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

Authors :
Rebekkah J. Hitti-Malin
Daan M. Panneman
Zelia Corradi
Erica G. M. Boonen
Galuh Astuti
Claire-Marie Dhaenens
Heidi Stöhr
Bernhard H. F. Weber
Dror Sharon
Eyal Banin
Marianthi Karali
Sandro Banfi
Tamar Ben-Yosef
Damjan Glavač
G. Jane Farrar
Carmen Ayuso
Petra Liskova
Lubica Dudakova
Marie Vajter
Monika Ołdak
Jacek P. Szaflik
Anna Matynia
Michael B. Gorin
Kati Kämpjärvi
Miriam Bauwens
Elfride De Baere
Carel B. Hoyng
Catherina H. Z. Li
Caroline C. W. Klaver
Chris F. Inglehearn
Kaoru Fujinami
Carlo Rivolta
Rando Allikmets
Jana Zernant
Winston Lee
Osvaldo L. Podhajcer
Ana Fakin
Jana Sajovic
Alaa AlTalbishi
Sandra Valeina
Gita Taurina
Andrea L. Vincent
Lisa Roberts
Raj Ramesar
Giovanna Sartor
Elena Luppi
Susan M. Downes
L. Ingeborgh van den Born
Terri L. McLaren
John N. De Roach
Tina M. Lamey
Jennifer A. Thompson
Fred K. Chen
Anna M. Tracewska
Smaragda Kamakari
Juliana Maria Ferraz Sallum
Hanno J. Bolz
Hülya Kayserili
Susanne Roosing
Frans P. M. Cremers
Source :
Biomolecules, Vol 14, Iss 3, p 367 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

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>A and CNGB3:c.1208G>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.

Details

Language :
English
ISSN :
2218273X
Volume :
14
Issue :
3
Database :
Directory of Open Access Journals
Journal :
Biomolecules
Publication Type :
Academic Journal
Accession number :
edsdoj.59ac914048b4e7daf70faf03534c762
Document Type :
article
Full Text :
https://doi.org/10.3390/biom14030367