USH2A mutational spectrum causing syndromic and non-syndromic retinal dystrophies in a large cohort of Mexican patients
Por:
Ordoñez-Labastida V., Chacon-Camacho, Oscar F., Lopez-Rodriguez, Victor R., Zenteno, Juan C.
Publicada:
29 abr 2023
Categoría:
Ophthalmology
Resumen:
Background: Mutations in the USH2A gene are the leading cause of both
non-syndromic autosomal recessive retinitis pigmentosa (RP) and Usher
syndrome, a syndromic form of RP characterized by retinal dystrophy and
sensorineural hearing loss. To contribute to the expansion of the
USH2A-related molecular spectrum, the results of genetic screening in a
large cohort of Mexican patients are presented.
Methods: The study population comprised 61 patients with a clinical
diagnosis of either non-syndromic RP (n = 30) or Usher syndrome type 2
(USH2; n = 31) who were demonstrated to carry biallelic pathogenic
variants in USH2A in a three-year period. Genetic screening was
performed either by gene panel sequencing or by exome sequencing. A
total of 72 available first-or second-degree relatives were also
genotyped for familial segregation of the identified variants.
Results: The USH2A mutational spectrum in RP patients included 39
distinct pathogenic variants, most of them of the missense type. The
most common RP-causing variants were p.Cys759Phe (c.2276G>T),
p.Glu767Serfs*21 (c.2299delG), and p.Cys319Tyr (c.956G>A), which
together accounted for 25% of all RP variants. Novel USH2A mutations
included three nonsense, two missense, two frameshift, and one
intragenic deletion. The USH2A mutational spectrum in USH2 patients
included 26 distinct pathogenic variants, most of them of the nonsense
and frameshift types. The most common Usher syndrome-causing variants
were p.Glu767Serfs*21 (c.2299delG), p.Arg334Trp (c.1000C>T), and
c.12067-2A>G), which together accounted for 42% of all USH2-related
variants. Novel Usher syndrome USH2A mutations included six nonsense,
four frameshift, and two missense mutations. The c.2299delG mutation was
associated with a common haplotype for SNPs located in exons 2-21 of
USH2A, indicating a founder mutation effect.
Conclusions: Our work expands the USH2A mutational profile by
identifying 20 novel pathogenic variants causing syndromic and
non-syndromic retinal dystrophy. The prevalent c.2299delG allele is
shown to arise from a founder effect. Our results emphasize the
usefulness of molecular screening in underrepresented populations for a
better characterization of the molecular spectrum of common monogenic
diseases.
Filiaciones:
Rare Disease Diagnostic Unit, Faculty of Medicine, National Autonomous University of Mexico (UNAM), Mexico City, Mexico
Department of Genetics, Institute of Ophthalmology “Conde de Valenciana”, Mexico City, Mexico
Faculty of Medicine, Autonomous University of the State of Morelos (UAEM), Morelos, Mexico
Carrera Médico Cirujano, Facultad de Estudios Superiores Iztacala, UNAM, Mexico City, Mexico
Department of Biochemistry, Faculty of Medicine, UNAM, Mexico City, Mexico
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