Digenic variant interpretation with hypothesis-driven explainable AI

Paoli, Federica De; Nicora, Giovanna; Berardelli, Silvia; Gazzo, Andrea; Bellazzi, Riccardo; Magni, Paolo; Rizzo, Ettore; Limongelli, Ivan; Zucca, Susanna

doi:10.1101/2023.10.02.560464

Cited by 2 publications

References 56 publications

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A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity

Moresco,

Rondinone,

Mauri

et al. 2024

Genes Genom

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Background Congenital anomalies of the knee are a spectrum of rare disorders with wide clinical and genetic variability, which are mainly due to the complex processes underlying knee development. Despite progresses in understanding pathomechanisms and associated genes, many patients remain undiagnosed. Objective To uncover the genetic bases of a congenital patellar dislocation affecting multiple family members with variable severity. Methods We performed ES in the proband and his father, both showing bilateral patellar dislocation, his sister with a milder similar condition, and his unaffected mother. Sanger sequencing was then performed in the proband’s brother and paternal aunt, both affected as well. Results ES and Sanger sequencing identified the presence of the novel heterozygous frameshift mutation c.735delT in the TBX4 gene in all affected family members. TBX4 is associated with autosomal dominant ischio-coxo-podo-patellar syndrome with/without pulmonary arterial hypertension (ICPPS, #147891), reaching a diagnosis in the family. Intrafamilial clinical heterogeneity suggests that other factors might be involved, such as additional variants in TBX4 or in other modifier genes. Interestingly, we identified three additional variants in the TBX4 gene in the proband only, whose phenotype is more severe. Despite being classified as benign, one of these variants is predicted to disrupt a splicing protein binding site, and may therefore affect TBX4 alternative splicing, accounting for the more severe phenotype of the proband. Conclusion We expand and further delineate the genotypic and phenotypic spectrum of ICPPS. Further studies are necessary to shed light on the potential effect of this variant and on the variable phenotypic expressivity of TBX4-related phenotypes.

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A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity

Moresco,

Rondinone,

Mauri

et al. 2024

Genes Genom

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Discovery of a Novel Missense Mutation in the RIMS1 Gene Potentially Enhances the Severity of Retinitis Pigmentosa (RP) Caused by RP1 Mutation in Humans

Lazaro-Guevara,

Garrido-Lopez,

Soberanis

et al. 2024

Preprint

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Retinitis pigmentosa (RP) is a genetically diverse disorder characterized by the progressive degeneration of photoreceptors, ultimately leading to vision impairment and potential blindness. Understanding the disease progression and developing effective therapies is challenging due to its complex genetic landscape. This study unveils a di-genic complexity in RP involving a novel missense mutation in the RIMS1 and RP1 genes, traditionally associated with Cone-Rod Dystrophy. This mutation potentially enhances the RP phenotype, particularly in cases caused by RP1 mutations. We conducted a comprehensive genetic analysis on a family with a severe form of RP, focusing on the combined effects of RIMS1 and RP1. Using a targeted gene panel of 322 inherited retinal dystrophy (IRD) genes, we discovered a significant interaction between the RIMS1 variant and RP1 mutation within the cohort. Interestingly, patients with identical mutations exhibited substantial disease severity and progression differences. This discrepancy was particularly apparent in Patient E_1, who experienced rapid vision decline, emphasizing the impact of the mutation when combined with RP1. Biological network analysis shed light on the intricate genetic interplay, indicating a complex mechanism of disease modulation. Our findings contribute to a more nuanced understanding of RP's genetic heterogeneity. The RIMS1 variant may serve as a modifier of the disease phenotype. This discovery expands our comprehension of the genetic factors influencing RP and underscores the importance of considering digenic interactions in future research and therapy development for retinal dystrophies.

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Digenic variant interpretation with hypothesis-driven explainable AI

Cited by 2 publications

References 56 publications

A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity

A novel frameshift TBX4 variant in a family with ischio-coxo-podo-patellar syndrome and variable severity

Discovery of a Novel Missense Mutation in the RIMS1 Gene Potentially Enhances the Severity of Retinitis Pigmentosa (RP) Caused by RP1 Mutation in Humans

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