Ian D Krantz

The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

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Publications (132)828.21 Total impact

  • European journal of human genetics: EJHG 12/2014; · 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; · 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. · 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. · 3.53 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; · 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. · 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; · 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 02/2014; · 2.30 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 02/2014; · 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. · 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; · 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 08/2013; · 5.05 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; · 2.30 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 07/2013; · 2.30 Impact Factor
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    ABSTRACT: OBJECTIVES:Cornelia de Lange syndrome (CdLS) is a genetic syndrome with multisystem abnormalities. Infections are a significant cause of morbidity and mortality. The goals of our study were to identify the frequency and types of infections in CdLS and to determine if underlying immunodeficiency contributes to the clinical spectrum of this syndrome.METHODS:We assessed infectious histories in 45 patients with CdLS and evaluated conventional immunologic screening tests in 27 patients. Among these 27 subjects, additional phenotypic enumeration of T-cell subsets, expression of activation markers in T cells, and production of cytokines in response to T-cell stimulants were studied in 12 CdLS subjects compared with 12 normal case control subjects.RESULTS:Recurrent infections were reported at high frequency in CdLS patients and included chronic ear infections (53%), chronic viral respiratory infections (46%), pneumonia (42%), sinus infections (33%), oral candidiasis (13%), sepsis (6%), and bacterial skin infections (4%). Full immune evaluation in 27 subjects led to identification of 9 cases of antibody deficiency syndrome in patients with severe forms of CdLS. Subjects with CdLS had decreased percentages of T regulatory cells and T follicular helper cells compared with normal control subjects (P < .05).CONCLUSIONS:This study identified for the first time a high frequency of antibody deficiency in CdLS subjects, indicating a critical need for screening and management of immunodeficiency in CdLS patients with a history of well-documented severe or recurrent infections. Furthermore, our results indicate that impaired T-cell populations may be associated with antibody deficiency in CdLS.
    PEDIATRICS 07/2013; · 5.30 Impact Factor
  • Thomas P Slavin, Ian Krantz
    American Journal of Medical Genetics Part A 05/2013; · 2.30 Impact Factor
  • Nature Medicine 05/2013; · 28.05 Impact Factor
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    ABSTRACT: Total anomalous pulmonary venous connection (TAPVC) is a potentially lethal congenital disorder that occurs when the pulmonary veins do not connect normally to the left atrium, allowing mixing of pulmonary and systemic blood. In contrast to the extensive knowledge of arterial vascular patterning, little is known about the patterning of veins. Here we show that the secreted guidance molecule semaphorin 3d (Sema3d) is crucial for the normal patterning of pulmonary veins. Prevailing models suggest that TAPVC occurs when the midpharyngeal endothelial strand (MES), the precursor of the common pulmonary vein, does not form at the proper location on the dorsal surface of the embryonic common atrium. However, we found that TAPVC occurs in Sema3d mutant mice despite normal formation of the MES. In these embryos, the maturing pulmonary venous plexus does not anastomose uniquely with the properly formed MES. In the absence of Sema3d, endothelial tubes form in a region that is normally avascular, resulting in aberrant connections. Normally, Sema3d provides a repulsive cue to endothelial cells in this area, establishing a boundary. Sequencing of SEMA3D in individuals with anomalous pulmonary veins identified a phenylalanine-to-leucine substitution that adversely affects SEMA3D function. These results identify Sema3d as a crucial pulmonary venous patterning cue and provide experimental evidence for an alternate developmental model to explain abnormal pulmonary venous connections.
    Nature medicine 05/2013; · 28.05 Impact Factor
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    ABSTRACT: Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome is an X-linked dominant condition characterized by the triad of ichthyosis follicularis, alopecia, and photophobia caused by mutations in the MBTPS2 gene. Herein we describe a proband with IFAP syndrome with mild cutaneous manifestations and a novel MBTPS2 mutation in the N-terminal transmembrane domain.
    Pediatric Dermatology 04/2013; · 1.52 Impact Factor
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    ABSTRACT: This report describes a three generation family with late onset bilateral sensorineural hearing impairment (BLSNHI) and tinnitus in which a novel mutation in the COCH gene was identified after a genome-wide linkage approach. The COCH gene is one of the few genes clinically examined when investigating the etiology of autosomal dominant late onset hearing impairment. Initially mutations in the COCH gene were only reported in exons 4 and 5, coding for the LCCL protein domain. More recently, additional mutations have been identified in exon 12, the only mutations identified outside of the LCCL domain. Currently clinical genetic testing for the COCH gene primarily focuses on identifying mutations in these three exons. In this study, we identify a novel mutation in the COCH gene in exon 11, which, like the exon 12 mutations, falls within the vWFA2 protein domain. This finding reinforces the need for clinical genetic screening of the COCH gene to be expanded beyond the current limited exon screening, as there is now more evidence to support that mutations in other areas of this gene are also causative of a similar form of late onset BLSNHI.
    American journal of otolaryngology 01/2013; · 1.08 Impact Factor

Publication Stats

7k Citations
828.21 Total Impact Points


  • 1997–2014
    • The Children's Hospital of Philadelphia
      • • Center for Biomedical Informatics
      • • Department of Pathology and Laboratory Medicine
      • • Department of Pediatrics
      • • Division of Human Genetics and Molecular Biology
      Philadelphia, 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
    • Johns Hopkins University
      • Department of Pathology
      Baltimore, MD, United States
    • Cleveland State University
      Cleveland, Ohio, United States
  • 2011
    • Universität zu Lübeck
      • Institut für Humangenetik
      Lübeck, Schleswig-Holstein, Germany
  • 2008
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2007
    • Memorial Sloan-Kettering Cancer Center
      • Department of Psychiatry & Behavioral Sciences
      New York City, NY, United States
    • Boston Children's Hospital
      Boston, Massachusetts, United States