Novel mutation in the choroideremia gene and multi-Mendelian phenotypes in Spanish families.
AIMS
We aimed to accurately diagnose several retinitis pigmentosa (RP) patients with complex ocular phenotypes by combining massive sequencing genetic diagnosis and powerful clinical imaging techniques.


METHODS
Whole-exome sequencing (WES) of selected patients from two RP families was undertaken. The variants identified were validated by Sanger sequencing and cosegregation analysis. Accurate clinical re-evaluation was performed using electrophysiological and visual field records as well as non-invasive imaging techniques, such as swept-source optical coherence tomography and fundus autofluorescence.


RESULTS
The WES results highlighted one novel and one reported causative mutations in the X-linked choroideremia gene (CHM), which challenged the initial RP diagnosis. Subsequent clinical re-evaluation confirmed the choroideremia diagnosis. Carrier females showed different degrees of affectation, even between twin sisters, probably due to lyonization. A severe multi-Mendelian phenotype was associated with coincidental dominant pathogenic mutations in two additional genes: PAX6 and PDE6B.


CONCLUSIONS
Genetic diagnosis via massive sequencing is instrumental in identifying causative mutations in retinal dystrophies and additional genetic variants with an impact on the phenotype. Multi-Mendelian phenotypes previously ascribed to rare syndromes can thus be dissected and molecularly diagnosed. Overall, the combination of powerful genetic diagnosis and clinical non-invasive imaging techniques enables efficient management of patients and their prioritisation for gene-specific therapies.
['de Castro-Miró|Marta|M|', 'Tonda|Raul|R|', 'Marfany|Gemma|G|', 'Casaroli-Marano|Ricardo P|RP|', 'Gonzàlez-Duarte|Roser|R|0000-0003-0093-923X']
D048868:Adaptor Proteins, Signal Transducing D000293:Adolescent D000328:Adult D015794:Choroideremia D004252:DNA Mutational Analysis D005260:Female D005451:Fluorescein Angiography D005654:Fundus Oculi D006801:Humans D008297:Male D008875:Middle Aged D009154:Mutation D010375:Pedigree D010641:Phenotype D012160:Retina D013030:Spain D041623:Tomography, Optical Coherence D055815:Young Adult D020691:rab GTP-Binding Proteins
imaging dystrophy Iris choroid diagnostic tests/investigation