Application of Next-Generation–Sequencing in Hearing Loss Diagnosis - Next Generation Sequencing Technologies in Medical Genetics - page 62

hearing loss is due to genetic factors and, in the remaining one-third of cases, it is
caused by environmental factors (Hilgert et al. 2009 ; Raviv et al. 2010 ). The environ-
mental factors that cause hearing loss include both prenatal and postnatal infections,
use of ototoxic drugs, and exposure to excessive noise. The majority of the inherited
form of hearing loss is monogenic, and it can be syndromic or nonsyndromic. In the
syndromic forms, hearing loss is accompanied by other physical manifestations, and
it accounts for about 30 % of the inherited hearing loss (Kochhar et al. 2007 ). Over
400 syndromes have been reported with hearing loss, and some of the common
forms of syndromic hearing loss including Usher, Pendred, Jervell and Lange-
Nielsen, Waardenburg, Branchio-oto-renal, and Stickler syndromes are among the
many (Cohen and Phillips 2012 ; Hilgert et al. 2009 ). The nonsyndromic forms of
hearing loss, with no other physical fi ndings, account for about 70 % of inherited
hearing loss. They are categorized into four different groups according to their mode
of inheritance: (1) autosomal recessive, (2) autosomal dominant, (3) X-linked, and
(4) maternal inheritance due to mutations in mitochondrial genes. The autosomal
recessive hearing loss is the most common type occurring in about 80 % of patients,
followed by autosomal dominant in about 20 %. The X-linked and mitochondrial
hearing loss are less common and account for only about 1 % of the patients
(Brownstein and Avraham 2009 ; Van Camp et al. 1997 ; Vandebona et al. 2009 ).

7.3 Nonsyndromic Hearing Loss

NSHL is extremely heterogeneous and, so far, over 150 loci responsible for this form
of hearing loss have been mapped. These loci are designated as DFN that is derived
from abbreviation of D ea FN ess followed by mode of transmission; DFNA refers to
loci for autosomal dominant forms, DFNB refers to loci for autosomal recessive, and
DFNX to X-linked forms. The numbers following the designation are chronological
order of locus identifi cation (DFNB1 refers to fi rst autosomal recessive locus). To
date, 40 autosomal recessive (ARNSHL), 27 autosomal dominant (ADNSHL), three
X-linked, and two mitochondrial genes have been identifi ed. Many of these genes
cause more than one form of hearing loss. For example, SLC26A4 , CDH23 , MYO7A ,
DFNB31 , USH1C , and others cause both syndromic and nonsyndromic forms;
TMC1 , GJB2 , GJB6 , MYO7A , and others may cause both autosomal dominant and
autosomal recessive forms of hearing loss. Mutations in the GJB2 , encoding con-
nexin 26, that cause DFNB1 are the most common cause of hearing loss and account
for about 50 % of the cases with autosomal recessive hearing loss in many popula-
tions (Cohen and Phillips 2012 ; Kochhar et al. 2007 ). The remaining cases are attrib-
utable to the mutations in other genes, and among others SLC26A4 , MYO7A , OTOF ,
CDH23 , and TMC1 are more prevalent (Hilgert et al. 2009 ). Mutations in the rest of
the genes are very rare; many of them have been found to cause hearing loss in one
or two consanguineous families (Kochhar et al. 2007 ; Zbar et al. 1998 ). Except
WFS1 , KCNQ4 , GJB2 , and COCH , most of the genes causing autosomal dominant
hearing loss are not a common cause of hearing loss (Hilgert et al. 2009 ).