Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a type of inherited cancer syndrome with a genetic predisposition to different types of cancer. There is an increased predisposition to cancers in the endometrium, colon, stomach, ovary, uterus, skin, kidney, and brain in patients of Lynch syndrome. We are reporting a 48-year-old male who presented with a pea-sized growth in his left arm which was found to be sebaceoma on histopathology. On further detailed history, examination, and genetic study, it was proved to be a familial case of Lynch syndrome. The case is being reported to stress the importance of knowledge about clinical manifestation, associated neoplasms, and molecular genetic profile of Lynch syndrome which will enable physicians and pathologists to provide highly targeted surveillance and management for patients with high cancer risk.
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract
PURPOSEHereditary breast and ovarian cancer (HBOC) syndrome is primarily characterized by mutations in the BRCA1/2 genes. There are several barriers to the implementation of genetic testing and counseling in India that may affect clinical decisions. These consensus recommendations were therefore convened as a collaborative effort to improve testing and management of HBOC in India.DESIGNRecommendations were developed by a multidisciplinary group of experts from the Indian Society of Medical and Pediatric Oncology and some invited experts on the basis of graded evidence from the literature and using a formal Delphi process to help reach consensus. PubMed and Google Scholar databases were searched to source relevant articles.RESULTSThis consensus statement provides practical insight into identifying patients who should undergo genetic counseling and testing on the basis of assessments of family and ancestry and personal history of HBOC. It discusses the need and significance of genetic counselors and medical professionals who have the necessary expertise in genetic counseling and testing. Recommendations elucidate requirements of pretest counseling, including discussions on genetic variants of uncertain significance and risk reduction options. The group of experts recommended single-site mutation testing in families with a known mutation and next-generation sequencing coupled with multiplex ligation probe amplification for the detection of large genomic rearrangements for unknown mutations. Recommendations for surgical and lifestyle-related risk reduction approaches and management using poly (ADP-ribose) polymerase inhibitors are also detailed.CONCLUSIONWith rapid strides being made in the field of genetic testing/counseling in India, more oncologists are expected to include genetic testing/counseling as part of their clinical practice. These consensus recommendations are anticipated to help homogenize genetic testing and management of HBOC in India for improved patient care.
Swaleha Nurulla Nadaf, Rahul T Chakor, Kaumil V Kothari, and Ashraf U Mannan
Subjects
autosomal recessive cerebellar ataxia 1 ataxia, amyotrophic lateral sclerosis, motor neuron disease, spinocerebellar ataxia of recessive ataxia, synaptic nuclear envelope protein 1 ataxia, Neurology. Diseases of the nervous system, RC346-429
Abstract
A 24-year-old female presented with wasting and weakness of both hands and fasciculations over the chin since 12 years, followed by imbalance while walking and speech changes since 10 years. Her 12-year-old sister also had a similar clinical presentation. There were fasciculations over the chin, tongue, hands, back, thighs with wasting and weakness in tongue, and C7, C8, T1 segments in both upper limbs along with bipyramidal signs. There was limb and gait ataxia. Magnetic resonance imaging brain showed pancerebellar atrophy, and electromyography was suggestive of anterior horn cell involvement in bulbar, cervical, thoracic, and lumbar segments. Next-generation sequencing identified a novel likely pathogenic deletion mutation: chr6:152527389_152527399del, c.22711_22721del, and p.Ala7571ArgfsTer4 in exon 125 of synaptic nuclear envelope protein 1 (SYNE1) gene. This mutation leads to frameshift and premature termination of the protein 'Nesprin 1'. Amyotrophic lateral sclerosis-like presentation followed by cerebellar ataxia have been described with SYNE1 ataxia. This unique phenotype and novel deletion mutation of SYNE1 gene is the first case reported from India.
Advithi Rangaraju, Shuba Krishnan, G. Aparna, Satish Sankaran, Ashraf U. Mannan, and B. Hygriv Rao
Subjects
Cardiac ion channels, Electrical storm, Ischemic cardiomyopathy, Sudden cardiac death, Ventricular tachycardia, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract
Electrical storm (ES) is a life threatening clinical situation. Though a few clinical pointers exist, the occurrence of ES in a patient with remote myocardial infarction (MI) is generally unpredictable. Genetic markers for this entity have not been studied. In the present study, we carried out genetic screening in patients with remote myocardial infarction presenting with ES by next generation sequencing and identified 25 rare variants in 19 genes predominantly in RYR2, SCN5A, KCNJ11, KCNE1 and KCNH2, CACNA1B, CACNA1C, CACNA1D and desmosomal genes - DSP and DSG2 that could potentially be implicated in electrical storm. These genes have been previously reported to be associated with inherited syndromes of Sudden Cardiac Death. The present study suggests that the genetic architecture in patients with remote MI and ES of unstable ventricular tachycardia may be similar to that of Ion channelopathies. Identification of these variants may identify post MI patients who are predisposed to develop electrical storm and help in risk stratification.
Defective autophagy has been linked to lipotoxicity in several cellular models. We aimed to investigate autophagy in lipid-stimulated hepatoma (Huh7) cells and tested whether 4-phenyl butyric acid (4-PBA), a chemical chaperone, has a beneficial role in hepatic fat accumulation and lipotoxicity. We report that long-term (24 h) exposure of hepatocytes to palmitate block autophagic flux that leads to lipid accumulation and cell death. Western blotting analysis showed increased accumulation of SQSTM1/p62, and decreased expression of Beclin1 and Atg7 in palmitate-treated cells. Autophagy inhibition by 3-methyladenine (3-MA) in palmitate-treated cells neither increased SQSTMI/p62 accumulation nor cell death, thus suggesting complete blockade of autophagy by palmitate. 4-PBA reduced lipid accumulation and cell death that were associated with restoration of autophagy. siRNA-mediated knockdown of Atg7 and presence of autophagy inhibitors, 3-MA and chloroquine, resulted in the decrease in lipid-lowering effect of 4-PBA, suggesting that 4-PBA mediates its lipid-lowering effect via autophagy. Apoptotic parameters, including altered Bcl2:Bax ratio and PARP1 cleavage induced by palmitate, were improved by 4-PBA. Our results indicate that palmitate impairs autophagy and increases lipid accumulation in Huh7 cells, whereas 4-PBA plays a protective role in lipid accumulation and lipotoxicity through activation of autophagy.
Purpose Colorectal cancer (CRC) is the fifth most common cancer in India, however, there is a paucity of systematically collected data related to its molecular epidemiology, specifically related to tumour microsatellite instability (MSI) and Lynch syndrome prevalence. Methods We prospectively recruited 207 unrelated patients who were diagnosed with CRC from whom primary tumour biopsy along with a matched blood sample was obtained. A sequential genetic testing approach for Lynch syndrome detection in colorectal cancer patients in accordance with the UK’s National Institute of Health and Care Excellence’s guideline (DG27) was utilised. Briefly, DNA from tumour biopsies were tested for MSI status followed BRAF V600E testing in samples which showed MSI-high result. Germline testing for the mismatch repair genes was carried in patients who had MSI-high and BRAF V600E negative tumours. Seventeen patients recanted their consent to participate in the study and therefore, results from 190 out of 207 patients is presented here. Results Mean age at cancer diagnosis across the cohort was 52.3 years with male to female ratio of 2:1 and 57.3% of the patients had tumours in the descending colon or rectum. MSI-high status was observed in 79 patients (42.6%) and, was inversely associated with age (OR = 0.95, 95% CI = 0.92–0.97, p = BRAF V600E negative mutation status (96%) and of these, 48 were diagnosed with Lynch syndrome (63%; MLH1 = 38, MSH2 = 4, MSH6 = 4, PMS2 = 1, EPCAM = 1). The variants c.154del and c.306G > T in the MLH1 gene were most commonly observed across Lynch syndrome patients in our cohort. Conclusions This is the first systematic evaluation of the molecular epidemiology of CRC in India. We observe a high proportion of patients with young onset CRC coupled with high prevalence of MSI-high status and Lynch syndrome. The study provides a unique opportunity to explore development of novel Lynch syndrome detection and cancer prevention pathway in Indian healthcare settings.
Salam, Moin U., Day, Tapan K., Ahmed, Ashraf U., Nessa, Bodrun, Haque, A. H. M. Mahfuzul, Subedi, Subash, Malik, Al Imran, Rahman, M. Matiur, and Erskine, William
The present study investigates the possible anti-nociceptive effect of intraperitoneal (i.p.) honokiol: a phenolic compound originally isolated from Magnolia officinalis, in acute and chronic inflammatory pain models. Doses of 0.1, 5, and 10 mg/kg honokiol were administered in carrageenan induced pain and the dose (honokiol 10 mg/kg i.p.) with most significant response among behavioral tests was selected for further experiments. The i.p. administration of honokiol inhibits mechanical hyperalgesia, mechanical allodynia, and thermal hyperalgesia, without causing any apparent toxicity. To elucidate the effect of honokiol on various cytokines and antioxidant enzymes, quantitative real-time-PCR was performed to determine the expression levels of pro-inflammatory cytokines and antioxidant enzymes. It is demonstrated that honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). Similarly, honokiol was also found to potentiate the expression of nuclear factor erythroid 2–related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) levels. Additionally, honokiol significantly reduced plasma nitrite levels as compared to complete Freund’s adjuvant (CFA) induced group. X-ray analysis and hematoxylin and eosin (H&E) staining of inflamed and treated paws showed that honokiol reduced the inflammation with significantly less leukocyte infiltration and soft tissue inflammation. In order to explore the possible mechanism of action of honokiol, agonists [piroxicam (5 mg/kg), tramadol (50 mg/kg), and gabapentin (5 mg/kg) i.p.] as well as antagonists [naloxone (4 mg/kg), olanzapine (10 mg/kg), and flumazenil (0.2 mg/kg) i.p.] were used to study involvement of various receptors on the anti-nociceptive effect of honokiol. The potential side effects of honokiol on muscle activity were assessed. An adverse effect testing of honokiol by liver and renal functions were also carried out. The effect of oral honokiol was also assessed on gastrointestinal (GIT) mucosa. Our results demonstrate that honokiol has a significant anti-nociceptive activity through inhibition of anti-inflammatory mediators.
Cenani Lenz syndrome is a rare autosomal recessive disorder associated with variable degree of limb malformations, dysmorphism, and renal agenesis. It is caused due to pathogenic variants in the LRP4 gene, which plays an important role in limb and renal development. Mutations in the APC gene have also been occasionally associated with CLS. The phenotypic spectrum ranges from mild to very severe perinatal lethal type depending on the type of variant. We report a pathogenic variant, c.2710 del T (p.Trp904GlyfsTer5) in theLRP4 gene, in a fetus with lethal Cenani Lenz syndrome with antenatal presentation of tetraphocomelia and symmetrical involvement of hands and feet.
Dhanya Yesodharan, Aparna Ganapathy, Michael M. Hoffmann, Shwetha Kuthiroly, Ashraf U Mannan, Sheela Nampoothiri, and Natasha Radhakrishnan
Subjects
medicine.medical_specialty, India, Consanguinity, Gastroenterology, 03 medical and health sciences, Lipoprotein lipase deficiency, 0302 clinical medicine, Recurrent pancreatitis, 030225 pediatrics, Internal medicine, Humans, Medicine, Child, Retrospective Studies, Hypertriglyceridemia, Lipoprotein lipase, business.industry, Infant, Newborn, Chylothorax, Retrospective cohort study, medicine.disease, Lipoprotein Lipase, Lipemia retinalis, Pediatrics, Perinatology and Child Health, Pancreatitis, Hyperlipoproteinemia Type I, business, 030217 neurology & neurosurgery
Abstract
To analyse the clinical and molecular spectrum of Lipoprotein Lipase (LPL) deficiency and to highlight the effect of a cost-effective indigenous diet for management of this disorder. This is a single-centre retrospective study. Fifteen patients from 14 kindreds with severe hypertriglyceridemia (more than 1000 mg/dl) were evaluated for a period of 12.5 y at Amrita Institute of Medical Sciences, Kerala, India. Thirteen of 15 patients were referred after incidental detection of lipemic plasma, 1/15 had chylothorax in the neonatal period and 1/15 had pancreatitis. The mean age of presentation was 7 mo (ranging from 2 d to 4 y), and 20% of the patients had a positive history of consanguinity. Hepatomegaly (15/15), splenomegaly (9/15) and lipemia retinalis (14/15) were common findings. Lipemia retinalis was a useful non-invasive diagnostic tool. All the patients were subjected to diet modification and followed up at regular intervals. Fourteen of 15 complied with the diet, resulting in a dramatic improvement in the fasting lipid profile; only 1/15 developed pancreatitis. Genetic screening analysis was offered to 14/15 patients (1/15 was lost to follow-up); six different variants were identified, of which two were novel variants. Lipemic serum, chylothorax and recurrent pancreatitis in children should raise the suspicion of Lipoprotein Lipase deficiency. Early diagnosis and prompt initiation of a stringent fat-restricted diet are the keys to success for the management of LPL deficiency and prevention of pancreatitis.
Qadri, Firdausi, Wierzba, Thomas F., Ali, Mohammad, Chowdhury, Fahima, Khan, Ashraful I., Saha, Amit, Khan, Iqbal A., Asaduzzaman, Muhammad, Akter, Afroza, Khan, Arifuzzaman, Begum, Yasmin A., Bhuiyan, Taufiqur R., Khanam, Farhana, Chowdhury, Mohiul I., Islam, Taufiqul, Chowdhury, Atique I., Rahman, Anisur, Siddique, Shah A., You, Young A., Kim, Deok R., Siddik, Ashraf U., Saha, Nirod C., Kabir, Alamgir, Cravioto, Alejandro, Desai, Sachin N., Singh, Ajit P., and Clemens, John D.
Ashraf U Mannan, Sagar Bhattad, Chitra Dinakar, Haneesha Pinnamaraju, and Aparna Ganapathy
Subjects
Male, medicine.medical_specialty, Adolescent, medicine.drug_class, DNA Mutational Analysis, Immunology, Antibiotics, Mucocutaneous Candidiasis, medicine.disease_cause, Immunophenotyping, Consanguinity, Medical microbiology, medicine, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Chronic mucocutaneous candidiasis, Genetic Association Studies, Adaptor Proteins, Signal Transducing, Genetic testing, Mutation, Bronchiectasis, medicine.diagnostic_test, business.industry, Candidiasis, Chronic Mucocutaneous, High-Throughput Nucleotide Sequencing, medicine.disease, Dermatology, Pedigree, Oral thrush, Th17 Cells, business, Biomarkers
Abstract
IL-17-mediated signaling is crucial in defense against fungi and bacteria. Defective Th17 immunity has been implicated in a group of disorders called chronic mucocutaneous candidiasis (CMC). TRAF3IP2 is an adaptor protein involved in downstream signaling for IL-17 receptors. An 18-year-old boy, product of consanguineous wedlock, presented with history of repeated episodes of oral thrush and recurrent pneumonia from first year of life. On examination, he was wasted and had oral thrush and abnormal dentition; grade 2 clubbing and respiratory system examination revealed coarse crepitations. On evaluation, HIV status was negative and basic immunological screen was unrewarding. Genetic testing by next-generation sequencing showed a novel homozygous mutation in TRAF3IP2 gene not reported to date. The defect is likely to cause ACT1 deficiency. He was started on antibiotic and antifungal prophylaxis and remains well on follow-up. We describe an adolescent boy with recurrent oral candidiasis and bronchiectasis due to a novel mutation in TRAF3IP2 gene, not reported to date. This is also the only second report of CMC due to ACT1 deficiency.
Mutations in sequestosome 1 (SQSTM1) gene are associated with neurodegenerative diseases, such as frontotemporal dementia and amyotrophic lateral sclerosis. Recently, mutation in SQSTM1 was also found to cause a progressive childhood-onset cerebellar ataxia. We describe here a case of progressive childhood-onset cerebellar ataxia with vertical supra nuclear gaze palsy with no family history and a normal magnetic resonance imaging (MRI) of brain. The clinical exome sequencing in this patient showed a homozygous mutation in SQSTM1. This case highlights the importance of next-generation sequencing in the diagnosis of inherited ataxia syndromes. SQSTM1 mutation should be considered in the differential diagnosis in a patient with both cerebellar ataxia and ophthalmological manifestations.
Avshesh Mishra, Minothi Parulekar, Anaita Udwadia Hegde, Ratna Dua Puri, Vamsi Veeramachaneni, T C Thyagarajan, M. Pradeep Kumar, Sheela Nampoothiri, Swetha Nayanala, Ramshekhar N. Menon, Soumya Sundaram, Vijayashree Gauribidanur Raghavendrachar, Mukunth Sadagopan, Frenny Sheth, Swathi M Chinnappa, Sobha George, Priyanka Kumar, Vykuntaraju K Gowda, Megha Rani Soni, Qurratulain Hasan, A. Radha Rama Devi, Neeta A. Naik, Preetha Tilak, Aparajit Sridharan, Vrajesh Udani, Ramesh Hariharan, Shanmukh Katragadda, Mahesh Kamate, S L Aswathy, Irene Rosita Pia Patric, Divya Pachat, Ashraf U Mannan, Vijay Chandru, Krati Shah, Aparna Ganapathy, H K Vidya, Mohandas Nair, Jayesh Sheth, Manasa B Prakash, Pooja Agrawal, Anil Vittal Kanthi, and P A Mohammed Kunju
Subjects
Data Analysis, Male, Multifactorial Inheritance, medicine.medical_specialty, Pediatrics, Ataxia, Neurology, India, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, 030212 general & internal medicine, Muscular dystrophy, Child, Genetic testing, Neuroradiology, medicine.diagnostic_test, business.industry, Leukodystrophy, High-Throughput Nucleotide Sequencing, medicine.disease, Child, Preschool, Mutation, Cohort, Female, Neurology (clinical), Nervous System Diseases, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract
Neurological disorders are clinically heterogeneous group of disorders and are major causes of disability and death. Several of these disorders are caused due to genetic aberration. A precise and confirmatory diagnosis in the patients in a timely manner is essential for appropriate therapeutic and management strategies. Due to the complexity of the clinical presentations across various neurological disorders, arriving at an accurate diagnosis remains a challenge. We sequenced 1012 unrelated patients from India with suspected neurological disorders, using TruSight One panel. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect mutations in 197 genes in 405 (40%) cases and 178 mutations were novel. The highest diagnostic rate was observed among patients with muscular dystrophy (64%) followed by leukodystrophy and ataxia (43%, each). In our cohort, 26% of the patients who received definitive diagnosis were primarily referred with complex neurological phenotypes with no suggestive diagnosis. In terms of mutations types, 62.8% were truncating and in addition, 13.4% were structural variants, which are also likely to cause loss of function. In our study, we observed an improved performance of multi-gene panel testing, with an overall diagnostic yield of 40%. Furthermore, we show that NGS (next-generation sequencing)-based testing is comprehensive and can detect all types of variants including structural variants. It can be considered as a single-platform genetic test for neurological disorders that can provide a swift and definitive diagnosis in a cost-effective manner.
Upendra Nongthomba, Berty Ashley, Ashraf U Mannan, Sankaramoorthy Aravind, Aparna Ramachandran, Arun Shastry, Keerthi Ramesh, and Aparna Ganapathy
Subjects
0301 basic medicine, Male, Duchenne muscular dystrophy, DNA Mutational Analysis, lcsh:Medicine, Dystrophin, Exon, 0302 clinical medicine, Gene duplication, Multiplex, 030212 general & internal medicine, Deletions, deletions - duchenne muscular dystrophy - multiplex ligation-dependent probe amplification - next-generation sequencing - partial deletion - single-nucleotide variation, multiplex ligation-dependent probe amplification, Child, Sequence Deletion, Sanger sequencing, Molecular Reproduction, Development & Genetics, High-Throughput Nucleotide Sequencing, General Medicine, Exons, Phenotype, Child, Preschool, symbols, Original Article, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, partial deletion, Adolescent, 030106 microbiology, India, Locus (genetics), single-nucleotide variation, Computational biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, symbols.namesake, medicine, Humans, Point Mutation, Multiplex ligation-dependent probe amplification, business.industry, Genome, Human, Point mutation, lcsh:R, medicine.disease, Muscular Dystrophy, Duchenne, Mutation, next-generation sequencing, business, Multiplex Polymerase Chain Reaction, Gene Deletion
Abstract
Background & objectives: Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder and is caused mainly by deletion, duplication and point mutations in the DMD gene. Diagnosis of DMD has been a challenge as the mutations in the DMD gene are heterogeneous and require more than one diagnostic strategy for the validation of the mutation. This study was planned to evaluate the targeted next-generation sequencing (NGS) as a single platform to detect all types of mutations in the DMD gene, thereby reducing the time and costs compared to conventional sequential testing and also provide precise genetic information for emerging gene therapies. Methods: The study included 20 unrelated families and 22 patients from an Indian population who were screened for DMD based on phenotypes such as scoliosis, toe walking and loss of ambulation. Peripheral blood DNA was isolated and subjected to multiplex ligation-dependent probe amplification (MLPA) and targeted NGS of the DMD gene to identify the nature of the mutation. Results: In the study patients, 77 per cent of large deletion mutations and 23 per cent single-nucleotide variations (SNVs) were identified. Novel mutations were also identified along with reported deletions, point mutations and partial deletions within the exon of the DMD gene. Interpretation & conclusions: Our findings showed the importance of NGS in the routine diagnostic practice in the identification of DMD mutations over sequential testing. It may be used as a single-point diagnostic strategy irrespective of the mutation type, thereby reducing the turnaround time and cost for multiple diagnostic tests such as MLPA and Sanger sequencing. Though MLPA is a sensitive technique and is the first line of a diagnostic test, the targeted NGS of the DMD gene may have an advantage of having a single diagnostic test. A study on a larger number of patients is needed to highlight NGS as a single, comprehensive platform for the diagnosis of DMD.
49-year-old female with mood symptoms and progressive personality change diagnosed as Fronto-temporal dementia. I NF1 i is also associated with several neurobehavioral phenotypes, such as ID, ASD, and ADHD.[12] This gene has the highest rate of de novo mutations in the human genome, with ~3000 disease-causing mutations reported. Gene identified was known to be related to the patient's phenotype, but the variant identified was novel, or a new molecular interacting partner(s) of a causative gene was found Neither the gene nor the variant identified had previously been specifically implicated in the patient's phenotype but may have biological and heuristic significance. Genetic variants identified with next-generation sequencing (NGS) could help in accurate diagnosis, provide insights into aspects of disease biology,[1] and, thus, lead to improved care. [Extracted from the article]
Pallavi Ghana, Kathy T. H. Tzeng, Aparna Ganapathy, Ramesh Hariharan, Radhakrishna Bettadapura, Ashwini Manjunath, Joline Dalton, Vamsi Veeramachaneni, Anand Janakiraman, Shradha Saraf, Ashraf U Mannan, Shanmukh Katragadda, Niveditha Ms, Kumar B V S S P Kotha, and Taryn O. Hall
Subjects
0301 basic medicine, Specific test, Computer science, Biochemistry (medical), Clinical Biochemistry, High-Throughput Nucleotide Sequencing, Sample (statistics), Genomics, 030105 genetics & heredity, computer.software_genre, DNA sequencing, Set (abstract data type), 03 medical and health sciences, 030104 developmental biology, Rare Diseases, Pharmacogenetics, Pharmacogenomics, Exome Sequencing, Humans, Data mining, Genetic Testing, computer, Exome sequencing, Reimbursement
Abstract
Background Multi–gene panel sequencing using next-generation sequencing (NGS) methods is a key tool for genomic medicine. However, with an estimated 140 000 genomic tests available, current system inefficiencies result in high genetic-testing costs. Reduced testing costs are needed to expand the availability of genomic medicine. One solution to improve efficiency and lower costs is to calculate the most cost-effective set of panels for a typical pattern of test requests. Methods We compiled rare diseases, associated genes, point prevalence, and test-order frequencies from a representative laboratory. We then modeled the costs of the relevant steps in the NGS process in detail. Using a simulated annealing-based optimization procedure, we determined panel sets that were more cost-optimal than whole exome sequencing (WES) or clinical exome sequencing (CES). Finally, we repeated this methodology to cost-optimize pharmacogenomics (PGx) testing. Results For rare disease testing, we show that an optimal choice of 4–6 panels, uniquely covering genes that comprise 95% of the total prevalence of monogenic diseases, saves $257–304 per sample compared with WES, and $66–135 per sample compared with CES. For PGx, we show that the optimal multipanel solution saves $6–7 (27%–40%) over a single panel covering all relevant gene–drug associations. Conclusions Laboratories can reduce costs using the proposed method to obtain and run a cost-optimal set of panels for specific test requests. In addition, payers can use this method to inform reimbursement policy.