Cytogenetic Testing Research Articles

Navigating diagnostic dilemmas: a rare presentation of extramedullary T-lymphoblastic leukemia/lymphoma with chronic myeloid leukemia.

Chronic myeloid leukemia (CML) typically presents in the chronic phase. The blast crisis phase in CML predominantly comprises the myeloid phenotype, while B-cell lymphoblastic crisis is common among the lymphoid lineages. Presentation as a T-lymphoblastic crisis is exceptionally rare. Little is known about its characteristics, treatment, and prognosis. This case study reports a patient who presented as an extramedullary blast crisis with T-lymphoblastic immunophenotype without a known prior diagnosis of CML. We performed hematoxylin and eosin staining, immunohistochemistry on the inguinal lymph node, and bone marrow biopsy. Ancillary studies including flow cytometry and cytogenetic testing were conducted as needed. BCR::ABL1 is quantitative real-time polymerase chain reaction monitored disease progression. Our patient is a 40-year-old male with no previous medical history who presented with neck stiffness and pain of one week in duration. Clinical evaluation revealed diffuse lymphadenopathy and splenomegaly. A biopsy from the inguinal lymph node revealed T-lymphoblastic lymphoma (T-LBL) (90%) and a population of myeloblasts (10%). Subsequent bone marrow biopsy showed myelocyte expansion, dwarf megakaryocytes, scattered myeloblasts (9%), and T-lymphoblasts (6%). Flow cytometry of the bone marrow aspirate revealed myeloblasts (5.4%) and T-lymphoblasts (6.3%). Genetic and molecular studies identified the BCR-ABL1 fusion. This case contributes to the medical literature by documenting a rare occurrence of extramedullary T-LBL with concurrent CML. The absence of a CML history makes the diagnosis particularly challenging and underscores the need for comprehensive and personalized treatment strategies.

Cytogenetic and photosynthetic responses of plants after exposure to water from a lake environment.

Plants are sensitive to environmental pollutants and are excellent organisms for genetic and physiological testing. Plant-based test systems are often used to study aquatic, aerial, and terrestrial pollution, especially Allium cepa, but studies with Tradescatia pallida specimens have gained prominence due to their sensitivity and applicability. Among the biomarkers, cytogenetic damage and chlorophyll levels are used in stress studies due to their responses to single or combined factors. The aim of this study was to evaluate cytogenetic and photosynthetic responses in T. pallida, and cytogenetic responses in A. cepa exposed to water from three sampling stations in the Juara lagoon (Municipality of Serra, ES, Brazil), collected in two sampling campaigns. The cytotoxic, genotoxic, and mutagenic potentials were analyzed using the T. pallida root tip mitosis assay and the Allium cepa test. Chloroplast pigment levels were measured in T. pallida leaves after chronic exposure to the lagoon water. The cytogenetic tests showed cytogenetic alterations at two sampling stations in at least one sampling campaign, suggesting the presence of potential pollutants, the effects of which were maximized during the rainy season. The study of photosynthetic metabolism in T. pallida showed a relationship between the levels of chloroplast pigments and the amount of nutrients present in the water.

10-Year Real-World Data on Acute Myeloid Leukemia:

Introduction: Despite advances in Acute Myeloid Leukemia (AML) diagnosis and treatment, the outcomes in low- and middle-income countries (LMIC) are far apart from those in high-income countries (HIC). Objective: To describe the clinical features and outcomes of AML patients in Brazil's public health system, we conducted a retrospective analysis of all cases of non-promyelocytic AML diagnosed within 10 years (2007- 2017) in northeastern Brazil, Bahia. Methodology: We analyzed the real-life outcomes of 62 patients diagnosed with non-promyelocytic AML between 2007 and 2017 at a university hospital in Northeast Brazil. We classified patients using the European LeukemiaNet 2022 guideline into favorable (n=8), intermediate (n=18), and adverse risk (n=7) groups. Twenty-nine were not otherwise classified because no cytogenetic and/or molecular tests were available at diagnosis. Results: Allogeneic bone marrow transplant (alloBMT) was performed in 16 patients (37%). Median overall survival (mOS) was seven months. Among patients receiving alloBMT, mOS was 49 months, while for the chemotherapy group, it was six months (P = 0.003). For 10-year real-life data, we found complete remission of 53%, 5-year OS of 27%, and a mortality rate during induction therapy of 27%, inferior to HIC. Conclusion: Inferior outcomes found in LMIC result from a multifactorial scenario and an unmet need in the worldwide panorama of AML.

Care of late intrauterine fetal death and stillbirth: Green-top Guideline No. 55.

A combination of mifepristone and a prostaglandin preparation should usually be recommended as the first-line intervention for induction of labour (Grade B). A single 200 milligram dose of mifepristone is appropriate for this indication, followed by: 24+0-24+6 weeks of gestation - 400 micrograms buccal/sublingual/vaginal/oral of misoprostol every 3 hours; 25+0-27+6 weeks of gestation - 200 micrograms buccal/sublingual/vaginal/oral of misoprostol every 4 hours; from 28+0 weeks of gestation - 25-50 micrograms vaginal every 4 hours, or 50-100 micrograms oral every 2 hours [Grade C]. There is insufficient evidence available to recommend a specific regimen of misoprostol for use at more than 28+0 weeks of gestation in women who have had a previous caesarean birth or transmural uterine scar [Grade D]. Women with more than two lower segment caesarean births or atypical scars should be advised that the safety of induction of labour is unknown [Grade D]. Staff should be educated in discussing mode of birth with bereaved parents. Vaginal birth is recommended for most women, but caesarean birth will need to be considered for some [Grade D]. A detailed informed discussion should be undertaken with parents of both physical and psychological aspects of a vaginal birth versus a caesarean birth [Grade C]. Parents should be cared for in an environment that provides adequate safety according to individual clinical circumstance, while meeting their needs to grieve and feel supported in doing so (GPP). Clinical and laboratory tests should be recommended to assess maternal wellbeing (including coagulopathy) and to determine the cause of fetal death, the chance of recurrence and possible means of avoiding future pregnancy complications [GradeD]. Parents should be advised that with full investigation (including postmortem and placental histology) a possible or probable cause can be found in up to three-quarters of late intrauterine fetal deaths [Grade B]. All parents should be offered cytogenetic testing of their baby, which should be performed after written consent is given (GPP). Parents should be advised that postmortem examination can provide information that can sometimes be crucial to the management of future pregnancy [Grade B].

Copy Number Analysis of Whole Exome Sequencing Data

Abstract Background Genetic alterations implicated in constitutional disorders range in size from single nucleotide substitutions to losses and gains of millions of bases. Whole exome sequencing (WES) captures many clinically relevant variants, but an analytic pipeline optimized for detection of small substitutions, insertions, and deletions may miss pathogenic copy number variants (CNVs). Historically, our laboratory performed separate cytogenetic tests to evaluate for larger genomic imbalances. Addition of copy number analysis to our WES pipeline could improve the assay’s diagnostic yield. This study describes part of our strategy to validate copy number analysis of our constitutional whole exome sequencing data. Methods We identified 18 CNV specimens that underwent both chromosomal microarray analysis (CMA) and WES between 2017 and 2023. Variants included 13 deletions (size range 14Kb-2Mb) and 5 duplications (size range 325Kb-10Mb). The standard method of constitutional copy number analysis in our clinical laboratory is CMA using the Affymetrix Cytoscan HD Array and analysis software. CNVs identified on CMA were reviewed with reference to the Database of Genomic Variants and multiple academic hospital databases. WES was performed on an Illumina sequencing system following capture-based library enrichment with the Integrated DNA Technologies xGen Exome Research, CNV Backbone, Human mtDNA Research, and Human ID Research Panel probes. CNVs identified on WES were called using the Broad Institute’s Genomic Analysis Toolkit (GATK) with a quality score cutoff of 120. Whole exome sequencing data was visualized on the Integrative Genomics Viewer. Results 14 out of 18 CNVs reported on CMA were also detected on WES with a quality score at or above 120 (78%). This includes 10 out of 13 deletions (77%) and 3 out of 5 duplications (60%). For both deletions and duplications, the size ranges of detected variants at or above the cutoff score and undetected variants overlapped. One duplication reported on CMA was detected on WES with a quality score below 120. Visualization of whole exome sequencing data showed variation in probe density that may have affected CNV calling. Conclusions The majority of CNVs reported after CMA (14/18, 78%) were also detected on WES data using a GATK quality score cutoff of 120. The data does not suggest an association between CNV size and detection by WES, although interpretation is limited by the small number of cases. Data visualization may be required to identify some CNVs. Future steps to characterize the limitations of copy number analysis of WES data include assessments of variance in probe density and read depth across the exome. Copy number analysis of WES data from cases with normal CMA results will also be performed for assay validation.

Collaboration between a veterinary laboratory and a clinical cytogenetics laboratory

Abstract Introduction/Objective One major issue facing pig breeders is the presence of karyotypic abnormalities which reduce fertility. Karyotypic abnormalities may also persist in breeding population increasing the magnitude of lost animal production over time. Assessment of porcine chromosomes is a valuable service to be offered to the livestock industry. Methods/Case Report Chromosome testing of young boars prior to breeding is mandatory in France and much of Western Europe. Such testing is not common in the USA even though chromosome abnormalities are known to exist in swine breeding populations. Due to the lack of this service in the US, we established a collaboration between a clinical cytogenetics laboratory and a veterinary laboratory to validate and offer karyotype testing for breeder boards. To established this service Kuster Research and Consulting, Inc (KRC), a veterinary consulting service in Atkinson Illinois, reached out to the Shivanand R. Patil Cytogenetics and Molecular Laboratory at University of Iowa Healthcare for assistance in setting up chromosome testing for breeder boars based on the laboratory’s experience in culturing mammalian cells for chromosome analysis. Technologists from KRC traveled to the clinical cytogenetics lab for training. After a dedicated period of work and collaboration, a reproducible culture and harvest protocol was developed to obtain G-band metaphase spreads. Additional assistance for analysis was provided by Dr. Alain Pinton at the National Veterinary College (ENVT) in Toulouse, France. Dr. Pinton’s cytogenetic laboratory provided training in porcine chromosome analysis as well as providing protocols used in that laboratory. Kuster Research and Consulting also worked with SmartType to adapt proprietary karyotype software to assist in analysis of porcine chromosomes. The collaboration established the first of its kind cytogenetic testing in a private USA veterinary laboratory, Results (if a Case Study enter NA) Active collaboration between clinical and veterinary service laboratories resulted in the successful development of testing protocols. In addition, the clinical lab gained experience in analysis of porcine chromosomes which has created opportunities for research using a porcine model. Conclusion Opportunities to share expertise should be sought and and encouraged to provide needed laboratory services in a non traditional setting.

Prevalence of Autosomal Monosomy and Trisomy Estimated Using Single Nucleotide Polymorphism Genotype Intensity Chip Information in a Large Population of Juvenile Dairy and Beef Cattle.

Aneuploidy, a genetic condition characterised by the deletion (monosomy) or duplication (trisomy) of a chromosome, has been extensively studied in humans, particularly in the context of trisomy on chromosome 21, also known as Down syndrome. Research on autosomal aneuploidy in live-born cattle has been limited to case reports, resulting in a lack of prevalence estimates of aneuploidy in cattle. Furthermore, the viability or lethality of aneuploidy on specific autosomes in cattle has not been well documented. The objective of this study was to estimate the prevalence of autosomal aneuploidy in a large population of new-born and juvenile beef and dairy cattle using single nucleotide polymorphism (SNP) chip genotype intensity data. Of the population of 779,138 cattle genotyped when younger than 15 months of age, 139 cattle (i.e., 0.017%) were diagnosed with one case of autosomal trisomy. Trisomy in only 10 different autosomes were detected (BTA 4, 6, 12, 15, 20, 24, 26, 27, 28 and 29) albeit the one case of trisomy detected on Bos taurus autosome (BTA) 4 was in an additional population of 341,927 cattle that were genotyped at > 15 months of age and was therefore excluded from prevalence estimates to minimise bias. The prevalence of trisomy per chromosome was generally inversely related to the length of the chromosome. Although the number of affected individuals was few, there was no evidence of differences in prevalence by breed, inbreeding level or parental age. The parental origin of the detected cases of trisomy was maternal for 92% of the cases. No cases of monosomy were detected despite the large dataset, which included calves genotyped at birth, indicating the potential lethal nature of monosomy in cattle. Cytogenetic testing was used to verify three of the animals with detected autosomal trisomy who were still alive. Eighteen of the 139 animals identified with autosomal trisomy were recorded as being stillborn, resulting in a prevalence of autosomal aneuploidy in live-born cattle of 0.015%. Of the 121 live-born cattle with autosomal trisomy, a total of 68 died on farm at, on average (standard deviation), 6.8 (8.7) months of age. All animals with autosomal trisomy on BTA 6, 12, 15, 20 or 24 were either stillborn or died on farm within 15 days of birth. This study is the first report of trisomy on BTA 4, 6, 15, 20 and 27 in live-born cattle, as well as the first to document fertile cows with trisomy on BTA 4, 27 or 28. Given that genotype intensity SNP data from SNP-chips are readily available, identifying animals affected with autosomal aneuploidy as well as quantifying and monitoring the incidence can be easily undertaken.

Cytogenetic-Phenotypic Profile of Filipinos with Myelodysplastic Syndrome in Makati Medical Center: A 10-Year Review

Hematologic malignancies remained to be a significant contributor in the Global Burden of Disease. Myelodysplastic syndrome is one of the hematologic malignancies and has remained to be underestimated, underreported, and underdiagnosed. It is a group of hematologic malignancies that proves a challenge in diagnosis and is characterized by clonal hematopoiesis, with one or more cytopenias. Data on Prevalence of Myelodysplastic syndrome globally is scarce, moreso, not available in the Philippines. This is the first clinical profile study in Myelodysplastic Syndrome in the Philippines. This 10-year study has shown that 240 patients were diagnosed to have Myelodysplastic syndrome but only 35 had the MDS Fluorescent-in-Situ Hybridization test done. The most common reasons for hematologic referral, chief complaint, signs, cytogenetic test are anemia, low hemoglobin, pallor and fatigue, del7q31 which belongs to the Good risk cytogenetic category respectively. The most common CBC findings were hemoglobin of 8 and above, ANC of above 800 and Platelets of 50 and higher. There was no noted significant difference in the clinical profile of patients with MDS based on FISH study results

12333 46 XX/XY Chimerism - Positive NIPT And Post-natal Karyotype Is It Real?

Abstract Disclosure: K.L. Del Rosario: None. N. Sheriden: None. N. Vijayakanthi: None. Introduction: Non-Invasive Prenatal Testing(NIPT) using cell free fetal DNA in plasma of pregnant women has become a routine part of prenatal care in screening for fetal aneuploidies including sex chromosome abnormalities in most regions around the world. False positive results are increasingly imposing challenges in pre-natal as well as post-natal care. Case Discussion: We report a neonate born at 32+2 weeks gestation to a 42-year-old G2 P2 mother. Pregnancy was complicated by insulin dependent maternal type 2 diabetes mellitus, maternal chronic hypertension and a positive NIPT for high-risk monosomy X. Prenatal ultrasound showed male anatomy. Interestingly on physical exam after birth, the neonate had typical male external genitalia with bilateral normal male gonads. Chromosome analysis done immediately after birth revealed the presence of two cell lines: 40 of the 50 cells (80%) had a normal female 46 XX karyotype and 10 of the 50 cells (20%) had a normal male 46 XY karyotype. These findings could be due to reabsorbed twin, Klinefelter syndrome with two trisomy rescue events, maternal cell contamination or true chimerism. In addition, fluorescence in situ hybridization (FISH) analysis for X and Y probes revealed the presence of two cell lines. The first cell line (70% of the cells) had two hybridization signals for chromosome X and the second cell line (∼25% of the cells) had one hybridization signal for chromosome X and one for chromosome Y. Postnatal ultrasound showed normal testicles with no evidence of Mullerian structures. Newborn screening was negative for congenital adrenal hyperplasia (CAH). Genetics was consulted and recommended repeat chromosomal analysis, parental testing to determine sex chromosome segregation, and follow-up with pediatric endocrinology. Repeat cytogenetic testing at 2 weeks of life resulted in a normal male chromosome complement of 46,XY. Previous abnormal cytogenetics were thought to be due to maternal cell contamination. Further endocrine labs showed LH(1.16 uIU/ml) and testosterone levels ( 87 ng/dL), appropriate levels for age indicating normal Hypothalamic Pituitary Gonadal (HPG) axis and testicular Leydig cell function. Since the family was previously counseled regarding the concept of maternal cell contamination, they expressed understanding and were happy with the update of the normal karyotype result. Conclusion: False-positive results concerning for rare chimerism on NIPT can occur and should prompt a thorough history, physical exam, ultrasound studies and repeat testing to confirm its presence. Careful consideration should be taken when counseling family about the implications of these results, especially communication about gender assignment of the infant. Presentation: 6/3/2024

Basic Cytogenetics and Karyotyping: Initial Step for Identification of Genetic Disease

Genetic disorders are conditions that arise from alterations in the DNA sequence, which can be inherited or occur spontaneously. These alterations may affect a single gene or multiple genes, and they can also be influenced by environmental factors. Knowledge about the importance of suitable cytogenetic tests, the challenges faced in cytogenetics, the importance of pre-investigation lab work, and post-lab communication are important for the establishment of any cytogenetic lab. Continuous medical education can help in upgrading the knowledge and skills of Medical Practitioners.

Genomic Instability in the Lymphocytes of Dogs with Squamous Cell Carcinoma.

Genome instability is a characteristic trait of tumours and includes changes in DNA and in chromosomes. The aim of the study was to identify chromosome damage using the sister chromatid exchange assay and DNA fragmentation by the comet assay in dogs with cancer, as well as to determine the suitability of these techniques for the assessment of chromatin stability in healthy and sick dogs. The assays identified genomic instabilities in dogs with cancer (squamous cell carcinoma) and in healthy dogs. The genetic assays are very sensitive and can be used as biomarkers of normal DNA replication and repair potential and the maintenance of control over the entire cell cycle. The use of the cytogenetic tests will enable the more precise assessment of genome stability and integrity in animals and make it possible to determine the number of chromosomal instabilities generated in a given individual, which can be indicative of its health status. The identification of instabilities can be used in routine diagnostic examination in dogs with cancer for more accurate diagnosis and prognosis.

Multiwell-based G0-PCC assay for radiation biodosimetry

In major radiological events, rapid assays to detect ionizing radiation exposure are crucial for effective medical interventions. The purpose of these assays is twofold: to categorize affected individuals into groups for initial treatments, and to provide definitive dose estimates for continued care and epidemiology. However, existing high-throughput cytogenetic biodosimetry assays take about 3 days to yield results, which delays critical interventions. We have developed a multiwell-based variant of the chemical-induced G0-phase Premature Chromosome Condensation Assay that delivers same-day results. Our findings revealed that using a concentration of phosphatase inhibitor lower than recommended significantly increases the yield of cells with highly condensed chromosomes. These chromosomes exhibited increased fragmentation in a dose-dependent manner, enabling to quantify radiation damage using a custom Deep Learning algorithm. This algorithm demonstrated reasonable performance in categorizing doses into distinct treatment groups (84% and 80% accuracy for three and four iso-treatment dose bins, respectively) and showed reliability in determining the actual doses received (correlation coefficient of 0.879). This method is amendable to full automation and has the potential to address the need for same-day, high-throughput cytogenetic test for both dose categorization and dose reconstruction in large-scale radiation emergencies.

Evaluation of Hi-C Sequencing for Detection of Gene Fusions in Hematologic and Solid Tumor Pediatric Cancer Samples.

Hi-C sequencing is a DNA-based next-generation sequencing method that preserves the 3D genome conformation and has shown promise in detecting genomic rearrangements in translational research studies. To evaluate Hi-C as a potential clinical diagnostic platform, analytical concordance with routine laboratory testing was assessed using primary pediatric leukemia and sarcoma specimens. Archived viable and non-viable frozen leukemic cells and formalin-fixed paraffin-embedded (FFPE) tumor specimens were analyzed. Pediatric acute myeloid leukemia (AML) and alveolar rhabdomyosarcoma (A-RMS) specimens with known genomic rearrangements were subjected to Hi-C to assess analytical concordance. Subsequently, a discovery cohort consisting of AML and acute lymphoblastic leukemia (ALL) cases without known genomic rearrangements based on prior clinical diagnostic testing was evaluated to determine whether Hi-C could detect rearrangements. Using a standard sequencing depth of 50 million raw read-pairs per sample, or approximately 5X raw genomic coverage, we observed 100% concordance between Hi-C and previous clinical cytogenetic and molecular testing. In the discovery cohort, a clinically relevant gene fusion was detected in 45% of leukemia cases (5/11). This study provides an institutional proof of principle evaluation of Hi-C sequencing to medical diagnostic testing as it identified several clinically relevant rearrangements, including those that were missed by current clinical testing workflows.

Improving genetic testing utilization in a tertiary care neonatal intensive care unit through quality improvement.

There is an increasing recognition of the importance of diagnosing genetic conditions with an ever-growing list of genetic testing options. However, most providers do not have formal genetics training, which makes choosing the most appropriate test to order challenging. Our project sought to improve cytogenetic testing utilization in a tertiary care neonatal intensive care unit (NICU) through utilizing quality improvement techniques, specifically the Model for Improvement framework with rapid Plan-Do-Study-Act cycles. Our project utilized various interventions including the implementation of a NICU genetic testing algorithm. Interventions demonstrated improvement in all areas, specifically a 92% reduction in unnecessary cytogenetic testing with improvement in the diagnostic rate. Our work also resulted in a 59% decrease in charges with an estimated projected savings of $21,000 per year. Quality improvement can minimize redundancies and inefficiencies in genetic testing in a Level IV NICU in a large tertiary care children's hospital and result in substantial cost-savings.

Cancer cytogenetics in the era of artificial intelligence: shaping the future of chromosome analysis.

Artificial intelligence (AI) has rapidly advanced in the past years, particularly in medicine for improved diagnostics. In clinical cytogenetics, AI is becoming crucial for analyzing chromosomal abnormalities and improving precision. However, existing software lacklearning capabilities from experienced users. AI integration extends to genomic data analysis, personalized medicineand research, but ethical concerns arise. In this article, we discuss the challenges of the full automation in cytogenetic test interpretation and focus on its importance and benefits.

71. Validation of automated cell counter instruments for downstream cytogenetic testing

71. Validation of automated cell counter instruments for downstream cytogenetic testing

A case of testicular diffuse large B-cell lymphoma with late relapse in the skin: the critical role of comparative phenotypic, clonality, and cytogenetic testing

A case of testicular diffuse large B-cell lymphoma with late relapse in the skin: the critical role of comparative phenotypic, clonality, and cytogenetic testing

Health Care Costs After Genome-Wide Sequencing for Children With Rare Diseases in England and Canada

Etiologic diagnoses for rare diseases can involve a diagnostic odyssey, with repeated health care interactions and inconclusive diagnostics. Prior studies reported cost savings associated with genome-wide sequencing (GWS) compared with cytogenetic or molecular testing through rapid genetic diagnosis, but there is limited evidence on whether diagnosis from GWS is associated with reduced health care costs. To measure changes in health care costs after diagnosis from GWS for Canadian and English children with suspected rare diseases. This cohort study was a quasiexperimental retrospective analysis across 3 distinct English and Canadian cohorts, completed in 2023. Mixed-effects generalized linear regression was used to estimate associations between GWS and costs in the 2 years before and after GWS. Difference-in-differences regression was used to estimate associations of genetic diagnosis and costs. Costs are in 2019 US dollars. GWS was conducted in a research setting (Genomics England 100 000 Genomes Project [100KGP] and Clinical Assessment of the Utility of Sequencing and Evaluation as a Service [CAUSES] Research Clinic) or clinical outpatient setting (publicly reimbursed GWS in British Columbia [BC], Canada). Participants were children with developmental disorders, seizure disorders, or both undergoing GWS between 2014 and 2019. Data were analyzed from April 2021 to September 2023. GWS and genetic diagnosis. Annual health care costs and diagnostic costs per child. Study cohorts included 7775 patients in 100KGP, among whom 788 children had epilepsy (mean [SD] age at GWS, 11.6 [11.1] years; 400 female [50.8%]) and 6987 children had an intellectual disability (mean [SD] age at GWS, 8.2 [8.4] years; 2750 female [39.4%]); 77 patients in CAUSES (mean [SD] age at GWS, 8.5 [4.4] years; 33 female [42.9%]); and 118 publicly reimbursed GWS recipients from BC (mean [SD] age at GWS, 5.5 [5.2] years; 58 female [49.2%]). GWS diagnostic yield was 143 children (18.1%) for those with epilepsy and 1323 children (18.9%) for those with an intellectual disability in 100KGP, 47 children (39.8%) in the BC publicly reimbursed setting, and 42 children (54.5%) in CAUSES. Mean annual per-patient spending over the study period was $5283 (95% CI, $5121-$5427) for epilepsy and $3373 (95% CI, $3322-$3424) for intellectual disability in the 100KGP, $724 (95% CI, $563-$886) in CAUSES, and $1573 (95% CI, $1372-$1773) in the BC reimbursed setting. Receiving a genetic diagnosis from GWS was not associated with changed costs in any cohort. In this study, receiving a genetic diagnosis was not associated with cost savings. This finding suggests that patient benefit and cost-effectiveness should instead drive GWS implementation.

Prenatal and Postnatal Diagnosis and Genetic Background of Corpus Callosum Malformations and Neonatal Follow-Up.

The corpus callosum is one of the five main cerebral commissures. It is key to combining sensory and motor functions. Its structure can be pathological (dysgenesis) or completely absent (agenesis). The corpus callosum dys- or agenesis is a rare disease (1:4000 live births), but it can have serious mental effects. In our study, we processed the data of 64 pregnant women. They attended a prenatal diagnostic center and genetic counseling from 2005 to 2019 at the Department of Obstetrics and Gynecology at Semmelweis University. The pregnancies had the following outcomes: 52 ended in delivery, 1 in spontaneous abortion, and 11 in termination of pregnancy (TOP) cases (n = 64). The average time of detection with imaging tests was 25.24 gestational weeks. In 16 cases, prenatal magnetic resonance imaging (MRI) was performed. If the abnormality was detected before the 20th week, a genetic test was performed on an amniotic fluid sample obtained from a genetic amniocentesis. Karyotyping and cytogenetic tests were performed in 15 of the investigated cases. Karyotyping gave normal results in three cases (46,XX or XY). In one of these cases, postnatally chromosomal microarray (CMA) was later performed, which confirmed Aicardi syndrome (3q21.3-21.1 microdeletion). In one case, postnatally, the test found Wiedemann-Rautenstrauch syndrome. In other cases, it found X ring, Di George syndrome, 46,XY,del(13q)(q13q22) and 46,XX,del(5p)(p13) (Cri-du-chat syndrome). Edwards syndrome was diagnosed in six cases, and Patau syndrome in one case. We found that corpus callosum abnormalities are often linked to chromosomal problems. We recommend that a cytogenetic test be performed in all cases to rule out inherited diseases. Also, the long-term outcome does not just depend on the disease's severity and the associated other conditions, and hence proper follow-up and early development are also key. For this reason, close teamwork between neonatology, developmental neurology, and pediatric surgery is vital.

HGG-35. SIGNIFICANT RESPONSE TO LAROTRECTINIB AS FIRST LINE THERAPY IN INFANT WITH INFANT-TYPE HEMISPHERIC GLIOMA

Abstract BACKGROUND Infant-type hemispheric gliomas represent a recent WHO classification of high grade pediatric brain tumors that are often characterized by NTRK, ROS1, MET or ALK fusions. Novel agents may target their driver mutations but are not yet considered front line therapy. METHODS Patient data was reviewed retrospectively through chart review. RESULTS A 7 day old male infant who presented with vomiting, shaking and a full fontanelle was found to have a 8.7 x 7.2 x 9.3 cm solid and cystic mass with internal hemorrhage in the right parietal and occipital lobes associated with significant mass effect and midline shift. He underwent VP shunt placement and tumor biopsy, but later developed seizures and declining mental status. Cyst decompression was used as stabilizing measure. Due to his very small size and tenuous clinical status full tumor resection was not feasible at that time. Pathology revealed an infant-type hemispheric glioma with ETV6-NTRK3 fusion. Although cytogenetic testing for NTRK alterations was negative, the fusion was confirmed by NGS. Given his age and the risks for electrolyte imbalances and cytopenias in a patient with recent hemorrhage, we elected to treat with Larotrectinib instead of traditional cytotoxic chemotherapy. He had notable disease response within 8 weeks and remains on drug 18 months later with continued response. His tumor now measures 2 x 1.5 x 1.6 cm. He has had one grade 3 toxicity with neutropenia, which was likely impacted by viral bone marrow suppression. He is currently meeting most developmental milestones but does have orthotics and sees speech therapy. CONCLUSIONS Targeted agents may represent a viable front line therapy to decrease tumor mass and temporize very young patients until they can undergo definitive resection and therapy. Future clinical trials will need to compare efficacy to current standards of care.