Extended mutation spectrum of Usher syndrome in Finland.
OBJECTIVE
The Finnish distribution of clinical Usher syndrome (USH) types is 40% USH3, 34% USH1 and 12% USH2. All patients with USH3 carry the founder mutation in clarin 1 (CLRN1), whereas we recently reported three novel myosin VIIA (MYO7A) mutations in two unrelated patients with USH1. This study was carried out to further investigate the USH mutation spectrum in Finnish patients.


METHODS
We analysed samples from nine unrelated USH patients/families without known mutations and two USH3 families with atypically severe phenotype. The Asper Ophthalmics USH mutation chip was used to screen for known mutations and to evaluate the chip in molecular diagnostics of Finnish patients.


RESULTS
The chip revealed a heterozygous usherin (USH2A) mutation, p.N346H, in one patient. Sequencing of MYO7A and/or USH2A in three index patients revealed two novel heterozygous mutations, p.R873W in MYO7A and c.14343+2T>C in USH2A. We did not identify definite pathogenic second mutations in the patients, but identified several probably nonpathogenic variations that may modify the disease phenotype. Possible digenism could not be excluded in two families segregating genomic variations in both MYO7A and USH2A, and two families with CLRN1 and USH2A.


CONCLUSIONS
We conclude that there is considerable genetic heterogeneity of USH1 and USH2 in Finland, making molecular diagnostics and genetic counselling of patients and families challenging.
The Folkhälsan Institute of Genetics, Biomedicum Helsinki, Helsinki, Finland. hanna.vastinsalo@helsinki.fi
Hanna
H
Västinsalo
Reetta
R
Jalkanen
Carsten
C
Bergmann
Christine
C
Neuhaus
Leenamaija
L
Kleemola
Liisa
L
Jauhola
Hanno Jörn
HJ
Bolz
Eeva-Marja
EM
Sankila
D000328:Adult; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005387:Finland / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D015995:Prevalence; D052245:Usher Syndromes / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
C437067:CLRN1 protein, human; C000631455:MYO7A protein, human; D008565:Membrane Proteins; D000081412:Myosin VIIa; D004247:DNA; D009218:Myosins