https://hdl.handle.net/20.500.14178/901 2026-07-22T13:00:23Z https://hdl.handle.net/20.500.14178/3878 Mechanistic modeling of recessive disease through allelic integration of variant effects Cubuk, Hasan; Plech, Marcin; Aslanzadeh, Vahid; Zikánová, Marie; Škopová, Václava; Kmoch, Stanislav; Shen, Yuxin; Marsh, Joseph A.; Kudla, Grzegorz Interpreting variants in recessive diseases is difficult because clinical severity depends on the combined function of both alleles. Deep mutational scanning (DMS) experiments can provide functional measurements at scale, but their scores often relate nonlinearly to true biochemical activity. Here, we describe a method for inferring enzymatic activities for thousands of variants by running two fitness assays at different expression levels and modeling the nonlinear activity-fitness relationship. These inferred activities allow the computation of a bi-allelic pathogenicity score that captures the joint effect of two alleles. We applied this approach to adenylosuccinate lyase (ADSL), quantifying the effects of >8,000 coding variants in a yeast-based DMS assay. The inferred activities separated pathogenic from benign alleles, and the bi-allelic scores correlated strongly with biochemical measurements and clinical outcomes, outperforming existing predictors. This framework provides a broadly applicable strategy for the mechanistic interpretation of variants in recessive enzymes. 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3877 A missense mutation in the SAA1 protein causing hereditary amyloid A amyloidosis Leung, Nelson; Hnízda, Aleš; McPhail, Ellen D.; Dasari, Surendra; Nosková, Lenka; Vyleťal, Petr; Mikšátko, Jiří; Piherová, Lenka; Kmochová, Tereza; Mušálková, Dita; Vaníčková, Zdislava; Radina, Martin; Zima, Tomáš; Hodaňová, Kateřina; Hartmannová, Hana; Stránecký, Viktor; Nasr, Samih H.; Ryšavá, Romana; Živná, Martina; Sikora, Jakub; Theis, Jason D.; Vrana, Julie A.; Buadi, Francis K.; Crooke, Stanley T.; Bleyer, Anthony; Kmoch, Stanislav In summary, guided by the patient's clinical course and diagnostic challenges, we report, for the first time, a family with autosomal dominant hereditary AA amyloidosis caused by a heterozygous SAA1 missense mutation, p.D34V. This mutation alters the primary structure of SAA1, dominantly enhances its aggregation, and produces a highly amyloidogenic protein capable of forming amyloid even at normal plasma SAA levels, affecting patients in their 20s and 30s. Importantly, the mutant protein escapes detection by routine clinical MS/MS amyloid typing because of its location between 2 trypsin cleavage sites. These findings highlight the need for genetic testing in AA amyloidosis without an inflammatory cause and caution that segmental duplications within SAA genes may complicate variant calling from short-read sequencing, further challenging diagnosis. Because of the unique pathogenesis of this family, the traditional immunosuppressive therapy used in AA amyloidosis would have no effect because the SAA levels were already low or normal. A novel approach to AA amyloidosis therapy would be required to treat members of this family and others like them. 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3876 Updated ENIGMA recommendations for reporting germline variants in cancer susceptibility genes and their translation into twenty languages De Nicolo, Arcangela; Eccles, Diana M.; Aaltonen, Kirsimari; Alhopuro, Pia; Ariansen, Sarah Louise; Biancolella, Michela; Caputo, Sandrine M.; Caron, Olivier; Cavalli, Pietro; Chiang, Jianbang; Claes, Kathleen B. M.; Cuaresma, Edgar Christian S.; de la Hoya, Miguel; De Pauw, Antoine; Diez, Orland; Dominguez-Valentin, Mev; Ehrencrona, Hans; Fjeldvaer, Magnhild K.; Fostira, Florentia; Francia, Marie Belle D.; Galego-Carro, Javier; Gomez Garcia, Encarna B.; Hassan, Nur Tiara; Hauke, Jan; Hirasawa, Akira; Huang, Xin; Ilagan-Cargullo, Elaine Marisse H.; Imoto, Issei; Jonnagadla, Sowmya; Karthikeyan, Manasadevi; Kleiblová, Petra; Konstantopoulou, Irene; Kowalik, Artur; Kvist, Anders; Lesueur, Fabienne; Li, Shao-Tzu; Lopez-Fernandez, Adria; Machackova, Eva; Martins, Alexandra; Mensenkamp, Arjen R.; Momozawa, Yukihide; Montalban, Gemma; Monteiro, Alvaro N. A.; Nevanlinna, Heli; Ngeow, Joanne; Palmero, Edenir Inez; Pedersen, Inge Sokilde; Que, Frances Victoria F.; Santamarina, Marta; Santana dos Santos, Elizabeth; Singer, Christian F.; Siolek, Monika; Solano, Angela R.; Soukupová, Jana; Suresh, Priyadharshin; Szczepaniak, Magdalena; Tan, Yen Y.; Teo, Soo Hwang; Tham, Emma; Thomassen, Mads; Tsaousis, Georgios; Hansen, Thomas van Overeem; Vega, Ana; Velasco-Sampedro, Eladio A.; Wangensteen, Teresia; Wappenschmidt, Barbara; Yannoukakos, Drakoulis; Yoon, Sook-Yee; Spurdle, Amanda B.; Radice, Paolo Genetic testing for cancer susceptibility underpins precision cancer prevention and care. Gaps in the healthcare providers' genetic literacy and an ambiguous lexicon for variant description may hinder proper delivery and clinical application of consistently trustworthy test results. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) international consortium supports controlled terminology and recommends a framework for reporting germline variants in cancer susceptibility genes, using breast cancer as an exemplar. Moving forward towards terminological coherence across disciplines and borders, the ENIGMA Clinical Working Group launched a multinational effort to release consortium-approved translations of the published recommendations. The herein reported Vocabulary Translation Project offered an opportunity to reappraise and align the reference text to the recent BRCA1 and BRCA2 specifications to the American College of Medical Genetics and Genomics/ Association for Molecular Pathology rules by the ENIGMA Variant Curation Expert Panel and to highlight 2026-01-01T00:00:00Z https://hdl.handle.net/20.500.14178/3875 Genotype-phenotype characteristics and disease progression of FAN1-related karyomegalic tubulointerstitial nephropathy Clince, Michelle; Elhassan, Elhussein A. E.; Kidd, Kendrah O.; Malamud, Emily; Mcanallen, Susan M.; Danial, Arbab; Chung, Byung Ha; Kim, Myungshin; Sayer, John A.; Al Alawi, Intisar; Bernards, Jelle; Jerbi, Mouna; Goucha, Rym; Ben Jemaa, Lamia; Rejeb, Imen; Patel, Chirag; Mallett, Andrew J.; Sperati, C. John; De Boeck, Koen; Muller, Maximilian; Stehle, Thomas; Guebessi, Nisrine Bennani; Robert, Thomas; Ivanyi, Bela; Csaszar, Ildiko; Shril, Shirlee; Zheng, Sijie; Mathew, Gerry George; Dirim, Merve Guzel; Dirim, Ahmet Burak; Mesnard, Laurent; Gueguen, Lorraine; Schafer, Franz; Bergmann, Carsten; Gale, Daniel P.; Halbritter, Jan; Claes, Kathleen J.; Knebelmann, Bertrand; Živná, Martina; Kmoch, Stanislav; Faguer, Stanislas; Hildebrandt, Friedhelm; Bleyer, Anthony J.; Conlon, Peter J. Introduction: Biallelic variants in Fanconi Anemia-associated Nuclease 1 (FAN1) cause karyomegalic tubulointerstitial nephropathy (KIN), a condition poorly characterized in terms of kidney survival, patient survival, and clinical characteristics. Therefore, we undertook a crosssectional collaborative study to better characterize KIN-FAN1. Methods: To gather data, we distributed a REDCap survey on clinical characteristics and genetic variants of KIN-FAN1 to colleagues and case report authors. Results: Based on the survey, we identified 86 families affected (122 individuals) from 22 countries. There were 56 families (83 individuals) with a genetic diagnosis of KIN-FAN1, including 38 distinct FAN1 variants, and 30 families (39 individuals) with KIN with no predisposing risk factors and without molecular FAN1 testing. The median age at presentation was 38.5 years (interquartile range: 29-43), 62% male. Of the cohort, 46% had asymptomatic elevation of liver function tests, 39% had pulmonary complications, and 6% developed cancer. The median age of kidney failure was 45 years (95% confidence interval (CI): 38-56). Of the cohort, 27.1% died at a median age of 55 years (95% CI: 43-75). Pulmonary complications was/were the cause of death in 15.4% of patients on dialysis and 23.1% of kidney transplant recipients. Compared to other variants, patients with the p.W707X-FAN1 variant were at a significantly higher risk of pulmonary complications (adjusted odds ratio: 8.26 (95% CI: 1.7-40.1) and had a significantly shorter lifespan (hazard ratio: 3.24 (95% CI: 1.13-9.28). No genetic covariates were statistically associated with the progression to kidney failure. Conclusions: Patients with KIN-FAN1 develop kidney failure at a median age of 45 years. Survival is compromised with many dying of pulmonary disease. 2026-01-01T00:00:00Z