Hearing impairment in Estonia: an algorithm to investigate genetic causes in pediatric patients.
OBJECTIVE
The present study was initiated to establish the etiological causes of early onset hearing loss (HL) among Estonian children between 2000-2009.


METHODS
The study group consisted of 233 probands who were first tested with an arrayed primer extension assay, which covers 199 mutations in 7 genes (GJB2, GJB6, GJB3, SLC26A4, SLC26A5 genes, and two mitochondrial genes - 12S rRNA, tRNASer(UCN)). From probands whose etiology of HL remained unknown, DNA analysis of congenital cytomegalovirus (CMV) infection and G-banded karyotype and/or chromosomal microarray analysis (CMA) were performed.


RESULTS
In 110 (47%) cases, the etiology of HL was genetic and in 5 (2%) congenital CMV infection was diagnosed. We found mutations with clinical significance in GJB2 (100 children, 43%) and in 2 mitochondrial genes (2 patients, 1%). A single mutation in SLC26A4 gene was detected in 5 probands (2.2%) and was considered diagnostic. In 4 probands a heterozygous IVS2-2A>G change in the SLC26A5 gene was found. We did not find any instances of homozygosity for this splice variant in the probands. CMA identified in 4 probands chromosomal regions with the loss of one allele. In 2 of them we were able to conclude that the found abnormalities are definitely pathogenic (12q13.3-q14.2 and 17q22-23.2 microdeletion), but the pathogenity of 2 other findings (3p26.2 and 1p33 microdeletion) remained unknown.


CONCLUSIONS
This practical diagnostic algorithm confirmed the etiology of early onset HL for 115 Estonian patients (49%). This algorithm may be generalized to other populations for clinical application.
R
R
Teek
K
K
Kruustük
R
R
Žordania
K
K
Joost
T
T
Kahre
N
N
Tõnisson
M
M
Nelis
O
O
Zilina
L
L
Tranebjaerg
T
T
Reimand
K
K
Ounap
D000293:Adolescent; D017668:Age of Onset; D000465:Algorithms; D027321:Anion Transport Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics*; D003586:Cytomegalovirus Infections / Q000150:complications / Q000235:genetics; D004957:Estonia; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000209:etiology* / Q000235:genetics* / Q000821:virology; D006320:Hearing Tests; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D012335:RNA, Ribosomal / Q000235:genetics; D000076988:Sulfate Transporters
D027321:Anion Transport Proteins; D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D026901:Membrane Transport Proteins; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; C085609:SLC26A4 protein, human; C498719:SLC26A5 protein, human; D000076988:Sulfate Transporters; D000072259:Connexin 26; C068044:GJB3 protein, human