense mutations in SGOL1, which encodes a component of the cohesin complex, in a newly described disorder termed Chronic Atrial and Intestinal Dysrhythmia (CAID) syndrome. These findings implicate cohesin in the regulation of intrinsic cardiac and intestinal rhythm and further expand the growing group of disorders termed the cohesinopathies.
    Nature Genetics 10/2014; 46(11):1157-8. DOI:10.1038/ng.3123 · 29.35 Impact Factor
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    ABSTRACT: Pallister Killian syndrome (OMIM: # 601803) is a rare multisystem disorder typically caused by tissue limited mosaic tetrasomy of chromosome 12p (isochromosome 12p). The clinical manifestations of Pallister Killian syndrome are variable with the most common findings including craniofacial dysmorphia, hypotonia, cognitive impairment, hearing loss, skin pigmentary differences and epilepsy. Isochromosome 12p is identified primarily in skin fibroblast cultures and in chorionic villus and amniotic fluid cell samples and may be identified in blood lymphocytes during the neonatal and early childhood period. We performed genomic expression profiling correlated with interphase fluorescent in situ hybridization and single nucleotide polymorphism array quantification of degree of mosaicism in fibroblasts from 17 Caucasian probands with Pallister Killian syndrome and 9 healthy age, gender and ethnicity matched controls. We identified a characteristic profile of 354 (180 up- and 174 down-regulated) differentially expressed genes in Pallister Killian syndrome probands and supportive evidence for a Pallister Killian syndrome critical region on 12p13.31. The differentially expressed genes were enriched for developmentally important genes such as homeobox genes. Among the differentially expressed genes, we identified several genes whose misexpression may be associated with the clinical phenotype of Pallister Killian syndrome such as downregulation of ZFPM2, GATA6 and SOX9, and overexpression of IGFBP2.
    PLoS ONE 10/2014; 9(10):e108853. DOI:10.1371/journal.pone.0108853 · 3.23 Impact Factor
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    ABSTRACT: Objectives: Exome sequencing (ES) is a single platform test that screens the exons of nearly all genes and is increasingly being used in the clinical diagnosis of hearing loss due to the large number of genes etiologically implicated. Our goals were to explore (1) the utility and limitations of ES for diagnosis in children with sensorineural hearing loss (SNHL) and (2) its ability to discover novel genes causing SNHL.
    Otolaryngology Head and Neck Surgery 09/2014; 151(1 Suppl):P247-P247. DOI:10.1177/0194599814541629a347 · 2.02 Impact Factor
  • Kosuke Izumi · Sarah Noon · Alisha Wilkens · Ian D Krantz ·
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    ABSTRACT: Exome sequencing enables us to screen most of the protein coding genes in an unbiased way, this technique represents an ideal tool to identify previously under- or unappreciated phenotypes associated with known disease genes and genetic disorders. Here we present an illustrative case that required exome sequencing to identify a genetic alteration associated with the clinical features. The phenotype of the proband included heterotaxy, double outlet right ventricle, common atrioventricular canal, total anomalous pulmonary venous connection, asplenia, failure to thrive and short stature. Exome sequencing demonstrated a frameshift mutation c.397_400del (p.P133GfsTer 42) in NKX2.5. Although a single previous case of heterotaxy was reported in a large familial case of NKX2.5, heterotaxy is not clinically appreciated to be a part of the phenotypic spectrum associated with NKX2.5 mutations. This case report demonstrates the utility of exome sequencing in expanding a phenotypic spectrum of a known Mendelian disorder. We predict that this type of unexpected identification of mutations in known-disease associated genes in patients with atypical or expanded phenotypes will occur with increasing frequency as the use of exome and genome sequencing become more common tools in diagnosing patients with syndromic and non-syndromic foms of structural birth defects.
    European Journal of Medical Genetics 08/2014; 57(10). DOI:10.1016/j.ejmg.2014.08.003 · 1.47 Impact Factor
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    ABSTRACT: Background Exome sequencing is a promising method for diagnosing patients with a complex phenotype. However, variant interpretation relative to patient phenotype can be challenging in some scenarios, particularly clinical assessment of rare complex phenotypes. Each patient’s sequence reveals many possibly damaging variants that must be individually assessed to establish clear association with patient phenotype. To assist interpretation, we implemented an algorithm that ranks a given set of genes relative to patient phenotype. The algorithm orders genes by the semantic similarity computed between phenotypic descriptors associated with each gene and those describing the patient. Phenotypic descriptor terms are taken from the Human Phenotype Ontology (HPO) and semantic similarity is derived from each term’s information content. Results Model validation was performed via simulation and with clinical data. We simulated 33 Mendelian diseases with 100 patients per disease. We modeled clinical conditions by adding noise and imprecision, i.e. phenotypic terms unrelated to the disease and terms less specific than the actual disease terms. We ranked the causative gene against all 2488 HPO annotated genes. The median causative gene rank was 1 for the optimal and noise cases, 12 for the imprecision case, and 60 for the imprecision with noise case. Additionally, we examined a clinical cohort of subjects with hearing impairment. The disease gene median rank was 22. However, when also considering the patient’s exome data and filtering non-exomic and common variants, the median rank improved to 3. Conclusions Semantic similarity can rank a causative gene highly within a gene list relative to patient phenotype characteristics, provided that imprecision is mitigated. The clinical case results suggest that phenotype rank combined with variant analysis provides significant improvement over the individual approaches. We expect that this combined prioritization approach may increase accuracy and decrease effort for clinical genetic diagnosis. Electronic supplementary material The online version of this article (doi:10.1186/1471-2105-15-248) contains supplementary material, which is available to authorized users.
    BMC Bioinformatics 07/2014; 15(1):248. DOI:10.1186/1471-2105-15-248 · 2.58 Impact Factor
  • Kosuke Izumi · Zhe Zhang · Maninder Kaur · Ian D Krantz ·
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    ABSTRACT: Pallister-Killian syndrome is a multisystem sporadic genetic diagnosis characterized by facial dysmorphia, variable developmental delay and intellectual impairment, hypotonia, seizures, diaphragmatic hernia, and other systemic abnormalities. Pallister-Killian syndrome is typically caused by the presence of a supernumerary isochromosome that is always present in a tissue limited mosaic pattern, resulting in tetrasomy 12p due to the two extra copies of 12p. We evaluated the potential contribution of microRNAs located on 12p to the pathogenesis of Pallister-Killian syndrome phenotype. Using skin fibroblast cell lines from 13 probands with Pallister-Killian syndrome and 5 normal matched controls, the expression level of 5 microRNAs located on 12p and their target gene mRNA levels were measured. All measured micro RNAs located on 12p were overexpressed in Pallister-Killian syndrome fibroblasts, although the fold difference of the expression level was lower than copy number differences. Among the five microRNAs, miR-1244 had the highest fold difference. Many of computer-predicted target genes of miR-1244 were downregulated in Pallister-Killian syndrome skin fibroblasts. In particular, expression levels of MEIS2 and UQCRB were significantly decreased in Pallister-Killian syndrome samples, and an inverse linear correlation was seen between the level of miR-1244 and MEIS2 and UQCRB expression levels. Since many of computer-predicted miR-1244 target genes play roles in transcriptional regulation, overexpression of miR-1244 due to tetrasomy 12p may contribute to the pleiotropic phenotype of Pallister-Killian syndrome by modulating its downstream target genes including MEIS2 and UQCRB.
    Chromosome Research 07/2014; 22(4). DOI:10.1007/s10577-014-9431-y · 2.48 Impact Factor

Publication Stats

9k Citations
958.96 Total Impact Points


  • 2015
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States
  • 1998-2015
    • The Children's Hospital of Philadelphia
      • • Center for Applied Genomics
      • • Division of Human Genetics and Molecular Biology
      • • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
  • 1998-2011
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 2007
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States
  • 1997
    • Stowers Institute for Medical Research
      Kansas City, Kansas, United States