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1. Clinical exome sequencing data from patients with inborn errors of immunity: Cohort level diagnostic yield and the benefit of systematic reanalysis

Author

Arts, Rob J.W., Bijker, Else M., Bruno, Mariolina, Hobo, Willemijn, Hoppenreijs, Esther, de Jonge, Marien I., van Laarhoven, Arjan, van der Molen, Renate, Oud, Manon, Schatorje, Ellen J.H., Smeets, Ruben, Sprenkeler, Evelien G.G., Stol, Kim, Verhagen, Lilly M., Zonneveld-Huijssoon, Evelien, Vorsteveld, Emil E., Van der Made, Caspar I., Smeekens, Sanne P., Schuurs-Hoeijmakers, Janneke H., Astuti, Galuh, Diepstra, Heleen, Gilissen, Christian, Hoenselaar, Evelien, Janssen, Alice, van Roozendaal, Kees, Engelen, Jettie Sikkema-van, Steyaert, Wouter, Weiss, Marjan M., Yntema, Helger G., Mantere, Tuomo, AlZahrani, Mofareh S., van Aerde, Koen, Derfalvi, Beata, Faqeih, Eissa Ali, Henriet, Stefanie S.V., van Hoof, Elise, Idressi, Eman, Issekutz, Thomas B., Jongmans, Marjolijn C.J., Keski-Filppula, Riikka, Krapels, Ingrid, te Loo, Maroeska, Mulders-Manders, Catharina M., ten Oever, Jaap, Potjewijd, Judith, Sarhan, Nora Tarig, Slot, Marjan C., Terhal, Paulien A., Thijs, Herman, Vandersteen, Anthony, Vanhoutte, Els K., van de Veerdonk, Frank, van Well, Gijs, Netea, Mihai G., Simons, Annet, and Hoischen, Alexander

Published
2024
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2. PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework

Author

Dingemans, Alexander J. M., Hinne, Max, Truijen, Kim M. G., Goltstein, Lia, van Reeuwijk, Jeroen, de Leeuw, Nicole, Schuurs-Hoeijmakers, Janneke, Pfundt, Rolph, Diets, Illja J., den Hoed, Joery, de Boer, Elke, Coenen-van der Spek, Jet, Jansen, Sandra, van Bon, Bregje W., Jonis, Noraly, Ockeloen, Charlotte W., Vulto-van Silfhout, Anneke T., Kleefstra, Tjitske, Koolen, David A., Campeau, Philippe M., Palmer, Elizabeth E., Van Esch, Hilde, Lyon, Gholson J., Alkuraya, Fowzan S., Rauch, Anita, Marom, Ronit, Baralle, Diana, van der Sluijs, Pleuntje J., Santen, Gijs W. E., Kooy, R. Frank, van Gerven, Marcel A. J., Vissers, Lisenka E. L. M., and de Vries, Bert B. A.

Published
2023
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6. The heterogeneous cancer phenotype of individuals with biallelic germline pathogenic variants in CHEK2

Author

Hinić, Snežana, Cybulski, Cezary, Van der Post, Rachel S., Vos, Janet R., Schuurs-Hoeijmakers, Janneke, Brugnoletti, Fulvia, Koene, Saskia, Vreede, Lilian, van Zelst-Stams, Wendy A.G., Kets, C. Marleen, Haadsma, Maaike, Spruijt, Liesbeth, Wevers, Marijke R., Evans, D. Gareth, Wimmer, Katharina, Schnaiter, Simon, Volk, Alexander E., Möllring, Anna, de Putter, Robin, Soikkonen, Leila, Kahre, Tiina, Tooming, Mikk, de Jong, Mirjam M., Vaz, Fátima, Mensenkamp, Arjen R., Genuardi, Maurizio, Lubinski, Jan, Ligtenberg, Marjolijn, Hoogerbrugge, Nicoline, and de Voer, Richarda M.

Published
2024
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7. Haploinsufficiency of ZFHX3, encoding a key player in neuronal development, causes syndromic intellectual disability

Author

Agrawal, Pankaj, Armstrong Scott, Daryl, Barkoudah, Elizabeth, Bellini, Melissa, Beneteau, Claire, Bjørgo, Kathrine, Brooks, Alice, Brown, Natasha, Castle, Alison, Castro, Diana, Chorin, Odelia, Cleghorn, Mark, Clement, Emma, Coman, David, Costin, Carrie, Devriendt, Koen, Dong, Dexin, Dries, Annika, Duelund Hjortshøj, Tina, Dyment, David, Eng, Christine, Genetti, Casie, Grano, Siera, Henneman, Peter, Heron, Delphine, Hoffmann, Katrin, Hom, Jason, Du, Haowei, Iascone, Maria, Isidor, Bertrand, Järvelä, Irma E., Jones, Julie, Keren, Boris, Koenig, Mary Kay, Kohlhase, Jürgen, Lalani, Seema, Le Caignec, Cedric, Lewis, Andi, Liu, Pengfei, Lovgren, Alysia, Lupski, James R., Lyons, Mike, Lysy, Philippe, Manning, Melanie, Marcelis, Carlo, McLean, Scott Douglas, Mercie, Sandra, Mertens, Mareike, Molin, Arnaud, Nizon, Mathilde, Nugent, Kimberly Margaret, Öhman, Susanna, O'Leary, Melanie, Okashah Littlejohn, Rebecca, Petit, Florence, Pfundt, Rolph, Pottocki, Lorraine, Raas-Rotschild, Annick, Ranguin, Kara, Revencu, Nicole, Rosenfeld, Jill, Rhodes, Lindsay, Santos Simmaro, Fernando, Sals, Karen, Schieving, Jolanda, Schrauwen, Isabelle, Schuurs-Hoeijmakers, Janneke H.M., Seaby, Eleanor G., Sheffer, Ruth, Snijders Blok, Lot, Sørensen, Kristina P., Srivastava, Siddharth, Stark, Zornitza, Stoeva, Radka, Stutterd, Chloe, Tan, Natalie B., Mathiesen Torring, Pernille, Vanakker, Olivier, van der Laan, Liselot, Ververi, Athina, Villavicencio-Lorini, Pablo, Vincent, Marie, Wand, Dorothea, Wessels, Marja, White, Sue, Wojcik, Monica H., Wu, Nan, Zhao, Sen, Pérez Baca, María del Rocío, Jacobs, Eva Z., Vantomme, Lies, Leblanc, Pontus, Bogaert, Elke, Dheedene, Annelies, De Cock, Laurenz, Haghshenas, Sadegheh, Foroutan, Aidin, Levy, Michael A., Kerkhof, Jennifer, McConkey, Haley, Chen, Chun-An, Batzir, Nurit Assia, Wang, Xia, Palomares, María, Carels, Marieke, Dermaut, Bart, Sadikovic, Bekim, Menten, Björn, Yuan, Bo, Vergult, Sarah, and Callewaert, Bert

Published
2024
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8. Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi DP, Huber, Hannes, Murry, Jaclyn B, Abramson, Jeff, Althoff, Thorsten, Banka, Siddharth, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J, Berland, Siren, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A, Braathen, Geir Julius, Busk, Øyvind L, Chenbhanich, Jirat, Denecke, Jonas, Escobar, Luis F, Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A, Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Le Guyader, Gwenael, Ljungblad, Ulf W, Brenman, Leslie Manace, Martinez-Agosto, Julian A, Might, Matthew, Miller, David T, Minks, Kelly Q, Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F, Parant, John M, Prescott, Trine, Rajabi, Farrah, Randrianaivo, Hanitra, Reiter, Simone F, Schuurs-Hoeijmakers, Janneke, Shieh, Perry B, Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander PA, Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H, Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Kreienkamp, Hans-Jürgen, and Lessel, Davor

Subjects
Biological Sciences, Genetics, Pediatric, Clinical Research, Mental Health, Prevention, Aetiology, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Detection, screening and diagnosis, Animals, Biomarkers, Gene Expression, Gene Knockdown Techniques, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, HEK293 Cells, Humans, Immunohistochemistry, Mutation, Neurodevelopmental Disorders, Phenotype, RNA Helicases, Zebrafish, Clinical Sciences
Abstract

BackgroundWe aimed to define the clinical and variant spectrum and to provide novel molecular insights into the DHX30-associated neurodevelopmental disorder.MethodsClinical and genetic data from affected individuals were collected through Facebook-based family support group, GeneMatcher, and our network of collaborators. We investigated the impact of novel missense variants with respect to ATPase and helicase activity, stress granule (SG) formation, global translation, and their effect on embryonic development in zebrafish. SG formation was additionally analyzed in CRISPR/Cas9-mediated DHX30-deficient HEK293T and zebrafish models, along with in vivo behavioral assays.ResultsWe identified 25 previously unreported individuals, ten of whom carry novel variants, two of which are recurrent, and provide evidence of gonadal mosaicism in one family. All 19 individuals harboring heterozygous missense variants within helicase core motifs (HCMs) have global developmental delay, intellectual disability, severe speech impairment, and gait abnormalities. These variants impair the ATPase and helicase activity of DHX30, trigger SG formation, interfere with global translation, and cause developmental defects in a zebrafish model. Notably, 4 individuals harboring heterozygous variants resulting either in haploinsufficiency or truncated proteins presented with a milder clinical course, similar to an individual harboring a de novo mosaic HCM missense variant. Functionally, we established DHX30 as an ATP-dependent RNA helicase and as an evolutionary conserved factor in SG assembly. Based on the clinical course, the variant location, and type we establish two distinct clinical subtypes. DHX30 loss-of-function variants cause a milder phenotype whereas a severe phenotype is caused by HCM missense variants that, in addition to the loss of ATPase and helicase activity, lead to a detrimental gain-of-function with respect to SG formation. Behavioral characterization of dhx30-deficient zebrafish revealed altered sleep-wake activity and social interaction, partially resembling the human phenotype.ConclusionsOur study highlights the usefulness of social media to define novel Mendelian disorders and exemplifies how functional analyses accompanied by clinical and genetic findings can define clinically distinct subtypes for ultra-rare disorders. Such approaches require close interdisciplinary collaboration between families/legal representatives of the affected individuals, clinicians, molecular genetics diagnostic laboratories, and research laboratories.

Published
2021

9. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author

Duijkers, Floor, Giltay, Jacques C., van Hest, Liselotte P., Kleefstra, Tjitske, Leter, Edward M., Nielsen, Maartje, Nijmeijer, Sebastiaan W.R., Olderode-Berends, Maran J.W., Hendricks, Linda A.J., Hoogerbrugge, Nicoline, Venselaar, Hanka, Aretz, Stefan, Spier, Isabel, Legius, Eric, Brems, Hilde, de Putter, Robin, Claes, Kathleen B.M., Evans, D. Gareth, Woodward, Emma R., Genuardi, Maurizio, Brugnoletti, Fulvia, van Ierland, Yvette, Dijke, Kim, Tham, Emma, Tesi, Bianca, Schuurs-Hoeijmakers, Janneke H.M., Branchaud, Maud, Salvador, Hector, Jahn, Arne, Schnaiter, Simon, Anastasiadou, Violetta Christophidou, Brunet, Joan, Oliveira, Carla, Roht, Laura, Blatnik, Ana, Irmejs, Arvids, Mensenkamp, Arjen R., and Vos, Janet R.

Published
2022
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10. KAT6A Syndrome: genotype–phenotype correlation in 76 patients with pathogenic KAT6A variants

Author

Kennedy, Joanna, Goudie, David, Blair, Edward, Chandler, Kate, Joss, Shelagh, McKay, Victoria, Green, Andrew, Armstrong, Ruth, Lees, Melissa, Kamien, Benjamin, Hopper, Bruce, Tan, Tiong Yang, Yap, Patrick, Stark, Zornitza, Okamoto, Nobuhiko, Miyake, Noriko, Matsumoto, Naomichi, Macnamara, Ellen, Murphy, Jennifer L, McCormick, Elizabeth, Hakonarson, Hakon, Falk, Marni J, Li, Dong, Blackburn, Patrick, Klee, Eric, Babovic-Vuksanovic, Dusica, Schelley, Susan, Hudgins, Louanne, Kant, Sarina, Isidor, Bertrand, Cogne, Benjamin, Bradbury, Kimberley, Williams, Mark, Patel, Chirag, Heussler, Helen, Duff-Farrier, Celia, Lakeman, Phillis, Scurr, Ingrid, Kini, Usha, Elting, Mariet, Reijnders, Margot, Schuurs-Hoeijmakers, Janneke, Wafik, Mohamed, Blomhoff, Anne, Ruivenkamp, Claudia AL, Nibbeling, Esther, Dingemans, Alexander JM, Douine, Emilie D, Nelson, Stanley F, Hempel, Maja, Bierhals, Tatjana, Lessel, Davor, Johannsen, Jessika, Arboleda, Valerie A, and Newbury-Ecob, Ruth

Subjects
Biological Sciences, Genetics, Prevention, Brain Disorders, Rare Diseases, Pediatric, Clinical Research, Digestive Diseases, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Adolescent, Adult, Child, Child, Preschool, Chromosome Deletion, Developmental Disabilities, Exome, Female, Genetic Association Studies, Genotype, Histone Acetyltransferases, Humans, Infant, Intellectual Disability, Male, Microcephaly, Mutation, Phenotype, Protein Isoforms, Young Adult, genetic diagnosis, phenotypic spectrum, KAT6A syndrome, chromatin modifiers, intellectual disability, DDD Study, KAT6A syndrome, chromatin modifiers, intellectual disability, Clinical Sciences, Genetics & Heredity
Abstract

PurposePathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported.MethodsWe obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review.ResultsWe identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype- phenotype correlations show that late-truncating pathogenic variants (exons 16-17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction.ConclusionOur data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management.

Published
2019

12. Histopathological phenotyping of cancers in PTEN Hamartoma Tumor Syndrome for improved recognition: A single‐center study.

Author

Schei‐Andersen, Ane J., Hendricks, Linda A. J., van der Post, Rachel S., Mensenkamp, Arjen R., Schieving, Jolanda, Adank, Muriel A., Duijkers, Floor, de Jong, Mirjam, Jongemans, Marjolijn C. J., van Hest, Liselotte P., van Ierland, Yvette, Kleefstra, Tjitske, Leter, Edward M., Nielsen, Maartje, Schuurs‐Hoeijmakers, Janneke H. M., Hoogerbrugge, Nicoline, and Vos, Janet R.

Subjects
HEREDITARY cancer syndromes, DISEASE risk factors, AGE of onset, BENIGN tumors, HUMAN genetics
Abstract

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early‐onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre‐screen for other PHTS features or direct germline testing. [ABSTRACT FROM AUTHOR]

Published
2024
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14. Prevalence of comorbidities in individuals with neurodevelopmental disorders from the aggregated phenomics data of 51,227 pediatric individuals

Author

Dingemans, Alexander J. M., primary, Jansen, Sandra, additional, van Reeuwijk, Jeroen, additional, de Leeuw, Nicole, additional, Pfundt, Rolph, additional, Schuurs-Hoeijmakers, Janneke, additional, van Bon, Bregje W., additional, Marcelis, Carlo, additional, Ockeloen, Charlotte W., additional, Willemsen, Marjolein, additional, van der Sluijs, Pleuntje J., additional, Santen, Gijs W. E., additional, Kooy, R. Frank, additional, Vulto-van Silfhout, Anneke T., additional, Kleefstra, Tjitske, additional, Koolen, David A., additional, Vissers, Lisenka E. L. M., additional, and de Vries, Bert B. A., additional

Published
2024
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15. Expanding the PRAAS spectrum: De novo mutations of immunoproteasome subunit β-type 10 in six infants with SCID-Omenn syndrome

Author

van der Made, Caspar I., primary, Kersten, Simone, additional, Chorin, Odelia, additional, Engelhardt, Karin R., additional, Ramakrishnan, Gayatri, additional, Griffin, Helen, additional, Schim van der Loeff, Ina, additional, Venselaar, Hanka, additional, Rothschild, Annick Raas, additional, Segev, Meirav, additional, Schuurs-Hoeijmakers, Janneke H.M., additional, Mantere, Tuomo, additional, Essers, Rick, additional, Esteki, Masoud Zamani, additional, Avital, Amir L., additional, Loo, Peh Sun, additional, Simons, Annet, additional, Pfundt, Rolph, additional, Warris, Adilia, additional, Seyger, Marieke M., additional, van de Veerdonk, Frank L., additional, Netea, Mihai G., additional, Slatter, Mary A., additional, Flood, Terry, additional, Gennery, Andrew R., additional, Simon, Amos J., additional, Lev, Atar, additional, Frizinsky, Shirley, additional, Barel, Ortal, additional, van der Burg, Mirjam, additional, Somech, Raz, additional, Hambleton, Sophie, additional, Henriet, Stefanie S.V., additional, and Hoischen, Alexander, additional

Published
2024
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16. Biallelic variants in TMEM222 cause a new autosomal recessive neurodevelopmental disorder

Author

Polla, Daniel L., Farazi Fard, Mohammad Ali, Tabatabaei, Zahra, Habibzadeh, Parham, Levchenko, Olga A., Nikuei, Pooneh, Makrythanasis, Periklis, Hussain, Mureed, von Hardenberg, Sandra, Zeinali, Sirous, Fallah, Mohammad-Sadegh, Schuurs-Hoeijmakers, Janneke H. M., Shahzad, Mohsin, Fatima, Fareeha, Fatima, Neelam, Kaat, Laura Donker, Bruggenwirth, Hennie T., Fleming, Leah R., Condie, John, Ploski, Rafal, Pollak, Agnieszka, Pilch, Jacek, Demina, Nina A., Chukhrova, Alena L., Sergeeva, Vasilina S., Venselaar, Hanka, Masri, Amira T., Hamamy, Hanan, Santoni, Federico A., Linda, Katrin, Ahmed, Zubair M., Nadif Kasri, Nael, de Brouwer, Arjan P. M., Bergmann, Anke K., Hethey, Sven, Yavarian, Majid, Ansar, Muhammad, Riazuddin, Saima, Riazuddin, Sheikh, Silawi, Mohammad, Ruggeri, Gaia, Pirozzi, Filomena, Eftekhar, Ebrahim, Taghipour Sheshdeh, Afsaneh, Bahramjahan, Shima, Mirzaa, Ghayda M., Lavrov, Alexander V., Antonarakis, Stylianos E., Faghihi, Mohammad Ali, and van Bokhoven, Hans

Published
2021
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17. OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition

Author

MMB Onderzoek en Onderwijs, Infection & Immunity, MMB Medische Staf, Arts, Rob J W, van der Linden, Tristan J, van der Made, Caspar I, Hendriks, Marianne M C, van der Heijden, Wouter A, de Mast, Quirijn, Schuurs-Hoeijmakers, Janneke H M, Simons, Annet, Spaan, András N, Mulders-Manders, Catharina M, van de Veerdonk, Frank L, MMB Onderzoek en Onderwijs, Infection & Immunity, MMB Medische Staf, Arts, Rob J W, van der Linden, Tristan J, van der Made, Caspar I, Hendriks, Marianne M C, van der Heijden, Wouter A, de Mast, Quirijn, Schuurs-Hoeijmakers, Janneke H M, Simons, Annet, Spaan, András N, Mulders-Manders, Catharina M, and van de Veerdonk, Frank L

Published
2024

18. Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS)

Author

Hendricks, Linda A.J., Verbeek, Katja C.J., Schuurs-Hoeijmakers, Janneke H.M., Mensenkamp, Arjen R., Brems, Hilde, de Putter, Robin, Anastasiadou, Violetta C., Villy, Marie Charlotte, Jahn, Arne, Steinke-Lange, Verena, Baldassarri, Margherita, Irmejs, Arvids, de Jong, Mirjam M., Links, Thera P., Leter, Edward M., Bosch, Daniëlle G.M., Høberg-Vetti, Hildegunn, Tveit Haavind, Marianne, Jørgensen, Kjersti, Mæhle, Lovise, Blatnik, Ana, Brunet, Joan, Darder, Esther, Tham, Emma, Hoogerbrugge, Nicoline, Vos, Janet R., Hendricks, Linda A.J., Verbeek, Katja C.J., Schuurs-Hoeijmakers, Janneke H.M., Mensenkamp, Arjen R., Brems, Hilde, de Putter, Robin, Anastasiadou, Violetta C., Villy, Marie Charlotte, Jahn, Arne, Steinke-Lange, Verena, Baldassarri, Margherita, Irmejs, Arvids, de Jong, Mirjam M., Links, Thera P., Leter, Edward M., Bosch, Daniëlle G.M., Høberg-Vetti, Hildegunn, Tveit Haavind, Marianne, Jørgensen, Kjersti, Mæhle, Lovise, Blatnik, Ana, Brunet, Joan, Darder, Esther, Tham, Emma, Hoogerbrugge, Nicoline, and Vos, Janet R.

Abstract

Females with PTEN Hamartoma Tumor Syndrome (PHTS) have breast cancer risks up to 76%. This study assessed associations between breast cancer and lifestyle in European female adult PHTS patients. Data were collected via patient questionnaires (July 2020–March 2023) and genetic diagnoses from medical files. Associations between lifestyle and breast cancer were calculated using logistic regression corrected for age. Index patients with breast cancer before PHTS diagnosis (breast cancer index) were excluded for ascertainment bias correction. In total, 125 patients were included who completed the questionnaire at a mean age of 44 years (SD = 13). This included 21 breast cancer indexes (17%) and 39 females who developed breast cancer at 43 years (SD = 9). Breast cancer patients performed about 1.1 times less often 0–1 times/week physical activity than ≥2 times (ORtotal-adj = 0.9 (95%CI 0.3–2.6); consumed daily about 1.2–1.8 times more often ≥1 than 0–1 glasses of alcohol (ORtotal-adj = 1.2 (95%CI 0.4–4.0); ORnon-breastcancer-index-adj = 1.8 (95%CI 0.4–6.9); were about 1.04–1.3 times more often smokers than non-smokers (ORtotal-adj = 1.04 (95%CI 0.4–2.8); ORnon-breastcancer-index-adj = 1.3 (95%CI 0.4–4.2)); and overweight or obesity (72%) was about 1.02–1.3 times less common (ORtotal-adj = 0.98 (95%CI 0.4–2.6); ORnon-breastcancer-index-adj = 0.8 (95%CI 0.3–2.7)). Similar associations between lifestyle and breast cancer are suggested for PHTS and the general population. Despite not being statistically significant, results are clinically relevant and suggest that awareness of the effects of lifestyle on patients’ breast cancer risk is important.

Published
2024

19. The genomic landscape of breast and non-breast cancers from individuals with germline CHEK2 deficiency.

Author

Hinić, Snežana, Post, Rachel S van der, Vreede, Lilian, Schuurs-Hoeijmakers, Janneke, Koene, Saskia, Jansen, Erik A M, Bervoets-Metge, Franziska, Mensenkamp, Arjen R, Hoogerbrugge, Nicoline, Ligtenberg, Marjolijn J L, and Voer, Richarda M de

Subjects
CHECKPOINT kinase 2, BREAST cancer, HOMOLOGOUS recombination, GERM cells, BRCA genes
Abstract

CHEK2 is considered to be involved in homologous recombination repair (HRR). Individuals who have germline pathogenic variants (gPVs) in CHEK2 are at increased risk to develop breast cancer and likely other primary cancers. PARP inhibitors (PARPi) have been shown to be effective in the treatment of cancers that present with HRR deficiency—for example, caused by inactivation of BRCA1/2. However, clinical trials have shown little to no efficacy of PARPi in patients with CHEK2 gPVs. Here, we show that both breast and non-breast cancers from individuals who have biallelic gPVs in CHEK2 (germline CHEK2 deficiency) do not present with molecular profiles that fit with HRR deficiency. This finding provides a likely explanation why PARPi therapy is not successful in the treatment of CHEK2 -deficient cancers. [ABSTRACT FROM AUTHOR]

Published
2024
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20. Lifestyle Factors and Breast Cancer in Females with PTEN Hamartoma Tumor Syndrome (PHTS)

Author

Hendricks, Linda A. J., primary, Verbeek, Katja C. J., additional, Schuurs-Hoeijmakers, Janneke H. M., additional, Mensenkamp, Arjen R., additional, Brems, Hilde, additional, de Putter, Robin, additional, Anastasiadou, Violetta C., additional, Villy, Marie-Charlotte, additional, Jahn, Arne, additional, Steinke-Lange, Verena, additional, Baldassarri, Margherita, additional, Irmejs, Arvids, additional, de Jong, Mirjam M., additional, Links, Thera P., additional, Leter, Edward M., additional, Bosch, Daniëlle G. M., additional, Høberg-Vetti, Hildegunn, additional, Tveit Haavind, Marianne, additional, Jørgensen, Kjersti, additional, Mæhle, Lovise, additional, Blatnik, Ana, additional, Brunet, Joan, additional, Darder, Esther, additional, Tham, Emma, additional, Hoogerbrugge, Nicoline, additional, and Vos, Janet R., additional

Published
2024
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21. OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition

Author

Arts, Rob J. W., primary, van der Linden, Tristan J., additional, van der Made, Caspar I., additional, Hendriks, Marianne M. C., additional, van der Heijden, Wouter A., additional, de Mast, Quirijn, additional, Schuurs-Hoeijmakers, Janneke H. M., additional, Simons, Annet, additional, Spaan, András N., additional, Mulders-Manders, Catharina M., additional, and van de Veerdonk, Frank L., additional

Published
2023
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22. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Blok, Lot Snijders, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot RF, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T, Hoischen, Alexander, Vissers, Lisenka ELM, Koemans, Tom S, Wissink-Lindhout, Willemijn, Eichler, Evan E, Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, van Bon, Bregje WM, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L, Van Dijck, Anke, Innes, A Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J, Henderson, Alex, Lynch, Sally A, Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Study, the DDD, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, van Gassen, Koen LI, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L, Pediaditakis, Igor, Haas, Stefan A, Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G, Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C, Stein, Quinn, Strauss, Kevin A, Brigatti, Karlla W, Keating, Katherine, Burton, Barbara K, Kim, Katherine H, Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D, Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M, van Roozendaal, Kees, Brunner, Han, Chung, Wendy K, Kooy, R Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G, Katsanis, Nicholas, and Kleefstra, Tjitske

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Amino Acid Substitution, Animals, Base Sequence, DEAD-box RNA Helicases, Embryo, Nonmammalian, Exome, Female, Gene Dosage, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Sequence Analysis, DNA, Sex Characteristics, Wnt Signaling Pathway, Zebrafish, DDD Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

23. Heterozygous OTULIN-variant related fasciitis and skin necrosis treated by TNF inhibition.

Author

Arts, Rob JW, primary, Linden, Tristan J van der, additional, de Made, Caspar I van, additional, Hendriks, Marianne MC, additional, Heijden, Wouter A van der, additional, de Mast, Quirijn, additional, Schuurs-Hoeijmakers, Janneke HM, additional, Simons, Annet, additional, Spaan, András N, additional, Mulders-Manders, Catharina M, additional, and de Veerdonk, Frank L van, additional

Published
2023
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25. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

Author

Jansen, Sandra, Hoischen, Alexander, Coe, Bradley P., Carvill, Gemma L., Van Esch, Hilde, Bosch, Daniëlle G. M., Andersen, Ulla A., Baker, Carl, Bauters, Marijke, Bernier, Raphael A., van Bon, Bregje W., Claahsen-van der Grinten, Hedi L., Gecz, Jozef, Gilissen, Christian, Grillo, Lucia, Hackett, Anna, Kleefstra, Tjitske, Koolen, David, Kvarnung, Malin, Larsen, Martin J., Marcelis, Carlo, McKenzie, Fiona, Monin, Marie-Lorraine, Nava, Caroline, Schuurs-Hoeijmakers, Janneke H., Pfundt, Rolph, Steehouwer, Marloes, Stevens, Servi J. C., Stumpel, Connie T., Vansenne, Fleur, Vinci, Mirella, van de Vorst, Maartje, Vries, Petra de, Witherspoon, Kali, Veltman, Joris A., Brunner, Han G., Mefford, Heather C., Romano, Corrado, Vissers, Lisenka E. L. M., Eichler, Evan E., and de Vries, Bert B. A.

Published
2018
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26. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome

Author

Hendricks, Linda A.J., Hoogerbrugge, Nicoline, Mensenkamp, Arjen R., Brunet, Joan, Lleuger-Pujol, Roser, Høberg-Vetti, Hildegunn, Haavind, Marianne Tveit, Innella, Giovanni, Turchetti, Daniela, Aretz, Stefan, Spier, Isabel, Tischkowitz, Marc, Jahn, Arne, Links, Thera P., Olderode-Berends, Maran J.W., Blatnik, Ana, Leter, Edward M., Evans, D. Gareth, Woodward, Emma R., Steinke-Lange, Verena, Anastasiadou, Violetta C., Colas, Chrystelle, Villy, Marie Charlotte, Benusiglio, Patrick R., Gerasimenko, Anna, Barili, Valeria, Branchaud, Maud, Houdayer, Claude, Tesi, Bianca, Yazicioglu, M. Omer, van der Post, Rachel S., Schuurs-Hoeijmakers, Janneke H.M., Vos, Janet R., Duijkers, Floor, van Ierland, Yvette, Hendricks, Linda A.J., Hoogerbrugge, Nicoline, Mensenkamp, Arjen R., Brunet, Joan, Lleuger-Pujol, Roser, Høberg-Vetti, Hildegunn, Haavind, Marianne Tveit, Innella, Giovanni, Turchetti, Daniela, Aretz, Stefan, Spier, Isabel, Tischkowitz, Marc, Jahn, Arne, Links, Thera P., Olderode-Berends, Maran J.W., Blatnik, Ana, Leter, Edward M., Evans, D. Gareth, Woodward, Emma R., Steinke-Lange, Verena, Anastasiadou, Violetta C., Colas, Chrystelle, Villy, Marie Charlotte, Benusiglio, Patrick R., Gerasimenko, Anna, Barili, Valeria, Branchaud, Maud, Houdayer, Claude, Tesi, Bianca, Yazicioglu, M. Omer, van der Post, Rachel S., Schuurs-Hoeijmakers, Janneke H.M., Vos, Janet R., Duijkers, Floor, and van Ierland, Yvette

Abstract

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. Methods: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. Results: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range ¼ 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] ¼ 43.0% to 66.4%) to 75.8% (95% CI ¼ 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI ¼ 2.1% to 18.6%) to 22.1% (95% CI ¼ 11.6% to 39.6%) and TC risks from 8.9% (95% CI ¼ 5.1% to 15.3%) to 20.5% (95% CI ¼ 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. Conclusions: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

Published
2023

27. Molecular mechanism of extracutaneous tumours in patients with basal cell nevus syndrome

Author

Verkouteren, Babette Ja, Roemen, Guido Mjm, Schuurs-Hoeijmakers, Janneke Hm, Abdul Hamid, Myrurgia, van Geel, Michel, Speel, Ernst-Jan M, Mosterd, Klara, Verkouteren, Babette Ja, Roemen, Guido Mjm, Schuurs-Hoeijmakers, Janneke Hm, Abdul Hamid, Myrurgia, van Geel, Michel, Speel, Ernst-Jan M, and Mosterd, Klara

Abstract

Basal cell nevus syndrome (BCNS) is a rare genetic disorder accompanied by a broad variety of tumours, of which basal cell carcinomas and odontogenic keratocysts are the most common. BCNS is caused by a germline or postzygotic mutation in either PTCH1 or SUFU As BCNS is a rare disease, it is difficult to establish whether less frequently occurring tumours are actually part of the syndrome. In this study, the molecular mechanism behind four extracutaneous tumours in patients with BCNS was elucidated. A leiomyoma of the testis and meningioma were confirmed to be associated with BCNS in two patients by presence of a second mutation or loss of heterozygosity in PTCH1 In a meningioma of a patient with a mosaic postzygotic PTCH1 mutation an association could not be conclusively confirmed. SUFU was probably not involved in the development of a thyroid carcinoma in a patient with a germline SUFU mutation. Hence, we have proven that meningioma and leiomyoma of the testis are rare extracutaneous tumours that are part of BCNS.

Published
2023

29. Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies

Author

Arts, Peer, Simons, Annet, AlZahrani, Mofareh S., Yilmaz, Elanur, AlIdrissi, Eman, van Aerde, Koen J., Alenezi, Njood, AlGhamdi, Hamza A., AlJubab, Hadeel A., Al-Hussaini, Abdulrahman A., AlManjomi, Fahad, Alsaad, Alaa B., Alsaleem, Badr, Andijani, Abdulrahman A., Asery, Ali, Ballourah, Walid, Bleeker-Rovers, Chantal P., van Deuren, Marcel, van der Flier, Michiel, Gerkes, Erica H., Gilissen, Christian, Habazi, Murad K., Hehir-Kwa, Jayne Y., Henriet, Stefanie S., Hoppenreijs, Esther P., Hortillosa, Sarah, Kerkhofs, Chantal H., Keski-Filppula, Riikka, Lelieveld, Stefan H., Lone, Khurram, MacKenzie, Marius A., Mensenkamp, Arjen R., Moilanen, Jukka, Nelen, Marcel, ten Oever, Jaap, Potjewijd, Judith, van Paassen, Pieter, Schuurs-Hoeijmakers, Janneke H. M., Simon, Anna, Stokowy, Tomasz, van de Vorst, Maartje, Vreeburg, Maaike, Wagner, Anja, van Well, Gijs T. J., Zafeiropoulou, Dimitra, Zonneveld-Huijssoon, Evelien, Veltman, Joris A., van Zelst-Stams, Wendy A. G., Faqeih, Eissa A., van de Veerdonk, Frank L., Netea, Mihai G., and Hoischen, Alexander

Published
2019
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30. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author

Hendricks, Linda A.J., primary, Hoogerbrugge, Nicoline, additional, Venselaar, Hanka, additional, Aretz, Stefan, additional, Spier, Isabel, additional, Legius, Eric, additional, Brems, Hilde, additional, de Putter, Robin, additional, Claes, Kathleen B.M., additional, Evans, D. Gareth, additional, Woodward, Emma R., additional, Genuardi, Maurizio, additional, Brugnoletti, Fulvia, additional, van Ierland, Yvette, additional, Dijke, Kim, additional, Tham, Emma, additional, Tesi, Bianca, additional, Schuurs-Hoeijmakers, Janneke H.M., additional, Branchaud, Maud, additional, Salvador, Hector, additional, Jahn, Arne, additional, Schnaiter, Simon, additional, Anastasiadou, Violetta Christophidou, additional, Brunet, Joan, additional, Oliveira, Carla, additional, Roht, Laura, additional, Blatnik, Ana, additional, Irmejs, Arvids, additional, Mensenkamp, Arjen R., additional, Vos, Janet R., additional, Duijkers, Floor, additional, Giltay, Jacques C., additional, van Hest, Liselotte P., additional, Kleefstra, Tjitske, additional, Leter, Edward M., additional, Nielsen, Maartje, additional, Nijmeijer, Sebastiaan W.R., additional, and Olderode-Berends, Maran J.W., additional

Published
2022
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31. Cancer risks by sex and variant type in PTEN Hamartoma Tumor Syndrome

Author

Hendricks, Linda A J, Hoogerbrugge, Nicoline, Mensenkamp, Arjen R, Brunet, Joan, Lleuger-Pujol, Roser, Høberg-Vetti, Hildegunn, Haavind, Marianne Tveit, Innella, Giovanni, Turchetti, Daniela, Aretz, Stefan, Spier, Isabel, Tischkowitz, Marc, Jahn, Arne, Links, Thera P, Olderode-Berends, Maran J W, Blatnik, Ana, Leter, Edward M, Evans, D Gareth, Woodward, Emma R, Steinke-Lange, Verena, Anastasiadou, Violetta C, Colas, Chrystelle, Villy, Marie-Charlotte, Benusiglio, Patrick R, Gerasimenko, Anna, Barili, Valeria, Branchaud, Maud, Houdayer, Claude, Tesi, Bianca, Yazicioglu, M Omer, van der Post, Rachel S, Schuurs-Hoeijmakers, Janneke H M, Vos, Janet R, MUMC+: DA KG Polikliniek (9), RS: FHML non-thematic output, Human genetics, CCA - Cancer biology and immunology, and Cancer Center Amsterdam

Subjects
Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], Cancer Research, All institutes and research themes of the Radboud University Medical Center, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], SDG 3 - Good Health and Well-being, Oncology, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14]
Abstract

Background PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. Methods This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. Results A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. Conclusions Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

Published
2022

32. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome

Author

Hendricks, Linda AJ, Hoogerbrugge, Nicoline, Mensenkamp, Arjen R, Brunet, Joan, Lleuger-Pujol, Roser, Høberg-Vetti, Hildegunn, Tveit Haavind, Marianne, Innella, Giovanni, Turchetti, Daniela, Aretz, Stefan, Spier, Isabel, Tischkowitz, Marc, Jahn, Arne, Links, Thera P, Olderode-Berends, Maran JW, Blatnik, Ana, Leter, Edward M, Evans, D Gareth, Woodward, Emma R, Steinke-Lange, Verena, Anastasiadou, Violetta C, Colas, Chrystelle, Villy, Marie-Charlotte, Benusiglio, Patrick R, Gerasimenko, Anna, Barili, Valeria, Branchaud, Maud, Houdayer, Claude, Tesi, Bianca, Yazicioglu, M Omer, Van Der Post, Rachel S, Schuurs-Hoeijmakers, Janneke HM, PTEN Study Group, Vos, Janet R, Hendricks, Linda AJ [0000-0002-1008-0265], Hoogerbrugge, Nicoline [0000-0003-2393-8141], Mensenkamp, Arjen R [0000-0003-3805-877X], Brunet, Joan [0000-0003-1945-3512], Tischkowitz, Marc [0000-0002-7880-0628], Links, Thera P [0000-0001-5327-1718], Vos, Janet R [0000-0001-8802-7002], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Cohort Studies, PTEN Phosphohydrolase, Humans, Female, Prospective Studies, Thyroid Neoplasms, Middle Aged, Hamartoma Syndrome, Multiple, Kidney Neoplasms, Germ-Line Mutation
Abstract

BACKGROUND: PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS: This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS: A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS: Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.

Published
2022
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33. PhenoScore: AI-based phenomics to quantify rare disease and genetic variation

Author

Dingemans, Alexander J M, primary, Hinne, Max, additional, Truijen, Kim M G, additional, Goltstein, Lia, additional, van Reeuwijk, Jeroen, additional, de Leeuw, Nicole, additional, Schuurs-Hoeijmakers, Janneke, additional, Pfundt, Rolph, additional, Diets, Illja J, additional, den Hoed, Joery, additional, de Boer, Elke, additional, Coenen-van der Spek, Jet, additional, Jansen, Sandra, additional, van Bon, Bregje W, additional, Jonis, Noraly, additional, Ockeloen, Charlotte, additional, Vulto-van Silfhout, Anneke T, additional, Kleefstra, Tjitske, additional, Koolen, David A, additional, Van Esch, Hilde, additional, Lyon, Gholson J, additional, Alkuraya, Fowzan S, additional, Rauch, Anita, additional, Marom, Ronit, additional, Baralle, Diana, additional, van der Sluijs, Pleuntje J, additional, Santen, Gijs W E, additional, Kooy, R Frank, additional, van Gerven, Marcel A J, additional, Vissers, Lisenka E L M, additional, and de Vries, Bert B A, additional

Published
2022
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34. Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study

Author

Hebert, Anne, primary, Simons, Annet, additional, Schuurs-Hoeijmakers, Janneke HM, additional, Koenen, Hans JPM, additional, Zonneveld-Huijssoon, Evelien, additional, Henriet, Stefanie SV, additional, Schatorjé, Ellen JH, additional, Hoppenreijs, Esther PAH, additional, Leenders, Erika KSM, additional, Janssen, Etienne JM, additional, Santen, Gijs WE, additional, de Munnik, Sonja A, additional, van Reijmersdal, Simon V, additional, van Rijssen, Esther, additional, Kersten, Simone, additional, Netea, Mihai G, additional, Smeets, Ruben L, additional, van de Veerdonk, Frank L, additional, Hoischen, Alexander, additional, and van der Made, Caspar I, additional

Published
2022
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35. Author response: Trio-based whole exome sequencing in patients with suspected sporadic inborn errors of immunity: A retrospective cohort study

Author

Hebert, Anne, primary, Simons, Annet, additional, Schuurs-Hoeijmakers, Janneke HM, additional, Koenen, Hans JPM, additional, Zonneveld-Huijssoon, Evelien, additional, Henriet, Stefanie SV, additional, Schatorjé, Ellen JH, additional, Hoppenreijs, Esther PAH, additional, Leenders, Erika KSM, additional, Janssen, Etienne JM, additional, Santen, Gijs WE, additional, de Munnik, Sonja A, additional, van Reijmersdal, Simon V, additional, van Rijssen, Esther, additional, Kersten, Simone, additional, Netea, Mihai G, additional, Smeets, Ruben L, additional, van de Veerdonk, Frank L, additional, Hoischen, Alexander, additional, and van der Made, Caspar I, additional

Published
2022
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37. Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

Author

Hendricks, Linda A.J., Hoogerbrugge, Nicoline, Venselaar, Hanka, Aretz, Stefan, Spier, Isabel, Legius, Eric, Brems, Hilde, de Putter, Robin, Claes, Kathleen B.M., Evans, D. Gareth, Woodward, Emma R., Genuardi, Maurizio, Brugnoletti, Fulvia, van Ierland, Yvette, Dijke, Kim, Tham, Emma, Tesi, Bianca, Schuurs-Hoeijmakers, Janneke H.M., Branchaud, Maud, Salvador, Hector, Jahn, Arne, Schnaiter, Simon, Anastasiadou, Violetta Christophidou, Brunet, Joan, Oliveira, Carla, Roht, Laura, Blatnik, Ana, Irmejs, Arvids, Mensenkamp, Arjen R., Vos, Janet R., Hendricks, Linda A.J., Hoogerbrugge, Nicoline, Venselaar, Hanka, Aretz, Stefan, Spier, Isabel, Legius, Eric, Brems, Hilde, de Putter, Robin, Claes, Kathleen B.M., Evans, D. Gareth, Woodward, Emma R., Genuardi, Maurizio, Brugnoletti, Fulvia, van Ierland, Yvette, Dijke, Kim, Tham, Emma, Tesi, Bianca, Schuurs-Hoeijmakers, Janneke H.M., Branchaud, Maud, Salvador, Hector, Jahn, Arne, Schnaiter, Simon, Anastasiadou, Violetta Christophidou, Brunet, Joan, Oliveira, Carla, Roht, Laura, Blatnik, Ana, Irmejs, Arvids, Mensenkamp, Arjen R., and Vos, Janet R.

Abstract

Background: Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study. Methods: Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age. Results: At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2. Conclusion: The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.

Published
2022

39. Clinical delineation of the PACS1-related syndrome—Report on 19 patients

Author

Schuurs-Hoeijmakers, Janneke H. M., Landsverk, Megan L., Foulds, Nicola, Kukolich, Mary K., Gavrilova, Ralitza H., Greville-Heygate, Stephanie, Hanson-Kahn, Andrea, Bernstein, Jonathan A., Glass, Jennifer, Chitayat, David, Burrow, Thomas A., Husami, Ammar, Collins, Kathleen, Wusik, Katie, van der Aa, Nathalie, Kooy, Frank, Brown, Kate Tatton, Gadzicki, Dorothea, Kini, Usha, Alvarez, Sara, Fernández-Jaén, Alberto, McGehee, Frank, Selby, Katherine, Tarailo-Graovac, Maja, Van Allen, Margot, van Karnebeek, Clara D. M., Stavropoulos, Dimitri J., Marshall, Christian R., Merico, Daniele, Gregor, Anne, Zweier, Christiane, Hopkin, Robert J., Chu, Yoyo Wing-Yiu, Chung, Brian Hon-Yin, de Vries, Bert B. A., Devriendt, Koenraad, Hurles, Matthew E., and Brunner, Han G.

Published
2016
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41. Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

Author

Solanich, Xavier, primary, Vargas-Parra, Gardenia, additional, van der Made, Caspar I., additional, Simons, Annet, additional, Schuurs-Hoeijmakers, Janneke, additional, Antolí, Arnau, additional, del Valle, Jesús, additional, Rocamora-Blanch, Gemma, additional, Setién, Fernando, additional, Esteller, Manel, additional, van Reijmersdal, Simon V., additional, Riera-Mestre, Antoni, additional, Sabater-Riera, Joan, additional, Capellá, Gabriel, additional, van de Veerdonk, Frank L., additional, van der Hoven, Ben, additional, Corbella, Xavier, additional, Hoischen, Alexander, additional, and Lázaro, Conxi, additional

Published
2021
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42. Additional file 4 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 4: Figure S2. De novo mosaicism in individual 6.

Published
2021
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43. Additional file 6 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 6. Clinical reports of here presented individuals.

Published
2021
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44. Additional file 5 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 5: Figure S3. Whole gene deletion in individual 24.

Published
2021
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45. Additional file 8 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 8: Figure S5. Recombinant protein variants of DHX30 induce the formation of cytoplasmic clusters.

Published
2021
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46. Additional file 1 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 1. Supplementary methods.

Published
2021
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47. Additional file 7 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 7: Figure S4. DHX30 WT acts as an ATP-dependent RNA helicase.

Published
2021
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48. Additional file 3 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Abstract

Additional file 3: Figure S1. Identified missense variants affect highly conserved amino acids.

Published
2021
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49. Additional file 9 of Genotype–phenotype correlations and novel molecular insights into the DHX30-associated neurodevelopmental disorders

Author

Mannucci, Ilaria, Dang, Nghi D. P., Huber, Hannes, Murry, Jaclyn B., Abramson, Jeff, Althoff, Thorsten, Siddharth Banka, Baynam, Gareth, Bearden, David, Beleza-Meireles, Ana, Benke, Paul J., Siren Berland, Bierhals, Tatjana, Bilan, Frederic, Bindoff, Laurence A., Braathen, Geir Julius, Busk, Øyvind L., Jirat Chenbhanich, Denecke, Jonas, Escobar, Luis F., Estes, Caroline, Fleischer, Julie, Groepper, Daniel, Haaxma, Charlotte A., Hempel, Maja, Holler-Managan, Yolanda, Houge, Gunnar, Jackson, Adam, Kellogg, Laura, Keren, Boris, Kiraly-Borri, Catherine, Kraus, Cornelia, Kubisch, Christian, Guyader, Gwenael Le, Ljungblad, Ulf W., Brenman, Leslie Manace, Martinez-Agosto, Julian A., Might, Matthew, Miller, David T., Minks, Kelly Q., Moghaddam, Billur, Nava, Caroline, Nelson, Stanley F., Parant, John M., Prescott, Trine, Rajabi, Farrah, Hanitra Randrianaivo, Reiter, Simone F., Schuurs-Hoeijmakers, Janneke, Shieh, Perry B., Slavotinek, Anne, Smithson, Sarah, Stegmann, Alexander P. A., Tomczak, Kinga, Tveten, Kristian, Wang, Jun, Whitlock, Jordan H., Zweier, Christiane, McWalter, Kirsty, Juusola, Jane, Quintero-Rivera, Fabiola, Fischer, Utz, Yeo, Nan Cher, Hans-Jürgen Kreienkamp, and Lessel, Davor

Subjects
animal structures, fungi, embryonic structures
Abstract

Additional file 9: Figure S6. Representative images of zebrafish embryos.

Published
2021
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50. Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

Author

Solanich, Xavier, Vargas-Parra, Gardenia, van der Made, Caspar I., Simons, Annet, Schuurs-Hoeijmakers, Janneke, Antolí, Arnau, del Valle, Jesús, Rocamora-Blanch, Gemma, Setién, Fernando, Esteller, Manel, van Reijmersdal, Simon V., Riera-Mestre, Antoni, Sabater-Riera, Joan, Capellá, Gabriel, van de Veerdonk, Frank L., van der Hoven, Ben, Corbella, Xavier, Hoischen, Alexander, Lázaro, Conxi, Solanich, Xavier, Vargas-Parra, Gardenia, van der Made, Caspar I., Simons, Annet, Schuurs-Hoeijmakers, Janneke, Antolí, Arnau, del Valle, Jesús, Rocamora-Blanch, Gemma, Setién, Fernando, Esteller, Manel, van Reijmersdal, Simon V., Riera-Mestre, Antoni, Sabater-Riera, Joan, Capellá, Gabriel, van de Veerdonk, Frank L., van der Hoven, Ben, Corbella, Xavier, Hoischen, Alexander, and Lázaro, Conxi

Abstract

Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.

Published
2021

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