Hector Mendez

All Publications

• Biallelic variants in RNU2-2 cause the most prevalent known recessive neurodevelopmental disorder. Nature genetics Greene, D., Mendez, R., Lees, J., Barbosa, M., Bruselles, A., Chiriatti, L., Ferraro, F., Mancini, C., Schot, R., Sleutels, F., Bertini, E., Bonner, D. E., Bouman, A., Brooks, A. S., Cassini, T. A., Ezell, K. M., Gomez-Ospina, N., Kleefstra, T., O'Donoghue, M., Rives, L., Shashi, V., Spillmann, R. C., Wafik, M., Freson, K., Barakat, T. S., Tartaglia, M., Bernstein, J. A., Mumford, A. D., Wheeler, M. T., Turro, E. 2026

  Abstract

  We recently showed that mutations in the snRNA genes RNU4-2 and RNU2-2 are prevalent causes of dominant neurodevelopmental disorders (NDDs). Here, by genetic association, we demonstrate the existence of a recessive form of RNU2-2 syndrome. We inferred a log Bayes factor for a recessive model of association of 18.2. Conditional on that model, 17 rare variants had a posterior probability of pathogenicity >0.8. This conservative threshold identified 18 probands and 5 affected siblings, each carrying two alleles in trans at these variants. A relaxed threshold of >0.6 identified a further 13 candidate probands. We identified nine further cases in replication collections. Affected individuals have intellectual disability, global developmental delay and seizures. Recessive RNU2-2 syndrome accounts for ~10% of families with a recessive NDD presently diagnosable by sequencing and affects ~60% as many families as the dominant RNU4-2-related NDD ReNU syndrome. The variants are predicted to destabilize stem loops and binding domains of U2-2 snRNA. Whole-blood RNA sequencing data showed a >90% reduction in the expression of pathogenic U2-2 alleles in biallelic cases and monoallelic carriers, albeit with wild-type compensation in carriers, pointing to a loss-of-expression mechanism.

  View details for DOI 10.1038/s41588-026-02539-5

  View details for PubMedID 41912932

  View details for PubMedCentralID 8457000

• Biallelic Variants in RNU6ATAC Result in a Minor Spliceopathy Characterized by Transcriptome-Wide Minor Intron Retention Events and Short Stature with Variable Multisystem Manifestations. HGG advances Mendez, R., Arriaga, T. M., Ma, J., Bonner, D. E., Emami, S., Levy, R. J., Alsagheir, A., Alhaddad, B., Bakur, K., Ungar, R. A., Matalon, D. R., Miller, A. M., Nguyen, J., Smith, K. S., Scott, S. A., Liao, L., Ng, Z., Marwaha, S., Ward, A., Novacic, D., Alkuraya, F. S., Bernstein, J. A., Ganesh, V. S., O'Donnell-Luria, A., Montgomery, S. B., Wheeler, M. T. 2026: 100588

  Abstract

  We report three individuals with biallelic variants in RNU6ATAC, which encodes the U6atac minor spliceosomal small nuclear RNA (snRNA), causing a multisystem minor spliceopathy. Through RNAseq analysis, we identified a distinctive excess of minor intron retention (MIR) in two unrelated individuals, which guided the identification of biallelic RNU6ATAC variants. The discovery cohort presented with variable multisystem manifestations. One individual presented with refractory epilepsy, microcephaly, developmental delay, ataxia, bilateral toe syndactyly, hypereosinophilia, and short stature, whereas the other exhibited failure to thrive, short stature, primary hypothyroidism, combined variable immunodeficiency, eosinophilic colitis, ichthyosis vulgaris, scoliosis, and chronic inflammatory demyelinating polyneuropathy without neurodevelopmental involvement. Despite organ-specific variation, both individuals displayed impaired growth and eosinophil-driven inflammation. Recently, we identified a third affected individual from an independent cohort whose phenotype bridges these features, combining microcephaly, growth failure with severe immunodeficiency, and skeletal abnormalities. The distinctive excess of MIR outliers in the discovery cohort supports minor spliceosome dysfunction, mirroring the molecular signature of RNU4ATAC-opathy. These findings nominate RNU6ATAC as a disease-associated gene, defining an expanded clinical spectrum of minor spliceopathies. Our study supports the power of integrating genomic and transcriptomic approaches for diagnosing splicing disorders and highlights the critical role of spliceosomal snRNAs in human disease.

  View details for DOI 10.1016/j.xhgg.2026.100588

  View details for PubMedID 41808409

• Transcriptome-wide outlier approach identifies individuals with minor spliceopathies. American journal of human genetics Arriaga, T. M., Mendez, R., Ungar, R. A., Bonner, D. E., Matalon, D. R., Lemire, G., Goddard, P. C., Padhi, E. M., Miller, A. M., Nguyen, J. V., Ma, J., Smith, K. S., Scott, S. A., Liao, L., Ng, Z., Marwaha, S., Bademci, G., Bivona, S. A., Tekin, M., Bernstein, J. A., Montgomery, S. B., O'Donnell-Luria, A., Wheeler, M. T., Ganesh, V. S. 2025

  Abstract

  RNA sequencing has improved the diagnostic yield of individuals with rare diseases. Current analyses predominantly focus on identifying outliers in single genes that can be attributed to cis-acting variants within the gene locus. This approach overlooks causal variants with trans-acting effects on splicing transcriptome wide, such as variants impacting spliceosome function. We present a transcriptomics-first method to diagnose individuals with rare diseases by examining transcriptome-wide patterns of splicing outliers. Using splicing outlier detection methods (FRASER and FRASER2), we characterized splicing outliers from whole blood for 385 individuals from the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) and Undiagnosed Diseases Network (UDN) consortia. We examined all individuals for excess intron retention outliers in minor intron-containing genes (MIGs). Minor introns, which account for 0.5% of all introns in the human genome, are removed by small nuclear RNAs (snRNAs) in the minor spliceosome. This approach identified five individuals with excess intron retention outliers in MIGs, all of whom were found to harbor rare, bi-allelic variants in minor spliceosome snRNAs. Four individuals had rare, compound heterozygous variants in RNU4ATAC, which aided the reclassification of four variants. Additionally, one individual had rare, highly conserved, compound heterozygous variants in RNU6ATAC that may disrupt the formation of the catalytic spliceosome, suggesting it is a gene associated with Mendelian disease. These results demonstrate that examining RNA-sequencing data for transcriptome-wide signatures can increase the diagnostic yield of individuals with rare diseases, provide variant-to-function interpretation of spliceopathies, and uncover gene-disease associations.

  View details for DOI 10.1016/j.ajhg.2025.08.018

  View details for PubMedID 40975062

• De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome. Nature Chen, Y., Dawes, R., Kim, H. C., Ljungdahl, A., Stenton, S. L., Walker, S., Lord, J., Lemire, G., Martin-Geary, A. C., Ganesh, V. S., Ma, J., Ellingford, J. M., Delage, E., D'Souza, E. N., Dong, S., Adams, D. R., Allan, K., Bakshi, M., Baldwin, E. E., Berger, S. I., Bernstein, J. A., Bhatnagar, I., Blair, E., Brown, N. J., Burrage, L. C., Chapman, K., Coman, D. J., Compton, A. G., Cunningham, C. A., D'Souza, P., Danecek, P., Délot, E. C., Dias, K. R., Elias, E. R., Elmslie, F., Evans, C. A., Ewans, L., Ezell, K., Fraser, J. L., Gallacher, L., Genetti, C. A., Goriely, A., Grant, C. L., Haack, T., Higgs, J. E., Hinch, A. G., Hurles, M. E., Kuechler, A., Lachlan, K. L., Lalani, S. R., Lecoquierre, F., Leitão, E., Fevre, A. L., Leventer, R. J., Liebelt, J. E., Lindsay, S., Lockhart, P. J., Ma, A. S., Macnamara, E. F., Mansour, S., Maurer, T. M., Mendez, H. R., Metcalfe, K., Montgomery, S. B., Moosajee, M., Nassogne, M. C., Neumann, S., O'Donoghue, M., O'Leary, M., Palmer, E. E., Pattani, N., Phillips, J., Pitsava, G., Pysar, R., Rehm, H. L., Reuter, C. M., Revencu, N., Riess, A., Rius, R., Rodan, L., Roscioli, T., Rosenfeld, J. A., Sachdev, R., Shaw-Smith, C. J., Simons, C., Sisodiya, S. M., Snell, P., St Clair, L., Stark, Z., Stewart, H. S., Tan, T. Y., Tan, N. B., Temple, S. E., Thorburn, D. R., Tifft, C. J., Uebergang, E., VanNoy, G. E., Vasudevan, P., Vilain, E., Viskochil, D. H., Wedd, L., Wheeler, M. T., White, S. M., Wojcik, M., Wolfe, L. A., Wolfenson, Z., Wright, C. F., Xiao, C., Zocche, D., Rubenstein, J. L., Markenscoff-Papadimitriou, E., Fica, S. M., Baralle, D., Depienne, C., MacArthur, D. G., Howson, J. M., Sanders, S. J., O'Donnell-Luria, A., Whiffin, N. 2024

  Abstract

  Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs. Using RNA-sequencing, we show how 5' splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

  View details for DOI 10.1038/s41586-024-07773-7

  View details for PubMedID 38991538

• Biallelic variants in the noncoding RNA gene RNU4-2 cause a recessive neurodevelopmental syndrome with distinct white matter changes. Nature genetics Rius, R., Blakes, A. J., Chen, Y., De Jonghe, J., Lecoquierre, F., Dawes, R., Cogne, B., Kim, H. C., Alvi, J. R., Amblard, F., Ansari, M., Arlt, A., Austin-Tse, C., Baer, S., Balasubramanian, M., Balton, E. V., Barcia, G., Beleza-Meireles, A., Bernstein, J. A., Beygo, J., Blanc, P., Bramswig, N. C., Braun, F., Buchzik, D., Calame, D. G., Campbell, J., Coutton, C., Cunningham, C. A., Dargie, N., Depienne, C., Dipple, K. M., Dieux, A., Dixit, A., Dreyer, L., Du, H., El Chehadeh, S., Field, M., Ewans, L. J., Geiger, V., Gibbs, R. A., Glass, I., Grunewald, O., Gueguen, P., Haack, T. B., Hadj Abdallah, H., Harbuz, R., Helbig, I., Horvath, J., Hustinx, A., Isidor, B., Jacquemont, M. L., Jamie, F., Jeanne, M., Kessler, R., Klinkhammer, H., Korenke, G. C., Kotzaeridou, U., Krawitz, P., Laurie, S., Leventer, R. J., Levy, R. J., Lupski, J. R., Marijon, P., McGinnis, K. E., Mendez, R., Messaoud, O., Nava, C., Nizard, M., O'Donnell-Luria, A., O'Leary, M. C., Olivieri, S., Parida, A., Pehlivan, D., Prentice, A. J., Posey, J. E., Reuter, C. M., Satre, V., Schluth-Bolard, C., Smol, T., Sultan, T., Taylor, J., Thauvin-Robinetvin, C., Thevenon, J., Uebergang, E., Ueberberg, S., Vincent-Delorme, C., Wassmer, E., Westwood, E., Wheeler, M. T., Gulec, E. Y., Vanderver, A., Vossough, A., Sanders, S. J., Banka, S., Findlay, G. M., MacArthur, D. G., Simons, C., Whiffin, N. 2026

  Abstract

  Genetic variants in RNU4-2, which is transcribed into the U4 small nuclear RNA component of the major spliceosome, were recently shown to cause ReNU syndrome, a prevalent dominant neurodevelopmental disorder (NDD). These variants almost exclusively arise de novo and cluster within 18 nucleotides of RNU4-2. Here we describe a new recessive NDD associated with homozygous and compound heterozygous variants in RNU4-2. We identify 38 individuals with biallelic variants outside the 18-nucleotide ReNU syndrome region that cluster within other functionally important elements of U4: Stem II, the k-turn and the Sm protein binding site. We characterize the clinical phenotype in 31 individuals, demonstrating that the recessive disorder is clinically distinct from ReNU syndrome and is associated with distinctive white matter abnormalities, including enlarged perivascular spaces. Finally, we find reduced RNU4-2 transcript levels in individuals with the recessive disorder, suggesting a loss-of-function disease mechanism that is distinct from the mechanism underlying ReNU syndrome. Together, these findings expand the genotypic and phenotypic spectrum of RNU4-2-associated NDDs.

  View details for DOI 10.1038/s41588-026-02554-6

  View details for PubMedID 41951959

  View details for PubMedCentralID 3119917

• Saturation editing of RNU4-2 reveals distinct dominant and recessive disorders. Nature De Jonghe, J., Kim, H. C., Adedeji, A., Leitão, E., Dawes, R., Kajba, C. M., Cogné, B., Chen, Y., Blakes, A. J., Simons, C., Rius, R., Alvi, J. R., Amblard, F., Austin-Tse, C., Baer, S., Balton, E. V., Blanc, P., Calame, D. G., Coutton, C., Cunningham, C. A., Dargie, N., Dipple, K. M., Du, H., El Chehadeh, S., Glass, I., Gleeson, J. G., Grunewald, O., Gueguen, P., Harbuz, R., Jacquemont, M. L., Leventer, R. J., Marijon, P., Messaoud, O., Sultan, T., Thauvin, C., Vincent-Delorme, C., Yilmaz Gulec, E., Thevenon, J., Mendez, R., MacArthur, D. G., Depienne, C., Nava, C., Whiffin, N., Findlay, G. M. 2026

  Abstract

  Recently, de novo variants in an 18-nucleotide region in the centre of RNU4-2 were shown to cause ReNU syndrome, a syndromic neurodevelopmental disorder that is predicted to affect tens of thousands of individuals worldwide1,2. RNU4-2 is a non-protein-coding gene that is transcribed into the U4 small nuclear RNA component of the major spliceosome3. ReNU syndrome variants disrupt spliceosome function and alter 5' splice site selection1,4. Here we performed saturation genome editing (SGE) of RNU4-2 to identify the functional and clinical impact of variants across the entire gene. The resulting SGE function scores, derived from variants' effects on cell fitness, discriminate ReNU syndrome variants from those observed in the population and markedly outperform in silico variant effect prediction. Using these data, we redefine the ReNU syndrome critical region at single-nucleotide resolution, resolve variant pathogenicity for variants of uncertain significance and show that SGE function scores delineate variants by phenotypic severity and the extent of observed splicing disruption. Furthermore, we identify variants affecting function in regions of RNU4-2 that are critical for interactions with other spliceosome components. We show that these variants cause a new recessive neurodevelopmental disorder that is distinct from ReNU syndrome. Together, this work defines the landscape of variant function across RNU4-2, providing critical insights for both diagnosis and therapeutic development.

  View details for DOI 10.1038/s41586-026-10334-9

  View details for PubMedID 41951737

  View details for PubMedCentralID 4536768

• Genetic Diagnosis and Discovery Enabled by Large Language Models. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Tu, T., Saab, K., Liu, W., Fang, Z., Cheng, Z., Spasic, S., Djurisic, M., Mohri, H., Ren, W., Palepu, A., Gottweis, J., Karthikesalingam, A., Kulkarni, K., Pawlosky, A., Bonner, D., Kravets, E., Marwaha, S., Mendez, H. R., Wheeler, M. T., Bernstein, J. A., Tsai, C. Y., Wu, C. C., Stankovic, K. M., Natarajan, V., Peltz, G. 2026: e18656

  Abstract

  Artificial intelligence (AI) has been used in many areas of medicine, and large language models (LLMs) have shown potential utility for various clinical applications. However, to determine if LLMs can accelerate the pace of genetic diagnosis and discovery, we examined whether recently developed LLMs (Med-PaLM 2 and Gemini) could assist in solving four types of genetic problems with sequentially increasing complexity. First, in response to free-text input, Med-PaLM 2 correctly identified murine genes with experimentally verified causative genetic factors for six previously studied murine models of biomedical traits. Second, Med-PaLM 2 identified a novel causative murine genetic factor for spontaneous hearing loss that was validated using knock-in mice. Third, we developed a retrieval and grounding pipeline that enabled Gemini 2.5 Pro to analyze large lists of genes, which contained genetic variants that were identified in the genomic sequences of 20 human subjects with hearing loss, and demonstrated that it can assist in identifying causative genetic factors for hearing loss. Fourth, we modified the genetic analysis pipeline to enable Gemini 2.5 Pro without any task-specific fine-tuning to identify causative genetic factors for six subjects with rare genetic diseases, which required 14 to 34 different terms to describe their multi-faceted symptom complexes. These results demonstrate that an AI pipeline can facilitate genetic diagnosis and discovery in mice and humans.

  View details for DOI 10.1002/advs.202518656

  View details for PubMedID 41655254

• Biallelic LAMP3 Variants in Five Families with Interstitial Lung Disease: Evidence of a Disease-Gene Association. Genetics in medicine : official journal of the American College of Medical Genetics Keehan, L. A., Ono-Minagi, H., Hadhud, M., Rips, J., Hinds, D. M., Fischer, A. J., Bartlett, J. A., McCray, P. B., Qawasmi, N., Nathan, N., Louvrier, C., Desroziers, T., Damme, M., Griese, M., Wegner, D. J., Cole, F. S., Wambach, J. A., Wheeler, M. T., Burbelo, P. D., Bonner, D. E., Bernstein, J. A., Chiorini, J. A., Breuer, O., Milla, C. 2026: 102531

  Abstract

  Genetic causes of surfactant dysfunction are associated with childhood interstitial lung disease (chILD). Lysosome-associated membrane glycoprotein 3 (LAMP3) is highly expressed within lamellar bodies of alveolar epithelial type II cells, and variants in LAMP3 have recently been suggested as a novel cause of chILD. This study describes the phenotypes of participants with biallelic variants in LAMP3 and presents functional studies evaluating the role of specific LAMP3 variants.Phenotypic data was collected through chart review and clinical evaluation. In vitro effects of LAMP3 variants were evaluated through immunohistochemistry, WB, and flow cytometry.Thirteen participants were identified with biallelic variants in LAMP3. They presented with variable phenotypes ranging from neonatal respiratory distress to asymptomatic in adulthood. All symptomatic participants demonstrated ground glass opacities early in life and lung fibrosis later in life. For one participant, BAL analysis showed abnormal surfactant protein composition and lung biopsy revealed irregular LB. In vitro studies in lung epithelial cells with induced expression of specific LAMP3 variants demonstrated reduced protein expression and abnormal glycosylation.Biallelic LAMP3 variants are associated with an interstitial lung disease phenotype with variable expressivity. Evaluation for LAMP3 variants should be considered in individuals with unexplained interstitial lung disease.

  View details for DOI 10.1016/j.gim.2026.102531

  View details for PubMedID 41653023

• GREGoR: accelerating genomics for rare diseases. Nature Dawood, M., Heavner, B., Wheeler, M. M., Ungar, R. A., LoTempio, J., Wiel, L., Berger, S., Bernstein, J. A., Chong, J. X., Délot, E. C., Eichler, E. E., Lupski, J. R., Shojaie, A., Talkowski, M. E., Wagner, A. H., Wei, C. L., Wellington, C., Wheeler, M. T., Carvalho, C. M., Gibbs, R. A., Gifford, C. A., May, S., Miller, D. E., Rehm, H. L., Samocha, K. E., Sedlazeck, F. J., Vilain, E., O'Donnell-Luria, A., Posey, J. E., Chadwick, L. H., Bamshad, M. J., Montgomery, S. B. 2025; 647 (8089): 331-342

  Abstract

  Rare diseases are collectively common, affecting approximately 1 in 20 individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in next-generation sequencing, development of new computational and functional genomics approaches to prioritize genes and variants and increased global sharing of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Furthermore, all data generated, currently representing over 7,500 individuals from over 3,000 families, are rapidly made available to researchers worldwide through the Analysis, Visualization and Informatics Lab-space (AnVIL) to catalyse global efforts to develop approaches for genetic diagnoses in rare diseases. Most of these families have undergone previous clinical genetic testing but remained unsolved, with most being exome-negative. Here we describe the collaborative research framework, datasets and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics.

  View details for DOI 10.1038/s41586-025-09613-8

  View details for PubMedID 41224980

  View details for PubMedCentralID 9119004

• Genetic Analysis Algorithm for the Study of Patients with Multiple Congenital Anomalies and Isolated Congenital Heart Disease. Genes Delea, M., Massara, L. S., Espeche, L. D., Bidondo, M. P., Barbero, P., Oliveri, J., Brun, P., Fabro, M., Galain, M., Fernández, C. S., Taboas, M., Bruque, C. D., Kolomenski, J. E., Izquierdo, A., Berenstein, A., Cosentino, V., Martinoli, C., Vilas, M., Rittler, M., Mendez, R., Furforo, L., Liascovich, R., Groisman, B., Rozental, S., Dain, L., 2022; 13 (7)

  Abstract

  Congenital anomalies (CA) affect 3-5% of newborns, representing the second-leading cause of infant mortality in Argentina. Multiple congenital anomalies (MCA) have a prevalence of 2.26/1000 births in newborns, while congenital heart diseases (CHD) are the most frequent CA with a prevalence of 4.06/1000 births. The aim of this study was to identify the genetic causes in Argentinian patients with MCA and isolated CHD. We recruited 366 patients (172 with MCA and 194 with isolated CHD) born between June 2015 and August 2019 at public hospitals. DNA from peripheral blood was obtained from all patients, while karyotyping was performed in patients with MCA. Samples from patients presenting conotruncal CHD or DiGeorge phenotype (n = 137) were studied using MLPA. Ninety-three samples were studied by array-CGH and 18 by targeted or exome next-generation sequencing (NGS). A total of 240 patients were successfully studied using at least one technique. Cytogenetic abnormalities were observed in 13 patients, while 18 had clinically relevant imbalances detected by array-CGH. After MLPA, 26 patients presented 22q11 deletions or duplications and one presented a TBX1 gene deletion. Following NGS analysis, 12 patients presented pathogenic or likely pathogenic genetic variants, five of them, found in KAT6B, SHH, MYH11, MYH7 and EP300 genes, are novel. Using an algorithm that combines molecular techniques with clinical and genetic assessment, we determined the genetic contribution in 27.5% of the analyzed patients.

  View details for DOI 10.3390/genes13071172

  View details for PubMedID 35885957

  View details for PubMedCentralID PMC9317700

• Oculocutaneous albinism type 1B associated with a functionally significant tyrosinase gene polymorphism detected with Whole Exome Sequencing. Ophthalmic genetics Mendez, R., Iqbal, S., Vishnopolska, S., Martinez, C., Dibner, G., Aliano, R., Zaiat, J., Biagioli, G., Fernandez, C., Turjanski, A., Campbell, A. J., Mercado, G., Marti, M. A. 2021; 42 (3): 291-295

  Abstract

  Background: Oculocutaneous albinism (OCA) is a Mendelian disorder characterized by hypopigmentation of the skin, hair, and eyes, hypoplastic fovea, and low vision, known to be caused by mutations in the Tyrosinase (TYR) gene. Among the known TYR variants, some reduce but do not completely eliminate tyrosinase activity, allowing residual production of melanin and resulting in a contradictory assignment as either pathogenic or benign, preventing a precise clinical diagnostic.Materials and Methods: In the present work, we performed Whole Exome Sequencing and subsequent Sanger sequencing in a young male clinically diagnosed with OCA.Results: Whole-exome sequencing analysis revealed the identification of two variants in trans in TYR. The first, corresponds to a known pathogenic variant G47D, while the second S192Y, was considered a polymorphism due to its relatively high frequency in the European population.Conclusion: The lack of other pathogenic variants in TYR, the reported reduced enzymatic activity (ca. 40% respect to wt) for S192Y, together with the structural in-silico analysis strongly suggest that both reported variants are jointly disease-causing and that S192Y should be considered as likely pathogenic, especially when it is found in trans with a null variant.

  View details for DOI 10.1080/13816810.2021.1888129

  View details for PubMedID 33599182

• A novel pathogenic frameshift variant of KAT6B identified by clinical exome sequencing in a newborn with the Say-Barber-Biesecker-Young-Simpson syndrome. Clinical dysmorphology Mendez, R., Delea, M., Dain, L., Rittler, M. 2020; 29 (1): 42-45

  View details for DOI 10.1097/MCD.0000000000000270

  View details for PubMedID 30921092