BACKGROUND: The aim of the study was to identify the molecular genetic cause of two different Mendelian traits with ocular involvement present in the members of a single consanguineous Czech Roma family. METHODS: We have performed ocular examination and review of medical records in two individuals diagnosed with nanophthalmos (proband and her father) and one individual followed for bilateral congenital cataract and microcornea (uncle of the proband). DNA of subjects with nanophthalmos was analysed by exome sequencing. Sanger sequencing was applied for targeted screening of potentially pathogenic variants and to follow segregation of identified variants within the family. RESULTS: A homozygous variant c.1509G>C; p.(Met503Ile), in PRSS56 was found in the two individuals affected with nanophthalmos. The change was absent from the gnomAD dataset, but two out of 118 control Roma individuals were also shown to be heterozygous carriers. Analysis of single nucleotide polymorphisms in linkage disequilibrium with the c.1509G>C in PRSS56 suggested a shared chromosomal segment. The nanophthalmos phenotype, characterized in detail in the younger individual, encompassed bilateral corneal steepening, retinal folds, buried optic head drusen, and restricted visual fields, but no signs of retinal dystrophy. A known pathogenic founder CTDP1 variant c.863+389C>T in a homozygous state was identified in the other family member confirming the suspected diagnosis of congenital cataracts, facial dysmorphism, and demyelinating neuropathy syndrome. CONCLUSIONS: Herein, we report the first occurrence of nanophthalmos in the Roma population. We have identified pseudodominant inheritance for this phenotype caused by a novel variant in PRSS56, representing a possible founder effect. Despite advances in genetic technologies such as exome sequencing, careful phenotype evaluation in patients from an isolated population, along with an awareness of population-specific founder effects, is necessary to ensure that accurate molecular diagnoses are made.

Department of Computer Science Czech Technical University Prague Karlovo Namesti 13 121 35 Prague Czech Republic

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Katerinska 30 120 00 Prague Czech Republic

Department of Ophthalmology 1st Faculty of Medicine Charles University and General University Hospital Prague U Nemocnice 2 128 08 Prague Czech Republic

Department of Ophthalmology 2nd Faculty of Medicine Charles University and Motol University Hospital 5 Uvalu 84 150 06 Prague Czech Republic

Department of Ophthalmology New Zealand National Eye Centre University of Auckland Private Bag 92019 Auckland 1142 New Zealand

Ophthalmology Department 3rd Faculty of Medicine Charles University and Teaching Hospital Kralovske Vinohrady Srobarova 1150 50 100 34 Prague Czech Republic

Research Unit for Rare Diseases 1st Faculty of Medicine Charles University and General University Hospital Prague Ke Karlovu 2 128 08 Prague Czech Republic

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