Esteban Astiazaran Symonds

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• Ngeow, J., Chiang, J., Astiazaran-Symonds, E., Balmaña, J., Cass, I., Kommoss, F. K., Foulkes, W. D., James, P. A., Katcher, A., Klugman, S., Livinski, A. A., Mak, J. S., Voian, N., Wick, M. J., Tischkowitz, M., Pal, T., Stewart, D. R., Hanson, H., & , A. P. (2025). Management of individuals with heterozygous germline pathogenic variants in RAD51C, RAD51D, and BRIP1: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics, 27(11), 101557.
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  RAD51C, RAD51D, and BRIP1 germline pathogenic variants (GPVs) are associated with increased lifetime risks of tubo-ovarian cancer. Resources for managing RAD51C, RAD51D, and BRIP1 heterozygotes in clinical practice are limited.
• Pal, T., Schon, K. R., Astiazaran-Symonds, E., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Livinski, A. A., Mak, J. S., Ngeow, J., Voian, N., Wick, M. J., Hanson, H., Stewart, D. R., Tischkowitz, M., & , A. P. (2025). Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics, 27(1), 101243.
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  ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited.
• Parenti, I., Hesters, A., Gil-Salvador, M., Duffy, L., Kanber, D., Beygo, J., Kerkhof, J., Steenpaß, L., Leitão, E., Woestefeld, J., Boone, P. M., Kao, E. M., Alabdi, L., Aldhalaan, H. M., Alkuraya, F. S., Alshammari, M. J., Antonarakis, S. E., Basel, D., Cassinari, K., , de Polli Cellin, L., et al. (2025). Pathogenic variants in the cohesin loader subunit MAU2 lead to a new Cornelia de Lange Syndrome subtype. medRxiv : the preprint server for health sciences.
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  The role of the cohesin complex depends on the cohesin loader proteins NIPBL and MAU2. While variants are a major cause of Cornelia de Lange Syndrome (CdLS), the role of in disease is unclear. We describe 18 individuals carrying 15 heterozygous variants and demonstrate pathogenicity through functional analyses. MAU2 in-frame variants predominantly impair NIPBL-MAU2 interaction, whereas truncating variants cause haploinsufficiency and lead to NIPBL reduction. Most patients exhibit a DNA methylation profile compatible with the CdLS episignature. We also identified two -specific episignatures that reflect variant-dependent molecular consequences. Affected individuals display a wide range of phenotypes, from classic CdLS to milder presentations, with short stature and microcephaly as consistent features. A heterozygous knockout mouse model recapitulated these traits, confirming the causal role of disruption . Our study establishes as a new CdLS-associated gene and delineates a -related chromatinopathy with variable expressivity.
• Hanson, H., Astiazaran-Symonds, E., Amendola, L. M., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Ngeow, J., Schmutzler, R., Voian, N., Wick, M. J., Pal, T., Tischkowitz, M., & Stewart, D. R. (2024). Response to Stern. Genetics in Medicine, 26(Issue 2). doi:10.1016/j.gim.2023.101030
• Kim, J., Ney, G., Frone, M. N., Haley, J. S., Mirshahi, U. L., Astiazaran-Symonds, E., Shandrina, M., Urban, G., Rao, H. S., Stahl, R., Golden, A., Yohe, M. E., Gross, A. M., Ding, Y., Carey, D. J., Gelb, B. D., & Stewart, D. R. (2024). Genomic ascertainment to quantify prevalence and cancer risk in adults with pathogenic and likely pathogenic germline variants in RASopathy genes. medRxiv : the preprint server for health sciences.
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  Genomic ascertainment of electronic health record-linked exome data in two large biobanks was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non- RAS/mitogen-activated protein kinase genes (RASopathies).
• Astiazaran-Symonds, E., Ney, G. M., Higgs, C., Oba, L., Srivastava, R., Livinski, A. A., Rosenberg, P. S., & Stewart, D. R. (2023). Cancer in Costello syndrome: a systematic review and meta-analysis. British Journal of Cancer, 128(Issue 11). doi:10.1038/s41416-023-02229-7
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  Background: Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS. Methods: We conducted a systematic review to identify CS cases to create a retrospective cohort. We tested genotype–phenotype correlations and calculated cumulative incidence and hazard rates (HR) for cancer and cancer-free death, standardised incidence rates (SIR) and survival after cancer. Results: This study includes 234 publications reporting 621 patients from 35 countries. Over nine percent had cancer, including rhabdomyosarcoma, bladder, and neuroblastoma. The rate of cancer and death associated with p.Gly12Ser were lower when compared to all other variants (P < 0.05). Higher mortality for p.Gly12Cys, p.Gly12Asp, p.Gly12Val and p.Gly60Val and higher malignancy rate for p.Gly12Ala were confirmed (P < 0.05). Cumulative incidence by age 20 was 13% (cancer) and 11% (cancer-free death). HR (death) was 3–4% until age 3. Statistically significant SIRs were found for rhabdomyosarcoma (SIR = 1240), bladder (SIR = 1971), and neuroblastoma (SIR = 60). Survival after cancer appeared reduced. Conclusions: This is the largest investigation of cancer in CS to date. The high incidence and SIR values found to highlight the need for rigorous surveillance and evidence-based guidelines for this high-risk population.
• Astiazaran-Symonds, E., Ney, G. M., Higgs, C., Oba, L., Srivastava, R., Livinski, A. A., Rosenberg, P. S., & Stewart, D. R. (2023). Cancer in Costello syndrome: a systematic review and meta-analysis. British journal of cancer, 128(11), 2089-2096.
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  Costello syndrome (CS) is a cancer-predisposition disorder caused by germline pathogenic variants in HRAS. We conducted a systematic review using case reports and case series to characterise cancer risk in CS.
• Feng, J., Karnes, J. H., & Symonds, E. A. (2023). Visualization and Quantification of the Association Between Breast Cancer and Cholesterol in the All of Us Research Program.. Cancer Informatics. doi:10.1177/11769351221144132
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  Epidemiologic evidence for the association of cholesterol and breast cancer is inconsistent. Several factors may contribute to this inconsistency, including limited sample sizes, confounding effects of antihyperlipidemic treatment, age, and body mass index, and the assumption that the association follows a simple linear function. Here, we aimed to address these factors by combining visualization and quantification a large-scale contemporary electronic health record database (the All of Us Research Program). We find clear visual and quantitative evidence that breast cancer is strongly, positively, and near-linearly associated with total cholesterol and low-density lipoprotein cholesterol, but not associated with triglycerides. The association of breast cancer with high-density lipoprotein cholesterol was non-linear and age dependent. Standardized odds ratios were 2.12 (95% confidence interval 1.9-2.48), P = 5.6 × 10-31 for total cholesterol; 1.99 (1.75-2.26), P = 2.6 × 10-26 for low-density lipoprotein cholesterol; 1.69 (1.3-2.2), P = 9.0 × 10-5 for high-density lipoprotein cholesterol at age < 56; and 0.65 (0.55-0.78), P = 1.2 × 10-6 for high-density lipoprotein cholesterol at age ⩾ 56. The inclusion of the lipid levels measured after antihyperlipidemic treatment in the analysis results in erroneous associations. We demonstrate that the use of the logistic regression without inspecting risk variable linearity and accounting for confounding effects may lead to inconsistent results.
• Feng, J., Symonds, E. A., & Karnes, J. H. (2023). Visualization and Quantification of the Association Between Breast Cancer and Cholesterol in the All of Us Research Program. Cancer informatics, 22, 11769351221144132.
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  Epidemiologic evidence for the association of cholesterol and breast cancer is inconsistent. Several factors may contribute to this inconsistency, including limited sample sizes, confounding effects of antihyperlipidemic treatment, age, and body mass index, and the assumption that the association follows a simple linear function. Here, we aimed to address these factors by combining visualization and quantification a large-scale contemporary electronic health record database (the All of Us Research Program). We find clear visual and quantitative evidence that breast cancer is strongly, positively, and near-linearly associated with total cholesterol and low-density lipoprotein cholesterol, but not associated with triglycerides. The association of breast cancer with high-density lipoprotein cholesterol was non-linear and age dependent. Standardized odds ratios were 2.12 (95% confidence interval 1.9-2.48),  = 5.6 × 10 for total cholesterol; 1.99 (1.75-2.26),  = 2.6 × 10 for low-density lipoprotein cholesterol; 1.69 (1.3-2.2),  = 9.0 × 10 for high-density lipoprotein cholesterol at age 
• Goldstein, A. M., Qin, R., Chu, E. Y., Elder, D. E., Massi, D., Adams, D. J., Harms, P. W., Robles-Espinoza, C. D., Newton-Bishop, J. A., Bishop, D. T., Harland, M., Holland, E. A., Cust, A. E., Schmid, H., Mann, G. J., Puig, S., Potrony, M., Alos, L., Nagore, E., , Millán-Esteban, D., et al. (2023). Association of germline variants in telomere maintenance genes ( and ) with spitzoid morphology in familial melanoma: A multi-center case series. JAAD international, 11, 43-51.
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  Spitzoid morphology in familial melanoma has been associated with germline variants in , a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation.
• Goldstein, A. M., Qin, R., Chu, E. Y., Elder, D. E., Massi, D., Adams, D. J., Harms, P. W., Robles-Espinoza, C. D., Newton-Bishop, J. A., Bishop, D. T., Harland, M., Holland, E. A., Cust, A. E., Schmid, H., Mann, G. J., Puig, S., Potrony, M., Alos, L., Nagore, E., , Millán-Esteban, D., et al. (2023). Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series. JAAD International, 11(Issue). doi:10.1016/j.jdin.2023.01.013
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  Background: Spitzoid morphology in familial melanoma has been associated with germline variants in POT1, a telomere maintenance gene (TMG), suggesting a link between telomere biology and spitzoid differentiation. Objective: To assess if familial melanoma cases associated with germline variants in TMG (POT1, ACD, TERF2IP, and TERT) commonly exhibit spitzoid morphology. Methods: In this case series, melanomas were classified as having spitzoid morphology if at least 3 of 4 dermatopathologists reported this finding in ≥25% of tumor cells. Logistic regression was used to calculate odds ratios (OR) of spitzoid morphology compared to familial melanomas from unmatched noncarriers that were previously reviewed by a National Cancer Institute dermatopathologist. Results: Spitzoid morphology was observed in 77% (23 of 30), 75% (3 of 4), 50% (2 of 4), and 50% (1 of 2) of melanomas from individuals with germline variants in POT1, TERF2IP, ACD, and TERT, respectively. Compared to noncarriers (n = 139 melanomas), POT1 carriers (OR = 225.1, 95% confidence interval: 51.7-980.5; P < .001) and individuals with TERF2IP, ACD, and TERT variants (OR = 82.4, 95% confidence interval: 21.3-494.6; P < .001) had increased odds of spitzoid morphology. Limitations: Findings may not be generalizable to nonfamilial melanoma cases. Conclusion: Spitzoid morphology in familial melanoma could suggest germline alteration of TMG.
• Hanson, H., Astiazaran-Symonds, E., Amendola, L. M., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Ngeow, J., Schmutzler, R., Voian, N., Wick, M. J., Pal, T., Tischkowitz, M., & Stewart, D. R. (2023). Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in Medicine, 25(Issue 10). doi:10.1016/j.gim.2023.100870
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  Purpose: Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited. Methods: An international workgroup developed guidance on clinical management of CHEK2 heterozygotes informed by peer-reviewed publications from PubMed. Results: Although CHEK2 is considered a moderate penetrance gene, cancer risks may be considered as a continuous variable, which are influenced by family history and other modifiers. Consequently, early cancer detection and prevention for CHEK2 heterozygotes should be guided by personalized risk estimates. Such estimates may result in both downgrading lifetime breast cancer risks to those similar to the general population or upgrading lifetime risk to a level at which CHEK2 heterozygotes are offered high-risk breast surveillance according to country-specific guidelines. Risk-reducing mastectomy should be guided by personalized risk estimates and shared decision making. Colorectal and prostate cancer surveillance should be considered based on assessment of family history. For CHEK2 heterozygotes who develop cancer, no specific targeted medical treatment is recommended at this time. Conclusion: Systematic prospective data collection is needed to establish the spectrum of CHEK2-associated cancer risks and to determine yet-unanswered questions, such as the outcomes of surveillance, response to cancer treatment, and survival after cancer diagnosis.
• Hanson, H., Astiazaran-Symonds, E., Amendola, L. M., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Ngeow, J., Schmutzler, R., Voian, N., Wick, M. J., Pal, T., Tischkowitz, M., & Stewart, D. R. (2023). Response to Stern. Genetics in medicine : official journal of the American College of Medical Genetics, 101030.
• Hanson, H., Astiazaran-Symonds, E., Amendola, L. M., Balmaña, J., Foulkes, W. D., James, P., Klugman, S., Ngeow, J., Schmutzler, R., Voian, N., Wick, M. J., Pal, T., Tischkowitz, M., Stewart, D. R., & , A. P. (2023). Management of individuals with germline pathogenic/likely pathogenic variants in CHEK2: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genetics in medicine : official journal of the American College of Medical Genetics, 25(10), 100870.
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  Although the role of CHEK2 germline pathogenic variants in cancer predisposition is well known, resources for managing CHEK2 heterozygotes in clinical practice are limited.
• Sargen, M. R., Kim, J., Potjer, T. P., Velthuizen, M. E., Martir-Negron, A. E., Odia, Y., Helgadottir, H., Hatton, J. N., Haley, J. S., Thone, G., Widemann, B. C., Gross, A. M., Yohe, M. E., Kaplan, R. N., Shern, J. F., Sundby, R. T., Astiazaran-Symonds, E., Yang, X. R., Carey, D. J., , Tucker, M. A., et al. (2023). Estimated Prevalence, Tumor Spectrum, and Neurofibromatosis Type 1-Like Phenotype of CDKN2A-Related Melanoma-Astrocytoma Syndrome. JAMA dermatology, 159(10), 1112-1118.
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  Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition.
• Astiazaran-Symonds, E., Graham, C., Kim, J., Tucker, M. A., Ingvar, C., Helgadottir, H., Pastorino, L., van Doorn, R., Sampson, J. N., Zhu, B., Bruno, W., Queirolo, P., Fornarini, G., Sciallero, S., Carter, B., Hicks, B., Hutchinson, A., Jones, K., Stewart, D. R., , Chanock, S. J., et al. (2022). Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in and Pancreatic Cancer. JCO precision oncology, 6, e2200145.
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  Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in . However, it is unclear what role this gene or other genes play in its etiology.
• Astiazaran-Symonds, E., Kim, J., Haley, J. S., Kim, S. Y., Rao, H. S., Center, R. G., Carey, D. J., Stewart, D. R., & Goldstein, A. M. (2022). A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes. Cancers, 14(Issue 13). doi:10.3390/cancers14133257
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  Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are ATM, BRCA1, BRCA2, CDKN2A, CHEK2, and PALB2. However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200, 600 and 175, 449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for CHEK2 to 0.05% for CDKN2A. The frequency of GPV in PDAC cases varied from 2.38% (ATM) to 0.19% (BRCA1 and CDKN2A). The RRs of PDAC were elevated for all genes except for BRCA1 and varied widely by gene from high (ATM) to low (CHEK2, BRCA2). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes.
• Astiazaran-Symonds, E., Kim, J., Haley, J. S., Kim, S. Y., Rao, H. S., Genetics Center, R., Carey, D. J., Stewart, D. R., & Goldstein, A. M. (2022). A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes. Cancers, 14(13).
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  Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are , , , , and . However, GPV prevalence and gene-specific associations have not been extensively studied in the general population. To further explore these associations, we analyzed genomic and phenotypic data obtained from the UK Biobank (UKB) and Geisinger MyCode Community Health Initiative (GHS) cohorts comprising 200,600 and 175,449 participants, respectively. We estimated the frequency and calculated relative risks (RRs) of heterozygotes in both cohorts and a subset of individuals with PDAC. The combined frequency of heterozygous carriers of GPV in the general population ranged from 1.22% for to 0.05% for . The frequency of GPV in PDAC cases varied from 2.38% ( to 0.19% ( and . The RRs of PDAC were elevated for all genes except for and varied widely by gene from high () to low (, ). This work expands our understanding of the frequencies of GPV heterozygous carriers and associations between PDAC and GPV in several important PDAC susceptibility genes.
• Astiazaran-Symonds, E., & Goldstein, A. M. (2021). A systematic review of the prevalence of germline pathogenic variants in patients with pancreatic cancer. Journal of gastroenterology, 56(8), 713-721.
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  The genetics of pancreatic ductal adenocarcinoma (PDAC) is complex with patients reported to harbor germline pathogenic variants (PVs) in many different genes. PDAC patients with familial pancreatic cancer (FPC) are more likely to carry germline PVs but there is no consensus main gene involved in FPC. We performed a systematic review of publications from PubMed and Scopus reporting PVs in patients with FPC, sporadic pancreatic cancer (SPC) and unselected cohorts of PDAC patients undergoing genetic testing and calculated a cumulative prevalence of PVs for each gene evaluated across these three groups of patients. When available, variants in the selected publications were reclassified according to the American College of Medical Genetics and Genomics classification system and used for prevalence calculations if classified as pathogenic or likely pathogenic. We observed an increased prevalence of PVs in FPC compared to SPC or unselected PDAC patients for most of the 41 genes reported. The genes with the highest prevalence of carriers of PVs in FPC were ATM, BRCA2, and CDKN2A. BRCA2 and ATM showed the highest prevalence of PVs in both SPC and unselected PDAC cohorts. Several genes with the highest prevalence of PVs are involved in breast and ovarian cancer suggesting strong overlap with underlying genetics in these disorders but no single gene was predominant. More research is needed to further understand the risk of PDAC associated with these many diverse genes.
• Xiao, C., Astiazaran-Symonds, E., Basu, S., Kisling, M., Scaglia, F., Chapman, K. A., Wang, Y., Vockley, J., & Ferreira, C. R. (2020). Mitochondrial energetic impairment in a patient with late-onset glutaric acidemia Type 2. American journal of medical genetics. Part A, 182(10), 2426-2431.
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  Glutaric acidemia type 2 (GA2), also called multiple acyl-CoA dehydrogenase deficiency, is an autosomal recessive disorder of fatty acid, amino acid, and choline metabolism resulting in excretion of multiple organic acids and glycine conjugates as well as elevation of various plasma acylcarnitine species (C4-C18). It is caused by mutations in the ETFA, ETFB, or ETFDH genes which are involved in the transfer of electrons from 11 flavin-containing dehydrogenases to Coenzyme Q (CoQ ) of the mitochondrial electron transport chain (ETC). We report a patient who was originally reported as the first case with primary myopathic CoQ deficiency when he presented at 11.5 years with exercise intolerance and myopathy that improved after treatment with ubiquinone and carnitine. At age 23, his symptoms relapsed despite increasing doses of ubiquinone and he was shown to have biallelic mutations in the ETFDH gene. Treatment with riboflavin was started and ubiquinone was changed to ubiquinol. After 4 months, the patient recovered his muscle strength with normalization of laboratory exams and exercise tolerance. Functional studies on fibroblasts revealed decreased levels of ETFDH as well as of very long-chain acyl-CoA dehydrogenase and trifunctional protein α. In addition, the mitochondrial mass was decreased, with increased formation of reactive oxygen species and oxygen consumption rate, but with a decreased spared respiratory capacity, and decreased adenosine triphosphate level. These findings of widespread dysfunction of fatty acid oxidation and ETC enzymes support the impairment of a larger mitochondrial ETC supercomplex in our patient.
• López, P. D., Andreias, L., Astiazarán-Symonds, E., & Chalabi, J. (2017). Fabry Disease: An Uncommon Cause of Renal Failure. American Journal of Medicine, 130(Issue 9). doi:10.1016/j.amjmed.2017.02.047
• López, P. D., Andreias, L., Astiazarán-Symonds, E., & Chalabi, J. (2017). Fabry Disease: An Uncommon Cause of Renal Failure. The American journal of medicine, 130(9), e389-e390.

Proceedings Publications

• Sargen, M. R., Kim, J., Potjer, T. P., Velthuizen, M. E., Martir-Negron, A. E., Odia, Y., Helgadottir, H., Hatton, J. N., Haley, J. S., Thone, G., Widemann, B. C., Gross, A. M., Yohe, M. E., Kaplan, R. N., Shern, J. F., Sundby, R. T., Astiazaran-Symonds, E., Yang, X. R., Carey, D. J., , Tucker, M. A., et al. (2023). Estimated Prevalence, Tumor Spectrum, and Neurofibromatosis Type 1-Like Phenotype of CDKN2A -Related Melanoma-Astrocytoma Syndrome. In JAMA dermatology, 159.
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  Importance: Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition. Objective: To estimate the prevalence and describe the tumor types of MAS. Design, Setting, and Participants: This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank [United Kingdom], Geisinger MyCode [US]) between January 1, 1976, and December 31, 2020. Patients with MAS with CDKN2A germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023. Main Outcomes and Measures: Disease prevalence and tumor frequency. Results: Prevalence of MAS ranged from 1 in 170503 (n = 1 case; 95% CI, 1:30098-1:965887) in Geisinger MyCode (n = 170503; mean [SD] age, 58.9 [19.1] years; 60.6% women; 96.2% White) to 1 in 39149 (n = 12 cases; 95% CI, 1:22396-1:68434) in UK Biobank (n = 469789; mean [SD] age, 70.0 [8.0] years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n = 12) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic CDKN2A splicing variant (c.151-1G>C) and was negative for NF1 genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in CDKN2A, including 1 individual with no detected variants in the NF1 gene. Conclusions and Relevance: This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.