RESUMEN
PURPOSE: Most classical aniridia is caused by PAX6 haploinsufficiency. PAX6 missense variants can be hypomorphic or mimic haploinsufficiency. We hypothesized that missense variants also cause previously undescribed disease by altering the affinity and/or specificity of PAX6 genomic interactions. METHODS: We screened PAX6 in 372 individuals with bilateral microphthalmia, anophthalmia, or coloboma (MAC) from the Medical Research Council Human Genetics Unit eye malformation cohort (HGUeye) and reviewed data from the Deciphering Developmental Disorders study. We performed cluster analysis on PAX6-associated ocular phenotypes by variant type and molecular modeling of the structural impact of 86 different PAX6 causative missense variants. RESULTS: Eight different PAX6 missense variants were identified in 17 individuals (15 families) with MAC, accounting for 4% (15/372) of our cohort. Seven altered the paired domain (p.[Arg26Gln]x1, p.[Gly36Val]x1, p.[Arg38Trp]x2, p.[Arg38Gln]x1, p.[Gly51Arg]x2, p.[Ser54Arg]x2, p.[Asn124Lys]x5) and one the homeodomain (p.[Asn260Tyr]x1). p.Ser54Arg and p.Asn124Lys were exclusively associated with severe bilateral microphthalmia. MAC-associated variants were predicted to alter but not ablate DNA interaction, consistent with the electrophoretic mobility shifts observed using mutant paired domains with well-characterized PAX6-binding sites. We found no strong evidence for novel PAX6-associated extraocular disease. CONCLUSION: Altering the affinity and specificity of PAX6-binding genome-wide provides a plausible mechanism for the worse-than-null effects of MAC-associated missense variants.
Asunto(s)
Anomalías del Ojo/genética , Predisposición Genética a la Enfermedad , Microftalmía/genética , Factor de Transcripción PAX6/genética , Adolescente , Adulto , Sitios de Unión/genética , Niño , Preescolar , Estudios de Cohortes , Proteínas de Unión al ADN/genética , Anomalías del Ojo/patología , Femenino , Heterocigoto , Humanos , Lactante , Masculino , Microftalmía/patología , Mutación Missense/genética , Linaje , Adulto JovenRESUMEN
Ophthalmology departments face intensifying pressure to expedite sight-saving treatments and reduce the global burden of disease. The use of electronic communication systems, digital imaging, and redesigned service care models is imperative for addressing such demands. The recently developed Scottish Eyecare Integration Project involves an electronic referral system from community optometry to the hospital ophthalmology department using National Health Service (NHS) email with digital ophthalmic images attached, via a virtual private network connection. The benefits over the previous system include reduced waiting times, improved triage, e-diagnosis in 20% without the need for hospital attendance, and rapid electronic feedback to referrers. We draw on the experience of the Scottish Eyecare Integration Project and discuss the global applications of this and other advances in teleophthalmology. We focus particularly on the implications for management and screening of chronic disease, such as glaucoma and diabetic eye disease, and ophthalmic disease, such as retinopathy of prematurity where diagnosis is almost entirely and critically dependent on fundus appearance. Currently in Scotland, approximately 75% of all referrals are electronic from community to hospital. The Scottish Eyecare Integration Project is globally the first of its kind and unique in a national health service. Such speedy, safe, and efficient models of communication are geographically sensitive to service provision, especially in remote and rural regions. Along with advances in teleophthalmology, such systems promote the earlier detection of sight-threatening disease and safe follow-up of non-sight-threatening disease in the community.