Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes

Towards Uncovering the Role of Incomplete Penetrance in Maculopathies through Sequencing of 105 Disease-Associated Genes. Hitti-Malin, R. J., Panneman, D. M., Corradi, Z., Boonen, E. G. M., Astuti, G., Dhaenens, C., Stöhr, H., Weber, B. H. F., Sharon, D., Banin, E., Karali, M., Banfi, S., Ben-Yosef, T., Glavač, D., Farrar, G. J., Ayuso, C., Liskova, P., Dudakova, L., Vajter, M., Ołdak, M., Szaflik, J. P., Matynia, A., Gorin, M. B., Kämpjärvi, K., Bauwens, M., De Baere, E., Hoyng, C. B., Li, C. H. Z., Klaver, C. C. W., Inglehearn, C. F., Fujinami, K., Rivolta, C., Allikmets, R., Zernant, J., Lee, W., Podhajcer, O. L., Fakin, A., Sajovic, J., AlTalbishi, A., Valeina, S., Taurina, G., Vincent, A. L., Roberts, L., Ramesar, R., Sartor, G., Luppi, E., Downes, S. M., van den Born, L. I., McLaren, T. L., De Roach, J. N., Lamey, T. M., Thompson, J. A., Chen, F. K., Tracewska, A. M., Kamakari, S., Sallum, J. M. F., Bolz, H. J., Kayserili, H., Roosing, S., & Cremers, F. P. M. Biomolecules, 14(3):367, March, 2024. Number: 3 Publisher: Multidisciplinary Digital Publishing Institute

Paper doi abstract bibtex

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G\textgreaterA and CNGB3:c.1208G\textgreaterA. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

@article{hitti-malin_towards_2024,
	title = {Towards {Uncovering} the {Role} of {Incomplete} {Penetrance} in {Maculopathies} through {Sequencing} of 105 {Disease}-{Associated} {Genes}},
	volume = {14},
	copyright = {http://creativecommons.org/licenses/by/3.0/},
	issn = {2218-273X},
	url = {https://www.mdpi.com/2218-273X/14/3/367},
	doi = {10.3390/biom14030367},
	abstract = {Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8\% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2\%), PRPH2 (6.7\%), CDHR1 (6.1\%), PROM1 (4.3\%) and RP1L1 (3.1\%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1\%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1:c.783G{\textgreater}A and CNGB3:c.1208G{\textgreater}A. Notably, segregation analysis was not routinely performed for variant phasing—a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2\%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.},
	language = {en},
	number = {3},
	urldate = {2024-03-25},
	journal = {Biomolecules},
	author = {Hitti-Malin, Rebekkah J. and Panneman, Daan M. and Corradi, Zelia and Boonen, Erica G. M. and Astuti, Galuh and Dhaenens, Claire-Marie and Stöhr, Heidi and Weber, Bernhard H. F. and Sharon, Dror and Banin, Eyal and Karali, Marianthi and Banfi, Sandro and Ben-Yosef, Tamar and Glavač, Damjan and Farrar, G. Jane and Ayuso, Carmen and Liskova, Petra and Dudakova, Lubica and Vajter, Marie and Ołdak, Monika and Szaflik, Jacek P. and Matynia, Anna and Gorin, Michael B. and Kämpjärvi, Kati and Bauwens, Miriam and De Baere, Elfride and Hoyng, Carel B. and Li, Catherina H. Z. and Klaver, Caroline C. W. and Inglehearn, Chris F. and Fujinami, Kaoru and Rivolta, Carlo and Allikmets, Rando and Zernant, Jana and Lee, Winston and Podhajcer, Osvaldo L. and Fakin, Ana and Sajovic, Jana and AlTalbishi, Alaa and Valeina, Sandra and Taurina, Gita and Vincent, Andrea L. and Roberts, Lisa and Ramesar, Raj and Sartor, Giovanna and Luppi, Elena and Downes, Susan M. and van den Born, L. Ingeborgh and McLaren, Terri L. and De Roach, John N. and Lamey, Tina M. and Thompson, Jennifer A. and Chen, Fred K. and Tracewska, Anna M. and Kamakari, Smaragda and Sallum, Juliana Maria Ferraz and Bolz, Hanno J. and Kayserili, Hülya and Roosing, Susanne and Cremers, Frans P. M.},
	month = mar,
	year = {2024},
	note = {Number: 3
Publisher: Multidisciplinary Digital Publishing Institute},
	keywords = {Alamut Visual Plus, inherited, macula, maculopathies, penetrance, retinal, sequencing},
	pages = {367},
}

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