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Next-generation sequencing data on inherited macular dystrophies (MD) shows significant impact among 1,036 Spanish families

Researchers at the Instituto de Investigación Sanitaria–Fundación Jiménez Díaz University Hospital, Universidad Autónoma de Madrid, has reported valuable clinical re-classifications from inherited dystrophies following next-generation sequencing (NGS) data among a cohort of Spanish families.  The Spanish study of 1,036 families was previously classified according to a priori clinical diagnoses, including Stargardt disease (STGD), cone and cone-rod dystrophy (CCRD) and other macular dystrophies (MD).  According to the researchers, the current work “provides for the first time a genetic landscape of 1,036 ar/sMD (autosomal recessive or sporadic) families according to their suspected diagnosis”.


The research team used NGS technologies to study a high number of genes and patients, parallelly using exome-targeted approaches or customized gene panels to also include non-coding regions and identifying new candidate genes.  These techniques were aimed to avoid time-consuming and low diagnostic rates to define previously unknown mutations or new genes. In their study, the results of the research reported that 677 patients (65%) had a confirmed genetic diagnosis, representing 78%, 63%, and 38% of STGD, CCRD, and other MD groups of patients, respectively. The ABCA4 gene is the most mutated gene in all groups identified, and a second pathogenic variant was found in 76% of STGD patients with one previously identified mutated ABCA4 allele. Autosomal dominant or X-linked mutations were additionally found in 5% of cases together with not-MD genes (CHM, EYS, RHO, RPGR, RLBP1, OPA1, and USH2A among others) leading to their reclassification. Finally, novel variants in the very rare genes of PLA2G5 and TTLL5 also revealed additional phenotypic associations.


The results of the work showed that until October 2020, a total of 1,036 ar/sMD cases had been studied, 744 recruited until 2017 (71.8%), and 292 new cases recruited during 2017–2020 period (28.2%. Of these 1,036 families, 570 (55.0%), 223 (21.5%), and 243 (23.5%) presented a clinical suspected diagnosis of STGD, CCRD, and other MD, respectively.  Commenting on the outcome of the genetics research, the authors stated that, “the analysis of >200 genes associated with retinal dystrophies and the entire locus of ABCA4 increase the rate of characterization, even regardless of available clinical and familiar data. The use of the suspected a priori diagnosis referred by the clinicians, especially in the past, could lead to clinical reclassifications to other inherited retinal dystrophies”.