Ian D Krantz

University of Pennsylvania, Filadelfia, Pennsylvania, United States

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Publications (137)848.48 Total impact

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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; DOI:10.1002/humu.22786 · 5.05 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.
  • American Journal of Medical Genetics Part A 03/2015; DOI:10.1002/ajmg.a.36946 · 2.30 Impact Factor
  • European journal of human genetics: EJHG 12/2014; DOI:10.1038/ejhg.2014.270 · 3.56 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 11/2014; DOI:10.1002/ajmg.c.31423 · 3.54 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 · 29.65 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 · 3.53 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 · 1.72 Impact Factor
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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 · 1.49 Impact Factor
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    ABSTRACT: 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.
    BMC Bioinformatics 07/2014; 15(1):248. DOI:10.1186/1471-2105-15-248 · 2.67 Impact Factor
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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; DOI:10.1007/s10577-014-9431-y · 2.69 Impact Factor
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is the prototype for the cohesinopathy disorders that have mutations in genes associated with the cohesin subunit in all cells. Roberts syndrome is the next most common cohesinopathy. In addition to the developmental implications of cohesin biology, there is much translational and basic research, with progress towards potential treatment for these conditions. Clinically, there are many issues in CdLS faced by the individual, parents and caretakers, professionals, and schools. The following abstracts are presentations from the 5th Cornelia de Lange Syndrome Scientific and Educational Symposium on June 20-21, 2012, in conjunction with the Cornelia de Lange Syndrome Foundation National Meeting, Lincolnshire, IL. The research committee of the CdLS Foundation organizes the meeting, reviews and accepts abstracts and subsequently disseminates the information to the families. In addition to the basic science and clinical discussions, there were educationally-focused talks related to practical aspects of management at home and in school. AMA CME credits were provided by Greater Baltimore Medical Center, Baltimore, MD. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 06/2014; 164(6). DOI:10.1002/ajmg.a.36417 · 2.30 Impact Factor
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    ABSTRACT: As more research studies incorporate next-generation sequencing (including whole-genome or whole-exome sequencing), investigators and institutional review boards face difficult questions regarding which genomic results to return to research participants and how. An American College of Medical Genetics and Genomics 2013 policy paper suggesting that pathogenic mutations in 56 specified genes should be returned in the clinical setting has raised the question of whether comparable recommendations should be considered in research settings. The Clinical Sequencing Exploratory Research (CSER) Consortium and the Electronic Medical Records and Genomics (eMERGE) Network are multisite research programs that aim to develop practical strategies for addressing questions concerning the return of results in genomic research. CSER and eMERGE committees have identified areas of consensus regarding the return of genomic results to research participants. In most circumstances, if results meet an actionability threshold for return and the research participant has consented to return, genomic results, along with referral for appropriate clinical follow-up, should be offered to participants. However, participants have a right to decline the receipt of genomic results, even when doing so might be viewed as a threat to the participants' health. Research investigators should be prepared to return research results and incidental findings discovered in the course of their research and meeting an actionability threshold, but they have no ethical obligation to actively search for such results. These positions are consistent with the recognition that clinical research is distinct from medical care in both its aims and its guiding moral principles.
    The American Journal of Human Genetics 05/2014; DOI:10.1016/j.ajhg.2014.04.009 · 11.20 Impact Factor
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    ABSTRACT: Pallister-Killian syndrome (PKS) is a sporadic multisystem genetic diagnosis characterized by facial dysmorphia, variable developmental delay and intellectual impairment, hypotonia, hearing loss, seizures, differences in skin pigmentation, temporal alopecia, diaphragmatic hernia, congenital heart defects, and other systemic abnormalities. Although congenital heart defects have been described in association with PKS, the full spectrum of heart disease is still not entirely known. Here, we describe the pattern of cardiac findings of 81 probands with PKS who have had at least one cardiac evaluation, demonstrating structural heart difference in 37% of our cohort (n = 30). Septal defects such as atrial or ventricular septal defects (n = 12) were the most commonly seen congenital heart differences. Additional findings included the occasional occurrence of bicuspid aortic valve, aortic dilatation, and cardiac hypertrophy/cardiomyopathy. We suggest cardiac evaluation for all individuals with PKS at the time of diagnosis as well as subsequent longitudinal follow-up to monitor for the development of cardiomyopathy and aortic dilatation. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 05/2014; 164(5). DOI:10.1002/ajmg.a.36413 · 2.30 Impact Factor
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    ABSTRACT: The cohesin complex is crucial for chromosome segregation during mitosis and has recently also been implicated in transcriptional regulation and chromatin architecture. The NIPBL protein is required for the loading of cohesin onto chromatin, but how and where cohesin is loaded in vertebrate cells is unclear. Heterozygous mutations of NIPBL were found in 50% of the cases of Cornelia de Lange Syndrome (CdLS), a human developmental syndrome with a complex phenotype. However, no defects in the mitotic function of cohesin have been observed so far and the links between NIPBL mutations and the observed developmental defects are unclear. We show that NIPBL binds to chromatin in somatic cells with a different timing than cohesin. Further, we observe that high-affinity NIPBL binding sites localize to different regions than cohesin and almost exclusively to the promoters of active genes. NIPBL or cohesin knockdown reduce transcription of these genes differently, suggesting a cohesin-independent role of NIPBL for transcription. Motif analysis and comparison to published data show that NIPBL co-localizes with a specific set of other transcription factors. In cells derived from CdLS patients NIPBL binding levels are reduced and several of the NIPBL-bound genes have previously been observed to be mis-expressed in CdLS. In summary, our observations indicate that NIPBL mutations might cause developmental defects in different ways. First, defects of NIPBL might lead to cohesin-loading defects and thereby alter gene expression and second, NIPBL deficiency might affect genes directly via its role at the respective promoters.
    PLoS Genetics 02/2014; 10(2):e1004153. DOI:10.1371/journal.pgen.1004153 · 8.17 Impact Factor
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    ABSTRACT: Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for more than 80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here we report a cohort of 35 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss of function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
    Human Molecular Genetics 01/2014; DOI:10.1093/hmg/ddu002 · 6.68 Impact Factor
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    ABSTRACT: Cornelia de Lange Syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. Clinical features include growth retardation, intellectual disability, limb defects, typical facial dysmorphism and other systemic involvement. The increased understanding of the genetic basis of CdLS has led to diagnostic improvement and expansion of the phenotype. Mutations in five genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8), all regulators or structural components of cohesin, have been identified. Approximately 60% of CdLS cases are due to NIPBL mutations, 5% caused by mutations in SMC1A, RAD21 and HDAC8 and one proband was found to carry a mutation in SMC3. To date 311 CdLS-causing mutations are known including missense, nonsense, small deletions and insertions, splice site mutations and genomic rearrangements. Phenotypic variability is seen both intra- and intergenically. This paper reviews the spectrum of CdLS mutations with a particular emphasis on their correlation to the clinical phenotype. This article is protected by copyright. All rights reserved.
    Human Mutation 12/2013; 34(12). DOI:10.1002/humu.22430 · 5.05 Impact Factor
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    ABSTRACT: Hearing impairment affects 1 in 650 newborns, making it the most common congenital sensory impairment. Autosomal recessive nonsyndromic sensorineural hearing impairment (ARNSHI) comprises 80% of familial hearing impairment cases. Mutations in GJB2 account for a significant number of ARNSHI (and up to 50% of documented recessive (e.g., more than 1 affected sibling) hearing impairment in some populations). Mutations in the GJB2 gene are amongst the most common causes of hearing impairment in populations of various ethnic backgrounds. Two mutations of this gene, 35delG and 167delT, account for the majority of reported mutations in Caucasian populations, especially those of Mediterranean and Ashkenazi Jewish background. The 235delC mutation is most prevalent in East Asian populations. Some mutations are of less well-characterized significance. The V37I missense mutation, common in Asian populations, was initially described as a polymorphism and later as a potentially pathogenic mutation. We report here on 15 unrelated individuals with ARNSHI and homozygosity for the V37I GJB2 missense mutation. Nine individuals are of Chinese ancestry, two are of unspecified Asian descent, one is of Japanese descent, one individual is of Vietnamese ancestry, one of Philippine background and one of Italian and Cuban/Caucasian background. Homozygosity for the V37I GJB2 mutation may be a more common pathogenic missense mutation in Asian populations, resulting in mild to moderate sensorineural hearing impairment. We report a presumed haplotype block specific to East Asian individuals with the V37I mutation encompassing the GJB2 gene that may account for the high prevalence in East Asian populations. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2013; 161(9). DOI:10.1002/ajmg.a.36042 · 2.30 Impact Factor
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    ABSTRACT: This report describes an algorithm developed to predict the pathogenicity of copy number variants (CNVs) in large sample cohorts. CNVs (genomic deletions and duplications) are found in healthy individuals and in individuals with genetic diagnoses, and differentiation of these two classes of CNVs can be challenging and usually requires extensive manual curation. We have developed PECONPI, an algorithm to assess the pathogenicity of CNVs based on gene content and CNV frequency. This software was applied to a large cohort of patients with genetically heterogeneous non-syndromic hearing loss to score and rank each CNV based on its relative pathogenicity. Of 636 individuals tested, we identified the likely underlying etiology of the hearing loss in 14 (2%) of the patients (1 with a homozygous deletion, 7 with a deletion of a known hearing loss gene and a point mutation on the trans allele and 6 with a deletion larger than 1 Mb). We also identified two probands with smaller deletions encompassing genes that may be functionally related to their hearing loss. The ability of PECONPI to determine the pathogenicity of CNVs was tested on a second genetically heterogenous cohort with congenital heart defects (CHDs). It successfully identified a likely etiology in 6 of 355 individuals (2%). We believe this tool is useful for researchers with large genetically heterogeneous cohorts to help identify known pathogenic causes and novel disease genes. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2013; 161(9). DOI:10.1002/ajmg.a.36038 · 2.30 Impact Factor
  • Thomas P Slavin, Ian Krantz
    American Journal of Medical Genetics Part A 07/2013; 161(7). DOI:10.1002/ajmg.a.35987 · 2.30 Impact Factor

Publication Stats

7k Citations
848.48 Total Impact Points

Institutions

  • 2015
    • University of Pennsylvania
      Filadelfia, Pennsylvania, United States
  • 1997–2015
    • The Children's Hospital of Philadelphia
      • • Division of Human Genetics and Molecular Biology
      • • Department of Pediatrics
      Filadelfia, Pennsylvania, United States
    • Stowers Institute for Medical Research
      Kansas City, Kansas, United States
  • 2009–2013
    • National Research Council
      • • Institute of Neurogenetics and Neuropharmacology IRGB
      • • Institute of Biomedical Technologies ITB
      Roma, Latium, Italy
    • Greenwood Genetic Center
      Greenwood, South Carolina, United States
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2012
    • Cleveland State University
      Cleveland, Ohio, United States
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
  • 2011
    • Universität zu Lübeck
      • Institut für Humangenetik
      Lübeck, Schleswig-Holstein, Germany
  • 2008
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
  • 2007
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States
    • Memorial Sloan-Kettering Cancer Center
      • Department of Psychiatry & Behavioral Sciences
      New York City, NY, United States
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2005
    • Northwestern Memorial Hospital
      Chicago, Illinois, United States
  • 1998
    • William Penn University
      Filadelfia, Pennsylvania, United States