About

Ian D. Krantz, M.D., is an Emeritus Professor and the Chief of Pediatrics (Human Genetics) at the Children's Hospital of Philadelphia. He is also a faculty member at the Perelman School of Medicine at the University of Pennsylvania. Dr. Krantz directs the Roberts Individualized Medical Genetics Center at CHOP, which facilitates genomic diagnostics across the enterprise and leverages clinical and genomic information for research. His clinical interests focus on dysmorphology and pediatric genetic disorders, with multispecialty clinics for conditions such as Alagille syndrome, Cornelia de Lange syndrome (CdLS), Pallister-Killian syndrome (PKS), CHOPS syndrome, and related diagnoses. He has established an endowed Center for Cornelia de Lange Syndrome and Related Diagnoses to improve care and advance research toward therapeutics. His research lab concentrates on elucidating the molecular causes of syndromic and non-syndromic human developmental disorders and birth defects, with major projects on the genome-wide implications of alterations in the cohesin complex, effects on gene expression in syndromes like CdLS and PKS, and identifying genomic contributors to congenital conditions such as diaphragmatic hernias and esophageal atresia. Dr. Krantz's work also involves studying the integration of genomic technologies into pediatric practice and establishing best practice guidelines.

Research topics

• Genetics
• Medicine
• Internal medicine
• Biology
• Pathology
• Pediatrics
• Psychology
• Intensive care medicine
• Emergency medicine

Selected publications

• Mutation type‐specific transcriptomic signatures and readthrough therapy rescue in <i>SMC1A</i> ‐related developmental and epileptic encephalopathy

  Epilepsia · 2026-03-02

  articleOpen access

  OBJECTIVE: This study was undertaken to investigate the molecular consequences of pathogenic variants in the SMC1A gene-particularly those associated with developmental and epileptic encephalopathy (DEE85)-and to evaluate the therapeutic potential of ataluren in restoring SMC1A function and mitigating disease-related transcriptomic and genomic alterations. METHODS: The study analyzed transcriptomic profiles from cell lines derived from individuals with DEE85 and Cornelia de Lange syndrome (CdLS), comparing the effects of different SMC1A variants. Particular focus was placed on nonsense variants and their impact on gene expression. Functional assays were conducted to assess the ability of ataluren to restore SMC1A protein expression, correct transcriptional defects, and reduce genomic instability. RESULTS: Transcriptomic alterations were strongly dependent on variant type, with nonsense variants causing the most profound gene expression changes. DEE85 and CdLS cell lines exhibited distinct transcriptional signatures. Treatment with ataluren led to successful restoration of SMC1A protein levels, partial correction of gene expression abnormalities, and a reduction in genomic instability in cells harboring nonsense variants. SIGNIFICANCE: These findings demonstrate that SMC1A-related epileptic encephalopathies are driven by variant-specific molecular mechanisms and highlight the therapeutic promise of ataluren for DEE85. The study supports further development of precision medicine strategies targeting nonsense variants in SMC1A, with potential implications for improving diagnosis, treatment, and quality of life in affected individuals.

  PublisherDOI

• Expanding the Audiological Phenotype Associated With Activity‐Dependent Neuroprotective Protein ( <scp>ADNP</scp> ) Syndrome: A Case Report and Literature Review Suggesting a Genotype/Phenotype Correlation

  American Journal of Medical Genetics Part A · 2026-04-03

  articleSenior author

  ADNP syndrome, also known as Helsmoortel-Van der Aa syndrome, is a rare dominant syndromic neurodevelopmental diagnosis. ADNP syndrome is caused by pathogenic variants in the gene encoding the activity-dependent neuroprotective homeobox protein (ADNP) that plays a critical role in embryonic and postnatal hippocampal development. ADNP syndrome has a broad range of symptoms including intellectual deficits, dysmorphic features, and behavioral changes including autism spectrum disorder (ASD). Hearing loss has been reported in approximately 11.7% of individuals with ADNP syndrome. In this paper, we report the clinical findings of an individual with ADNP syndrome (c.2630_2633del; p.Asp877Valfs*36) who presents with unilateral hearing loss and confirmed ipsilateral cochlear nerve deficiency. This is the first report of cochlear nerve deficiency in an individual with ADNP syndrome and based on this review of published ADNP syndrome cases, hearing loss may be more prominent in this diagnosis than previously reported.

  PublisherDOI

• Genomic Contributors to Congenital Diaphragmatic Hernia: Results of Exome Sequencing in 560 Probands and Cross Reference of Findings in an Independent Cohort

  American Journal of Medical Genetics Part A · 2026-04-06

  articleOpen access

  There is a strong genetic contribution to the etiology of congenital diaphragmatic hernia (CDH). This study evaluated genetic testing results and diagnostic yield for fetuses and children with CDH. This was a retrospective cohort study of exome sequencing (ES) performed at GeneDx for fetuses and children ≤ 18 years of age with CDH compared with genome sequencing (GS) from an institutional cohort. ES was available for 560 individuals (62% [n = 349] complex/syndromic; 38% [n = 211] isolated/non-syndromic) with a reportable finding identified in 61% (n = 342) overall, including 64% in complex/syndromic cases and 56% in isolated/non-syndromic cases. In the institutional cohort, GS was available for 84 individuals (19% [n = 16] complex/syndromic; 81% [n = 68] isolated/non-syndromic). In this sub-cohort, 70 individuals had variants (539 total) in genes in which variants were reported in the GeneDx cohort (234 genes). The study cohort was compared to an unrelated cohort with neural tube defects and, when evaluating 73 genes with variants present in > 1 GeneDx proband, we noted a significantly higher variant burden in the CDH cohort. Overlap of genes with variants among unrelated cohorts suggests a potential etiologic association of many known and novel CDH genes; however, additional research is needed to understand the genes' causative roles as well as the impact of non-coding and gene-environment influences on the etiology of CDH.

  PublisherDOI

• Summary of the Inaugural <scp>ReNU</scp> Hope Conference and Scientific Symposium, July 23–25, 2025, Long Island, New York

  American Journal of Medical Genetics Part A · 2026-02-19

  articleSenior author

  The inaugural ReNU Hope Conference and Scientific Symposium was held from July 23-25, 2025 in Long Island, New York. This historic conference brought together the researchers responsible for the groundbreaking discovery of RNU4-2/ReNU syndrome, families, scientists, clinicians, trainees, therapeutic developers, and industry leaders from around the world. The key themes that emerged included: (1) Early recognition and diagnosis of ReNU Syndrome, (2) optimizing clinical care for this complex condition, (3) the importance of the family experience, (4) a need to elucidate the underlying genetic mechanism, (5) a need for quality natural history data and validated endpoints, and (6) exploring approaches to therapeutic development. This summary provides a broad overview of the conference, highlights the key presentations and discussions, and delineates priorities moving forward.

  PublisherDOI

• SWING regions prime chromatin for nuclear speckle mediated gene regulation

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-10-03

  preprintOpen access

  Nuclear speckles have long been recognized as RNA-rich nuclear bodies, yet their role in genome organization and gene regulation remains incompletely understood. Using a rapid dTAG mediated degradation system to simultaneously deplete SON and SRRM2, the core structural components of nuclear speckles, we identify a novel class of genomic regions, which we term SWING regions. Upon speckle disruption, SWING regions relocate to the nuclear periphery and acquire repressive histone marks such as H3K9me3, accompanied by gene downregulation, particularly of genes involved in developmental pathways. Consistent with this, depletion of Lamin A reduces lamina association of SWING regions and enhances their association with nuclear speckles, supporting a bidirectional balance between these two nuclear compartments. Notably, human mutations in SON and SRRM2 are associated with neurodevelopmental disorders characterized by intellectual disability and global developmental delay. Patient-derived cells bearing such mutations similarly exhibit SWING region relocalization and gene repression, underlining a role for speckles in developmental gene regulation. We also report that drug-induced speckle rejuvenation partially rescues aberrant SWING-region localization to the nuclear lamina in patient-derived cells and iPSCs with acute depletion of SON. These findings identify SWING regions as an intermediate chromatin state positioned between nuclear speckles and the lamina, maintained by opposing functions from both structures. Our work reveals a mechanism underlying the contribution of nuclear bodies to 3D genome organization, highlights the importance of nuclear speckles and SWING regions in developmental regulation, and provides a potential therapeutic intervention in speckle dysfunction.

  PublisherOA PDFDOI

• CTCF/RAD21 organize the ground state of chromatin–nuclear speckle association

  Nature Structural & Molecular Biology · 2025-02-21 · 11 citations

  articleOpen access
  PublisherOA PDFDOI

• Whole Genome Sequencing Improves the Identification of Pathogenic and Novel Variation in Nonsyndromic Hearing Loss

  Human Mutation · 2025-01-01

  articleOpen access

  Background Genetic testing is essential to the diagnosis of nonsyndromic bilateral sensorineural hearing loss (BSNHL), where pathogenic variants in GJB2 are the most common cause. Current testing strategies often fail to provide a comprehensive diagnosis and typically require the use of multiple testing methodologies. This study evaluated the diagnostic utility of genome sequencing (GS) in a cohort with heterozygosity for GJB2 pathogenic variants and BSNHL. Methods A retrospective cohort of 23 individuals with BSNHL and a heterozygous pathogenic variant in GJB2 underwent targeted GJB2 resequencing and variant reinterpretation. Those without biallelic GJB2 variants upon single gene reanalysis proceeded to exome sequencing (ES) using a large virtual panel of hearing loss–associated genes. Subjects with no definitive diagnosis from ES subsequently underwent GS. Variants were interpreted using hearing loss–specific ACMG guidelines and published literature. Results Three individuals were diagnosed with biallelic pathogenic variants upon GJB2 single gene reanalysis. ES identified a definitive or likely diagnosis in five different hearing loss–related genes in 5/20 (25%) individuals, while two additional cases remained inconclusive due to novel or ambiguous variants in two other hearing loss–associated genes. GS of the remaining 15 cases yielded diagnoses in three individuals, including the identification of deletions in LOXHD1 and STRC , and a recently characterized 125 kb deletion overlapping CRYL1 , which refines a critical upstream regulatory region associated with GJB2 ‐related hearing loss. Overall, 11/23 (48%) individuals received a diagnosis with our stepwise testing approach, with GS providing sequencing coverage of all findings. Conclusion GS improves diagnostic yield in patients with BSNHL, capturing both SNVs and CNVs missed by ES and targeted testing, and supports its adoption as a comprehensive first‐tier diagnostic test for nonsyndromic hearing loss.

  PublisherOA PDFDOI

• International electronic health record-derived COVID-19 clinical course profiles: the 4CE consortium

  UNC Libraries · 2025-06-26

  articleOpen access
  PublisherDOI

• Rapid targeted analysis of the genome: Rapid genomic sequencing in critically ill infants

  Genetics in Medicine Open · 2025-11-21

  articleOpen access

  Purpose: We developed a genome sequencing-based test (Rapid Targeted Analysis of the Genome for Infants [rTAG-I]) to minimize turnaround time while maximizing diagnostic yield and access to rapid sequencing for critically ill infants. We sought to create a system of predicting which infants would have a molecular finding. Methods: We performed a prospective observational study of infants referred for genetics consult who received rTAG-I testing, which analyzes 3183 curated genes with phenotype-agnostic prioritization of pathogenic and likely pathogenic variants. Infants were stratified by perceived likelihood of a diagnostic result and divided into "Likely," "Uncertain," and "Not Likely." We also assessed whether reportable findings correlated with patient phenotypes. Results: We identified reportable findings in 133/400 (33%) infants. Access to rapid testing increased from 1% to 20% of all infants hospitalized in the neonatal/infant intensive care unit and cardiac intensive care unit, with a median turnaround time of 4.9 days. rTAG-I performed as well as exome/genome sequencing. Clinically associated results were identified in 59% of the "Likely" group and 9% of the "Not Likely" group. Conclusion: rTAG-I produced a high rate of reportable findings with a rapid turnaround time. Our ability to predict infants who would benefit most was imperfect, reinforcing that broad access to genome-based testing is still required.

  PublisherDOI

• Recurrent missense variant identified in two unrelated families with <scp><i>MPZL2</i></scp>‐related hearing loss, expanding the variant spectrum associated with <scp>DFNB111</scp>

  American Journal of Medical Genetics Part A · 2024-01-10

  articleOpen access

  MPZL2-related hearing loss is a rare form of autosomal recessive hearing loss characterized by progressive, mild sloping to severe sensorineural hearing loss. Thirty-five previously reported patients had biallelic truncating variants in MPZL2, with the exception of one patient with a missense variant of uncertain significance and a truncating variant. Here, we describe the clinical characteristics and genotypes of five patients from four families with confirmed MPZL2-related hearing loss. A rare missense likely pathogenic variant [NM_005797.4(MPZL2):c.280C>T,p.(Arg94Trp)] located in exon 3 was confirmed to be in trans with a recurrent pathogenic truncating variant that segregated with hearing loss in three of the patients from two unrelated families. This is the first recurrent likely pathogenic missense variant identified in MPZL2. Apparently milder or later-onset hearing loss associated with rare missense variants in MPZL2 indicates that some missense variants in this gene may cause a milder phenotype than that resulting from homozygous or compound heterozygous truncating variants. This study, along with the identification of truncating loss of function and missense MPZL2 variants in several diverse populations, suggests that MPZL2-related hearing loss may be more common than previously appreciated and demonstrates the need for MPZL2 inclusion in hearing loss testing panels.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21HD050538

  NIH · $425k · 2011

• Medical Genetics Research Training Grant

  NIH · $8.9M · 1997–2027

• NIH Grant R01HD039323

  NIH · $1.3M · 2007

• NIH Grant R01DC005247

  NIH · $1.7M · 2007

• NIH Grant K08DK002541

  NIH · $623k · 2003

Frequent coauthors

• Nancy B. Spinner

  Children's Hospital of Philadelphia

  273 shared

• Matthew A. Deardorff

  California University of Pennsylvania

  179 shared

• David A. Piccoli

  113 shared

• Maninder Kaur

  99 shared

• Laird G. Jackson

  Drexel University

  84 shared

• Laura K. Conlin

  University of Pennsylvania

  80 shared

• Kosuke Izumi

  75 shared

• Dinah Clark

  70 shared

Labs

• Krantz Lab at the Children's Hospital of PhiladelphiaPI

Education

• M.D., Medicine

  Tel Aviv University Sackler Faculty of Medicine

  1991