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1. Long-term outcome of high-grade serous carcinoma established in risk-reducing salpingo-oophorectomy specimens in asymptomatic BRCA1/2 germline pathogenic variant carriers

Author

Stroot, Iris A.S., Bart, Joost, Hollema, Harry, Jalving, Mathilde, Wagner, Marise M., Yigit, Refika, van Doorn, Helena C., de Hullu, Joanne A., Gaarenstroom, Katja N., van Beurden, Marc, van Lonkhuijzen, Luc R.C.W., Slangen, Brigitte F.M., Zweemer, Ronald P., Gómez García, Encarna B., Ausems, Margreet G.E.M., Boere, Ingrid A., van Hest, Liselotte P., Duijkers, Floor A.M., van Asperen, Christi J., Schmidt, Marjanka K., Wevers, Marijke R., Ruijs, Marielle W.G., Devilee, Peter, Collée, J. Margriet, HEBON investigators, de Bock, Geertruida H., and Mourits, Marian J.E.

Published
2024
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3. Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Author

van der Werf-’t Lam, Anne-Sophie, Terlouw, Diantha, Tops, Carli M., van Kan, Merel S., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-ten Broeke, Sanne W., Bleeker, Fonnet E., Gomez Garcia, Encarna B., de Wind, Niels, van Wezel, J. Tom, Morreau, Hans, Suerink, Manon, and Nielsen, Maartje

Published
2023
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4. Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome–Associated Colorectal Carcinomas

Author

Terlouw, Diantha, Bajwa-ten Broeke, Sanne W., Rodríguez-Girondo, Mar, van Egmond, Demi, Langers, Alexandra M.J., van Leerdam, Monique E., Rayner, Emily, van Asperen, Christi J., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bleeker, Fonnet E., Gomez Garcìa, Encarna B., Suerink, Manon, Tops, Carli M., de Wind, Niels, Helderman, Noah c., Van Der Werf-’T Lam, Anne-Sophie, Morreau, Hans, Boot, Arnoud, Van Wezel, Tom, and Nielsen, Maartje

Published
2023
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5. No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation

Author

Genetica, Genetica Oper.Mang. Clinical Genetics, Cancer, Genetica Klinische Genetica, Child Health, Onderzoek Beeld, Bakhuizen, Jette J., Postema, Floor A.M., van Rijn, Rick R., van Schuppen, Joost, Duijkers, Floor A.M., van Noesel, Carel J.M., Hennekam, Raoul C., Jongmans, Marjolijn C.J., Savci-Heijink, C. Dilara, Smetsers, Stephanie E., Terheggen-Lagro, Suzanne W.J., Hopman, Saskia M.J., Oomen, Matthijs W.N., Merks, Johannes H.M., Genetica, Genetica Oper.Mang. Clinical Genetics, Cancer, Genetica Klinische Genetica, Child Health, Onderzoek Beeld, Bakhuizen, Jette J., Postema, Floor A.M., van Rijn, Rick R., van Schuppen, Joost, Duijkers, Floor A.M., van Noesel, Carel J.M., Hennekam, Raoul C., Jongmans, Marjolijn C.J., Savci-Heijink, C. Dilara, Smetsers, Stephanie E., Terheggen-Lagro, Suzanne W.J., Hopman, Saskia M.J., Oomen, Matthijs W.N., and Merks, Johannes H.M.

Published
2024

6. Long-term outcome of high-grade serous carcinoma established in risk-reducing salpingo-oophorectomy specimens in asymptomatic BRCA1/2 germline pathogenic variant carriers

Author

MS Gynaecologische Oncologie, Cancer, Genetica, Genetica Klinische Genetica, Stroot, Iris A.S., Bart, Joost, Hollema, Harry, Jalving, Mathilde, Wagner, Marise M., Yigit, Refika, van Doorn, Helena C., de Hullu, Joanne A., Gaarenstroom, Katja N., van Beurden, Marc, van Lonkhuijzen, Luc R.C.W., Slangen, Brigitte F.M., Zweemer, Ronald P., Gómez García, Encarna B., Ausems, Margreet G.E.M., Boere, Ingrid A., van Hest, Liselotte P., Duijkers, Floor A.M., van Asperen, Christi J., Schmidt, Marjanka K., Wevers, Marijke R., Ruijs, Marielle W.G., Devilee, Peter, Collée, J. Margriet, HEBON investigators, investigators, de Bock, Geertruida H., Mourits, Marian J.E., MS Gynaecologische Oncologie, Cancer, Genetica, Genetica Klinische Genetica, Stroot, Iris A.S., Bart, Joost, Hollema, Harry, Jalving, Mathilde, Wagner, Marise M., Yigit, Refika, van Doorn, Helena C., de Hullu, Joanne A., Gaarenstroom, Katja N., van Beurden, Marc, van Lonkhuijzen, Luc R.C.W., Slangen, Brigitte F.M., Zweemer, Ronald P., Gómez García, Encarna B., Ausems, Margreet G.E.M., Boere, Ingrid A., van Hest, Liselotte P., Duijkers, Floor A.M., van Asperen, Christi J., Schmidt, Marjanka K., Wevers, Marijke R., Ruijs, Marielle W.G., Devilee, Peter, Collée, J. Margriet, HEBON investigators, investigators, de Bock, Geertruida H., and Mourits, Marian J.E.

Published
2024

7. Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome

Author

Genetica, Genetica Klinische Genetica, Child Health, van der Werf-'t Lam, Anne Sophie, Rodriguez-Girondo, Mar, Villasmil, Mandy, Tops, Carli M., van Hest, Liselotte, Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis, Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-ten Broeke, Sanne W., Bleeker, Fonnet, Gomez Garcia, Encarna B., Dominguez-Valentin, Mev, Møller, Pal, Suerink, Manon, Nielsen, Maartje, Genetica, Genetica Klinische Genetica, Child Health, van der Werf-'t Lam, Anne Sophie, Rodriguez-Girondo, Mar, Villasmil, Mandy, Tops, Carli M., van Hest, Liselotte, Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis, Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-ten Broeke, Sanne W., Bleeker, Fonnet, Gomez Garcia, Encarna B., Dominguez-Valentin, Mev, Møller, Pal, Suerink, Manon, and Nielsen, Maartje

Published
2024

8. The detection of a strong episignature for Chung–Jansen syndrome, partially overlapping with Börjeson–Forssman–Lehmann and White–Kernohan syndromes

Author

Vos, Niels, Haghshenas, Sadegheh, van der Laan, Liselot, Russel, Perle K.M., Rooney, Kathleen, Levy, Michael A., Relator, Raissa, Kerkhof, Jennifer, McConkey, Haley, Maas, Saskia M., Vissers, Lisenka E.L.M., de Vries, Bert B.A., Pfundt, Rolph, Elting, Mariet W., van Hagen, Johanna M., Verbeek, Nienke E., Jongmans, Marjolijn C.J., Lakeman, Phillis, Rumping, Lynne, Bosch, Danielle G.M., Vitobello, Antonio, Thauvin-Robinet, Christel, Faivre, Laurence, Nambot, Sophie, Garde, Aurore, Willems, Marjolaine, Genevieve, David, Nicolas, Gaël, Busa, Tiffany, Toutain, Annick, Gérard, Marion, Bizaoui, Varoona, Isidor, Bertrand, Merla, Giuseppe, Accadia, Maria, Schwartz, Charles E., Ounap, Katrin, Hoffer, Mariëtte J.V., Nezarati, Marjan M., van den Boogaard, Marie José H., Tedder, Matthew L., Rogers, Curtis, Brusco, Alfredo, Ferrero, Giovanni B., Spodenkiewicz, Marta, Sidlow, Richard, Mussa, Alessandro, Trajkova, Slavica, McCann, Emma, Mroczkowski, Henry J., Jansen, Sandra, Donker-Kaat, Laura, Duijkers, Floor A.M., Stuurman, Kyra E., Mannens, Marcel M.A.M., Alders, Mariëlle, Henneman, Peter, White, Susan M., Sadikovic, Bekim, van Haelst, Mieke M., Vos, Niels, Haghshenas, Sadegheh, van der Laan, Liselot, Russel, Perle K.M., Rooney, Kathleen, Levy, Michael A., Relator, Raissa, Kerkhof, Jennifer, McConkey, Haley, Maas, Saskia M., Vissers, Lisenka E.L.M., de Vries, Bert B.A., Pfundt, Rolph, Elting, Mariet W., van Hagen, Johanna M., Verbeek, Nienke E., Jongmans, Marjolijn C.J., Lakeman, Phillis, Rumping, Lynne, Bosch, Danielle G.M., Vitobello, Antonio, Thauvin-Robinet, Christel, Faivre, Laurence, Nambot, Sophie, Garde, Aurore, Willems, Marjolaine, Genevieve, David, Nicolas, Gaël, Busa, Tiffany, Toutain, Annick, Gérard, Marion, Bizaoui, Varoona, Isidor, Bertrand, Merla, Giuseppe, Accadia, Maria, Schwartz, Charles E., Ounap, Katrin, Hoffer, Mariëtte J.V., Nezarati, Marjan M., van den Boogaard, Marie José H., Tedder, Matthew L., Rogers, Curtis, Brusco, Alfredo, Ferrero, Giovanni B., Spodenkiewicz, Marta, Sidlow, Richard, Mussa, Alessandro, Trajkova, Slavica, McCann, Emma, Mroczkowski, Henry J., Jansen, Sandra, Donker-Kaat, Laura, Duijkers, Floor A.M., Stuurman, Kyra E., Mannens, Marcel M.A.M., Alders, Mariëlle, Henneman, Peter, White, Susan M., Sadikovic, Bekim, and van Haelst, Mieke M.

Abstract

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung–Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung–Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White–Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson–Forssman–Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung–Jansen, Börjeson–Forssman–Lehmann and White–Kernohan syndromes.

Published
2024

9. Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome

Author

van der Werf-'t Lam, Anne Sophie, Rodriguez-Girondo, Mar, Villasmil, Mandy, Tops, Carli M., van Hest, Liselotte, Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis, Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-ten Broeke, Sanne W., Bleeker, Fonnet, Gomez Garcia, Encarna B., Dominguez-Valentin, Mev, Møller, Pal, Suerink, Manon, Nielsen, Maartje, van der Werf-'t Lam, Anne Sophie, Rodriguez-Girondo, Mar, Villasmil, Mandy, Tops, Carli M., van Hest, Liselotte, Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis, Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-ten Broeke, Sanne W., Bleeker, Fonnet, Gomez Garcia, Encarna B., Dominguez-Valentin, Mev, Møller, Pal, Suerink, Manon, and Nielsen, Maartje

Abstract

Background: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. Patients and Methods: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). Results: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77–1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43–1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46–0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52–1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65–1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64–1.19). Discussion and Conclusion: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Published
2024

10. No Pathogenic DICER1 Gene Variants in a Cohort Study of 28 Children With Congenital Pulmonary Airway Malformation

Author

Bakhuizen, Jette J., primary, Postema, Floor A.M., additional, van Rijn, Rick R., additional, van Schuppen, Joost, additional, Duijkers, Floor A.M., additional, van Noesel, Carel J.M., additional, Hennekam, Raoul C., additional, Jongmans, Marjolijn C.J., additional, Savci-Heijink, C. Dilara, additional, Smetsers, Stephanie E., additional, Terheggen-Lagro, Suzanne W.J., additional, Hopman, Saskia M.J., additional, Oomen, Matthijs W.N., additional, and Merks, Johannes H.M., additional

Published
2023
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11. Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome–Associated Colorectal Carcinomas

Author

Helderman, Noah c., primary, Van Der Werf-’T Lam, Anne-Sophie, additional, Morreau, Hans, additional, Boot, Arnoud, additional, Van Wezel, Tom, additional, Nielsen, Maartje, additional, Terlouw, Diantha, additional, Bajwa-ten Broeke, Sanne W., additional, Rodríguez-Girondo, Mar, additional, van Egmond, Demi, additional, Langers, Alexandra M.J., additional, van Leerdam, Monique E., additional, Rayner, Emily, additional, van Asperen, Christi J., additional, van Hest, Liselotte P., additional, Gille, Hans J.P., additional, Duijkers, Floor A.M., additional, Wagner, Anja, additional, Eikenboom, Ellis L., additional, Letteboer, Tom G.W., additional, de Jong, Mirjam M., additional, Bleeker, Fonnet E., additional, Gomez Garcìa, Encarna B., additional, Suerink, Manon, additional, Tops, Carli M., additional, and de Wind, Niels, additional

Published
2023
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12. Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Author

van der Werf-'t Lam, Anne Sophie, Terlouw, Diantha, Tops, Carli M., van Kan, Merel S., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-Ten Broeke, Sanne W., Bleeker, Fonnet E., Gomez Garcia, Encarna B., de Wind, Niels, van Wezel, J. Tom, Morreau, Hans, Suerink, Manon, Nielsen, Maartje, van der Werf-'t Lam, Anne Sophie, Terlouw, Diantha, Tops, Carli M., van Kan, Merel S., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa-Ten Broeke, Sanne W., Bleeker, Fonnet E., Gomez Garcia, Encarna B., de Wind, Niels, van Wezel, J. Tom, Morreau, Hans, Suerink, Manon, and Nielsen, Maartje

Abstract

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.

Published
2023

13. Molecular Profile of MSH6-Associated Colorectal Carcinomas Shows Distinct Features From Other Lynch Syndrome–Associated Colorectal Carcinomas

Author

Helderman, Noah c., Van Der Werf-’T Lam, Anne Sophie, Terlouw, Diantha, Bajwa-ten Broeke, Sanne W., Rodríguez-Girondo, Mar, van Egmond, Demi, Langers, Alexandra M.J., van Leerdam, Monique E., Rayner, Emily, van Asperen, Christi J., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bleeker, Fonnet E., Gomez Garcìa, Encarna B., Suerink, Manon, Tops, Carli M., de Wind, Niels, Morreau, Hans, Boot, Arnoud, Van Wezel, Tom, Nielsen, Maartje, Helderman, Noah c., Van Der Werf-’T Lam, Anne Sophie, Terlouw, Diantha, Bajwa-ten Broeke, Sanne W., Rodríguez-Girondo, Mar, van Egmond, Demi, Langers, Alexandra M.J., van Leerdam, Monique E., Rayner, Emily, van Asperen, Christi J., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bleeker, Fonnet E., Gomez Garcìa, Encarna B., Suerink, Manon, Tops, Carli M., de Wind, Niels, Morreau, Hans, Boot, Arnoud, Van Wezel, Tom, and Nielsen, Maartje

Published
2023

14. A Likely Pathogenic variant in the KBTBD13Gene: A Case Series of Three Patients with Nemaline Myopathy Type 6

Author

van Kleef, Esmee S.B., Bouman, Karlijn, Molenaar, Joery P.F., de Winter, Josine M., Duijkers, Floor A.M., Eftimov, Filip, Verschuuren-Bemelmans, Corien C., van der Laan, Tineke, Küsters, Benno, Malfatti, Edoardo, Kamsteeg, Erik-Jan, van Engelen, Baziel G.M., Ottenheijm, Coen A.C., Doorduin, Jonne, and Voermans, Nicol C.

Abstract

Nemaline myopathy type 6 (NEM6) or KBTBD13-related congenital myopathy is the most prevalent type of nemaline myopathy in the Netherlands and is characterised by mild childhood-onset axial, proximal and distal muscle weakness with prominent neck flexor weakness combined with slowness of movements. The most prevalent variant in the Netherlands is the c.1222C > T p.(Arg408Cys) variant in the KBTBD13gene, also called the Dutch founder variant. To provide a comprehensive clinical and functional characterisation of three patients to assess the pathogenicity of a newly identified variant in the KBTBD13gene. We present three cases (Patient 1: female, 76 years old; Patient 2: male, 63 years old; and his brother Patient 3: male, 61 years old) with a c.1222C > A p.(Arg408Ser) variant in the KBTBD13gene. Patient 1 was also included previously in a histopathological study on NEM6. Symptoms of muscle weakness started in childhood and progressed to impaired functional abilities in adulthood. All three patients reported slowness of movements. On examination, they have mild axial, proximal and distal muscle weakness. None of the patients exhibited cardiac abnormalities. Spirometry in two patients showed a restrictive lung pattern. Muscle ultrasound showed symmetrically increased echogenicity indicating fatty replacement and fibrosis in a subset of muscles and histopathological analyses revealed nemaline rods and cores. Slower muscle relaxation kinetics with in vivofunctional tests was observed. This was confirmed by in vitrofunctional tests showing impaired relaxation kinetics in isolated muscle fibres. We found a genealogic link between patient 1, and patient 2 and 3 nine generations earlier. The c.1222C > A p.(Arg408Ser) variant in the KBTBD13gene is a likely pathogenic variant causing NEM6.

Published
2024
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17. Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy

Author

Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgios, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K., Yeh, Yu Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, Macinnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, De Koning, Tom, Den Dunnen, Wilfred, Dijkstra, Gerard, Van Spaendonck, Karin, Van Gent, Dik C., Aronica, Eleonora M., Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nicholas, Duijkers, Floor A.M., Taniguchi-Ikeda, Mariko, De Giorgio, Roberto, Bonora, Elena, Chakrabarty, Sanjiban, Kellaris, Georgios, Tsutsumi, Makiko, Bianco, Francesca, Bergamini, Christian, Ullah, Farid, Isidori, Federica, Liparulo, Irene, Diquigiovanni, Chiara, Masin, Luca, Rizzardi, Nicola, Cratere, Mariapia Giuditta, Boschetti, Elisa, Papa, Valentina, Maresca, Alessandra, Cenacchi, Giovanna, Casadio, Rita, Martelli, Pierluigi, Matera, Ivana, Ceccherini, Isabella, Fato, Romana, Raiola, Giuseppe, Arrigo, Serena, Signa, Sara, Sementa, Angela Rita, Severino, Mariasavina, Striano, Pasquale, Fiorillo, Chiara, Goto, Tsuyoshi, Uchino, Shumpei, Oyazato, Yoshinobu, Nakamura, Hisayoshi, Mishra, Sushil K., Yeh, Yu Sheng, Kato, Takema, Nozu, Kandai, Tanboon, Jantima, Morioka, Ichiro, Nishino, Ichizo, Toda, Tatsushi, Goto, Yu Ichi, Ohtake, Akira, Kosaki, Kenjiro, Yamaguchi, Yoshiki, Nonaka, Ikuya, Iijima, Kazumoto, Mimaki, Masakazu, Kurahashi, Hiroki, Raams, Anja, Macinnes, Alyson, Alders, Mariel, Engelen, Marc, Linthorst, Gabor, De Koning, Tom, Den Dunnen, Wilfred, Dijkstra, Gerard, Van Spaendonck, Karin, Van Gent, Dik C., Aronica, Eleonora M., Picco, Paolo, Carelli, Valerio, Seri, Marco, Katsanis, Nicholas, Duijkers, Floor A.M., Taniguchi-Ikeda, Mariko, and De Giorgio, Roberto

Abstract

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized

Published
2021

18. Dilation of the Aorta Ascendens Forms Part of the Clinical Spectrum of HCN4 Mutations

Author

Vermeer, Alexa M.C., primary, Lodder, Elisabeth M., additional, Thomas, Dierk, additional, Duijkers, Floor A.M., additional, Marcelis, Carlo, additional, van Gorselen, Edwin O.F., additional, Fortner, Philipp, additional, Buss, Sebastian J., additional, Mereles, Derliz, additional, Katus, Hugo A., additional, Wilde, Arthur A.M., additional, Bezzina, Connie R., additional, Boekholdt, S. Matthijs, additional, Schweizer, Patrick A., additional, and Christiaans, Imke, additional

Published
2016
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24. Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6Pathogenic Variant Carriers

Author

van der Werf – ’t Lam, Anne-Sophie, Terlouw, Diantha, Tops, Carli M., van Kan, Merel S., van Hest, Liselotte P., Gille, Hans J.P., Duijkers, Floor A.M., Wagner, Anja, Eikenboom, Ellis L., Letteboer, Tom G.W., de Jong, Mirjam M., Bajwa - ten Broeke, Sanne W., Bleeker, Fonnet E., Gomez Garcia, Encarna B., de Wind, Niels, Tom van Wezel, J., Morreau, Hans, Suerink, Manon, and Nielsen, Maartje

Abstract

Diagnosis of Lynch Syndrome (LS) caused by a pathogenic germline MSH6variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. The aim of this study was to identify the various causes of the discordant phenotypes of colorectal and endometrial carcinomas (CRC/EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6variant diagnosed with CRC or EC were categorized based on an MSI/IHC test outcome that might fail to result in a diagnosis of LS (e.g. retained staining of all four mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6variant carriers with CRC or EC (n=590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, two out of three MSI/IHC cases were found to be concordant with the MSH6variant, and NGS showed that four discordant IHC results were actually sporadic rather than LS-associated tumors. In one case, somatic events explained the discordant phenotype. The use of reflex IHC MMR testing, the current standard in most Western countries, may lead to misdiagnosis of germline MSH6variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should still be considered in case of a strong positive family history. Germline DNA analysis of the MMR genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.

Published
2023
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