Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4488_Библиотеки_им_академика_М_И_Перельмана
.pdf
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
dierent between individuals within the same family. Autosomal
dominant conditions may also demonstrate reduced or incomplete penetrance, where not every individual with a known
pathogenic variant in the hearing loss gene manifests hearing
loss. An autosomal dominant hearing loss phenotype tends to be
late-onset and less severe than most recessive forms of hearing
loss, and it may be progressive.
Common autosomal dominant hearing loss syndromes include
branchio-oto-renal (BOR), Waardenburg, and Treacher Collins
syndromes.
Pearl
The presentation of autosomal dominant hearing loss is quite
variable but is typically late-onset and progressive, in contrast
a
b
X-Linked Inheritance
Father
Carrier Mother
to recessive hearing loss, which tends to be more severe and is
more likely to have a congenital or prelingual presentation.
X-Linked Inheritance
Hearing loss may also be transmitted as an X-linked condition,
indicating that the pathogenic variant is in a gene on the X
chromosome. Boys are more likely to have hearing loss with this
mode of inheritance than girls are, as they have only one X chromosome, and thus only one variant of these genes instead of two,
as illustrated in Fig. 3.2c. If a woman has a pathogenic variant
on one of her X chromosomes, she will either have unaected
hearing or have a milder form of hearing loss than a man with
the same variant. X-linked inheritance is characterized by a lack
of male-to-male transmission.
Sons of a woman with a hearing loss variant on her X chromo-
some would have a 50% chance of hearing loss. Daughters of a
woman with a hearing loss variant on one of her X chromosomes
would have a 50% chance of being carriers and having some hearing loss. All the daughters of a man with X-linked hearing loss will
be carriers of the hearing loss gene, as they can inherit only the X
chromosome with the pathogenic variant from their father. Alport
syndrome is an example of a well-known X-linked disorder that
primarily aects men, yet aected women are common.
Mitochondrial Inheritance
The chromosomes in the nucleus are not the only location of DNA
in a human cell. Mitochondria, organelles of the cell important for
energy metabolism, have a small genome that consists of a small
Son
(25%)
c
Fig. 3.2 Inheritance patterns. (a) Autosomal recessive inheritance.
Unaected carrier parents have a 25% chance, in each pregnancy, to
have a child with hearing loss. (b) Autosomal dominant inheritance.
One aected parent with a 50% chance, in each pregnancy, to have a
child with hearing loss. (c) X-linked inheritance. Carrier mother has a
50% chance, in each pregnancy, to pass the pathogenic variant. There
is a 25% chance in each pregnancy of a son with hearing loss. (Adapted
from www.jnetics.org.)
Affected son
(25%)
Daughter
(25%)
Carrier daughter
(25%)
circular DNA approximately 16,000 base pairs in size containing a
small number of genes. Mitochondrial DNA (mtDNA) is inherited
from the mother, as it can be passed to ospring only through the egg
cell; sperm contribute no mitochondria to ospring. The pedigree
may show many aected siblings, and possibly variable expression,
as the mother may be more mildly aected or unaected.
Sequence variants in mtDNA are associated with both nonsyndromic and syndromic hearing loss. Hearing loss occurs in over half
of those with syndromic mitochondrial disorders, such as mitochondrial encephalopathy, lactic acidosis, and stroke (MELAS).12 The
31
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
m.1555A>G variant (that is, replacement of the base adenine with
guanine at position 1,555 on the mitochondrial genome) is associated with aminoglycoside antibiotic exposure–induced hearing
loss as well as congenital hearing loss.13 Hearing loss phenotypes
associated with nonsyndromic mitochondrial inheritance are most
often moderate to profound in degree, and onset of mitochondrial
hearing loss may be in childhood or later.14 When the hearing loss is
triggered by administration of aminoglycosides, bilateral severe to
profound hearing loss occurs within days.
15
Mosaicism
A person’s genetic makeup is typically the same in all of the cells
of his or her body. In cases of mosaicism, genetic variants are
present in some cells of the body, and not in others. A case report
described by Schimmenti et al16 illustrates mosaicism in a child
with profound hearing loss and a single hearing loss variant in
GJB2. The parent was tested and did not have the allele in her
blood. Subsequently, the parent was counseled that the hearing
loss was likely recessive. The parent had a second child with a
di erent partner, and the second child also had hearing loss.
Tissue from a cheek swab revealed that the parent was mosaic
for a single dominant allele in GJB2. Although the parent did
not have hearing loss, she did have hyperkeratosis of the dorsal
surfaces of her hands and feet.
3.6 Nonsyndromic Forms of
Genetic Hearing Loss
Nonsyndromic causes of hearing loss account for 70% of genetic
hearing loss (Fig. 3.1). In populations around the world, variants in
GJB2 account for 50% of cases with nonsyndromic recessive hearing
loss. Nonsyndromic dominant hearing loss accounts for approxi-
mately 20% of inherited nonsyndromic hearing loss.17 An overlap
exists in some genes that show both dominant and recessive
inheritance patterns (Fig. 3.3). For example, most GJB2 variants are
associated with recessive hearing loss, but some show dominant
inheritance patterns.18 Further information about individual genes
can be found at the Hereditary Hearing Loss Homepage19 and the
Online Mendelian Inheritance in Man (OMIM) site.
20
Pearl
A majority of childhood hearing loss is autosomal recessive and
nonsyndromic, meaning that the child’s parents are una ected
carriers of the variant gene, and the hearing loss exists as an isolated condition without the involvement of other systems (e.g.,
una ected vision, normal kidney function).
Autosomal
Recessive
DFNB
MYO15A SLC26A4 TMIE TMPRSS3
OTOF CDH23 GIPC3 STRC USH1C
OTOG OTOA PCDH15 RDX GRXCR1
TRIOBP CLDN14 MYO3A WHRN
ESRRB ESPN MYO6 HGF ILDR1
ADCY1 CIB2 MARVELD2 BDP1
PJVK SLC22A4 SLC26A5 LRTOMT
DCDC2 LHFPL5 S1PR2 PNPT1
BSND MSRB3 SYNE4 LOXHD1
TPRN GPSM2 PTPRQ OTOGL
TBC1D24 ELMOD3 KARS
SERPINB6 CABP2 NARS2 MET
TSPEAR TMEM132E GRXCR2 EPS8
CLIC5 FAM65B CDC14A EPS8L2
WBP2 ROR1
66 Genes
COL11A2
X-linked
DFNX
GJB2
GJB6
MYO7A
TMC1
TECTA
PRPS1
POU3F4
SMPX
COL4A6
AIFM1
Autosomal
Dominant
DFNA
CRYM DIAPH1 KCNQ4
GJB3 MYH14 CEACAM16
DFNA5 WFS1 COCH
EYA4 POU4F3 MYH9
ACTG1 MYO6 SIX1
SLC17A8 GRHL2 P2RX2
CCDC50 MIRN96 TJP2
TNC DIABLO TBC1D24
OSBPL2 HOMER2
MCM2 KITLG CD164
DMXL2
36 genes
Fig. 3.3 List of nonsyndromic hearing loss genes, arranged by inheritance mode. Based on http:// hereditaryhearingloss.org, accessed July 2017.
32
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
3.6.1 Describing Nonsyndromic Hearing
Loss: DFN Loci
As a rule, genes are identified by abbreviations that begin with a
letter and contain one or more letters or numbers, usually referring to the protein they code for or a condition a variant causes.
For example, the MYO7A gene codes for the protein myosin VIIa.
For genes that have variants that cause hearing loss, there is
another possible nomenclature system, where the name begins
with the prefix DFN (for deafness), followed by a letter that designates the mode of inheritance and a number to be used as a
reference to hearing loss phenotypes associated with the locus.
Genetics professionals may use either system: they may refer to
the specific gene to describe what causes the hearing loss or may
use the DFN nomenclature (Table 3.1). Both systems are recorded
at the OMIM site.
Table 3.1 DFN nomenclature for hearing loss-related gene locations
(loci)
DFN Term Inheritance
DFNA Dominant DFNA11 (autosomal dominant form of
DFNB Recessive DFNB2 (autosomal recessive form of
DFNX X-linked DFNX2 (X-linked form of POU3F4).
MT Mitochondrial MT-RNR1 (mitochondrial 12S ribosomal
20
Example Loci/Phenotypes
Mode
MYO7A). Nonsyndromic postlingual,
progressive bilateral sensorineural
hearing loss.
MYO7A). Nonsyndromic congenital or
childhood-onset bilateral sensorineural
hearing loss.
Nonsyndromic conductive hearing loss
with stapes xation.
RNA). Nonsyndromic 1555A>G variant
related to aminoglycoside-induced
hearing loss.
Pearl
Some genes may be inherited as dominant or recessive alleles
(e.g., GJB2). Some genes (MYO7A) may be associated with
recessive nonsyndromic hearing loss, dominant nonsyndromic
hearing loss, or recessive syndromic hearing loss.
3.6.2 GJB2 (Connexin 26)
The gene GJB2 encodes connexin 26, a gap-junction protein
expressed in the cochlea and important for the viability of hair
cells and spiral ganglion neurons.21 Initially, GJB2 variants were
thought to be associated with profound, congenital hearing
loss; however, it is now known that GJB2 is related to many
phenotypic variations,22 and hearing loss may escape diagnosis
until later in life. Hearing loss due to GJB2 pathogenic variants is
exclusively sensorineural, congenital, bilateral, and slowly progressive, ranging from mild to profound in severity.
loss due to GJB2 is more common in Asian and Caucasian groups
than in other ethnic groups,
accounts for up to 70% of hearing loss–causing variants in many
populations.25 In Asian populations, c.235delC and p.V37I are
more common.26 GJB2 variants are rare in Africa.
Rare, dominant GJB2 variants may be present as a syndromic
hearing loss associated with skin findings such as ichthyosis
(dry, scaly, or aky skin, a common finding with keratitis-
ichthyosis-deafness [KID] syndrome) or other skin conditions such
as hyperkeratosis in Vohwinkel syndrome and Bart-Pumphrey
syndrome.
28,29
11, 24
and the single variant of c.35delG
22,27
22,23
Hearing
Special Consideration
Pearl
Detailed audiometric phenotyping should support genotypic
information.
Pathogenic variants in the gene MYO7A are associated with
Usher syndrome type 1B and profound, congenital sensorineural hearing loss, yet this gene may also cause autosomal dominant and autosomal recessive nonsyndromic hearing loss. The
g
enetic hearing loss can be described as DFNA11 if the MYO7A
pathogenic variant is inherited as a nonsyndromic dominant
hearing loss, or as DFNB2 if inherited as a nonsyndromic recessive hearing loss.
A complete reference of genetic variations associated with
hearing loss phenotypes can be found at the Hereditary Hearing
Loss Homepage.
19
For African and Hispanic populations, the genes that cause
hearing loss are still not well known. However, this should not
preclude genetic evaluation and testing for individuals from
these population groups.
3.6.3 Nonsyndromic X-linked
Five known genes are associated with nonsyndromic X-linked
hearing loss: PRPS1, POU3F4, COL4A6, SMPX, and AIFM1. The PRPS1
gene encodes an enzyme necessary for metabolism, and both overactivity (also called superactivity) and loss of function have been
identified. Overactivity results in hearing loss in addition to neurological problems and hyperuricemia. The variant causing loss of
function is referred to as DFNX1 (X-linked nonsyndromic deafness)
and associated with forms of Charcot-Marie-Tooth (CMT) disease.
The POU3F4 gene regulates the activity of other genes, making
its protein a transcription factor. This gene plays a role in the
development of the middle and inner ears, with variants causing a
mixed or conductive hearing loss.30 The conductive component is
due to congenital fixation of the stapes. Aected individuals are at
33
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
risk for perilymphatic gusher during attempted surgery to repair
the stapes fixation at the oval window; perilymphatic gusher can
lead to total loss of hearing.
The COL4A6 gene encodes one of the subunits of type IV collagen found in membranes, which attaches layers of tissues in the
body. Hearing loss is sensorineural in nature, with boys exhibiting
a greater degree of loss than girls.
The SMPX gene is known to encode a protein responsible for
the cytoskeleton of inner hair cells, with variants causing sensorineural hearing loss. It may be mild and progressive in girls and
women, whereas boys exhibit severe hearing loss early in life.
AIFM1, the gene that encodes a protein that plays roles in oxidative phosphorylation and programmed cell death, was recently
identified in two families with X-linked auditory neuropathy
and late-onset peripheral sensory neuropathy.33 This variant is
designated DFNX5 as well as AUNX1 (for auditory neuropathy,
X-linked, 1).
31
32
3.6.4 Nonsyndromic Mitochondrial
The MTRNR1 gene has variants associated with both aminoglycoside-induced hearing loss and nonsyndromic hearing loss.
Variants in this gene are associated with sensorineural hearing
loss even when there is no documented exposure to aminogly-
cosides. The m.1555 A > G variant in the mitochondrial 12S rRNA
gene (MTRNR1), the most frequently found variant, increases
susceptibility to aminoglycoside ototoxicity. Most reports to
date show that the m.1555A>G variant has penetrance close to
100% when patients are exposed to aminoglycosides such as
gentamicin, tobramycin, amikacin, kanamycin, or streptomycin.
In the United States, nonsyndromic, prelingual mitochondrial
deafness is estimated to aect one out of every 20,000 to 40,000
babies.34 In Spain, it is estimated that a single mitochondrial
variant accounts for 15 to 20 percent of cases of nonsyndromic
hearing loss, even in the absence of exposure to aminoglycosides.
Preventive measures for those who carry the variant may include
avoidance of aminoglycosides and noise exposure, whenever
possible.
35
3.7 Syndromic Forms of Genetic
Hearing Loss
Syndromic forms of hearing loss are associated with abnormal-
ities in other body systems, and more than 400 recognizable
patterns have been tied to hearing loss.6 Thirty percent of
genetic hearing loss is associated with a syndrome. Additional
syndromic causes of hearing loss are included in Table 3.2.
Complete references can be found at OMIM,20 the Hereditary
Hearing Loss Homepage,19 Genetics Home Reference,36 and the
book Hereditary Hearing Loss and Its Syndromes.
37
Usher type 1 consists of profound hearing loss, vestibular
symptoms, and retinitis pigmentosa (RP) beginning in a child’s
first decade of life; Usher type 2 is characterized by congenital,
sloping moderate-severe hearing loss and RP in the first to second
decade of life; and Usher type 3 is characterized by progressive
hearing loss, variable vestibular symptoms, and variable onset of
RP.19 A small percentage of people with Usher syndrome will have
only one detectable pathogenic variant.
3.7.2 Pendred Syndrome
Pendred syndrome is an autosomal recessive endocrine disorder
associated with variations in the SLC26A4 gene, thyroid goiter,
enlarged vestibular aqueduct (EVA) and/or Mondini malformation, possible balance problems, and hearing loss.
loss is sensorineural or mixed, often severe to profound, and
may be congenital, sudden, or progressive. Pendred syndrome
is the most common syndromic hearing loss and accounts for
4 to 10% of all cases of hereditary hearing loss.
with Pendred syndrome typically carry two SLC26A4 variants. If
EVA and variants of SLC26A4 exist in the absence of thyroid dysfunction, the hearing loss is considered nonsyndromic (DFNB4).
Individuals with DFNB4 tend to have one or no pathogenic variants in SLC26A4.
42
39,40
Hearing
34,41
Individuals
Special Consideration
Individuals with unilateral hearing loss and genetic variants in
SLC26A4 will typically experience hearing loss progression to
the other ear, whereas individuals with Waardenburg syndrome
usually do not demonstrate progression to the other ear.
3.7.3 Waardenburg Syndrome
Waardenburg syndrome (WS) can be identified by the clinical
features of a white forelock; pale blue eyes, dierent-colored
eyes, or two dierent colors in the same eye; wide-spaced eyes;
pigmentary anomalies; gastrointestinal disturbances; and hearing loss. There are four distinct types of WS. WS type 1 is char-
acterized by a white forelock or early graying of the hair in 45%
of individuals and by congenital bilateral or unilateral hearing
loss in 60% of cases. Hearing loss does not typically progress with
WS.43 Waardenburg syndrome is an autosomal dominant disorder and has variable expression of its clinical features within
families. A small number of cases may be autosomal recessive or
may be due to new variants.
3.7.1 Usher Syndrome
Usher syndrome is the most common cause of concurrent
deafness and blindness in adults. There are three types of Usher
syndrome, all of which are transmitted via autosomal recessive
inheritance. In the United States, 4.4 per 100,000 individuals are
estimated to have Usher syndrome.
34
38
BOR syndrome is characterized by preauricular pits or tags;
malformed or misshapen ears; middle or inner ear anatomical
dierences; defects in kidney structure or function; and hearing
loss, which may be conductive, sensorineural, or mixed. An
estimated 5% of individuals with BOR have profound hearing
loss.44 This autosomal dominant disorder occurs in 1 in 40,000
3.7.4 BOR Syndrome
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
Table 3.2 Syndromes associated with genetic hearing loss
Syndrome Features Inheritance patterns Gene(s)
Alport syndrome Progressive hearing loss, blood in urine, hypertension 80% X-linked
Biotinidase deciency If untreated, seizures, hypotonia, breathing problems, vision
BOR syndrome Preauricular pits or tags, malformed or misshapen ears,
CHARGE syndrome Ocular, ear, and heart defects, delayed growth and
Craniosynostoses
(Apert syndrome, Crouzon
syndrome, Pfeier syndrome)
Jervell and Lange-Nielsen
syndrome
MELAS syndrome Stroke, cortical blindness, recurrent headaches, seizures,
MERRF syndrome Epilepsy, muscle twitches, muscle weakness, ataxia Mitochondrial MTTK, MTTL1, MTTH, MTTS1,
Neurobromatosis type 2 Vestibular schwannoma on cranial nerve VIII AD NF2
Pendred syndrome Thyroid goiter, EVA and/or Mondini malformation AR SLC26A4 (PDS), FOXI1
Stickler syndrome High myopia, risk of retinal detachment, very exible joints,
Treacher Collins syndrome Craniofacial malformations, malformed ears, small or absent
Usher syndrome Vestibular problems, retinitis pigmentosa AR Type 1: MYO7A, USH1C, CDH23,
Waardenburg syndrome White forelock; pale blue eyes, dierent colored eyes, or
Wolfram (DIDMOAD)
syndrome
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; BOR, branchio-oto-renal; CHARGE, coloboma, heart anomaly, choanal atresia, retardation,
genital and ear anomalies; DIDMOAD, diabetes insipidus, diabetes mellitus, optic atrophy, deafness; EVA, enlarged vestibular aqueduct; MELAS, mitochondrial
encephalopathy, lactic acidosis, strokelike episodes; MERRF, myoclonic epilepsy with ragged red bers.
Source: Information retrieved from Genetics Home Reference
loss, ataxia
middle or inner ear anatomic dierences, defects in kidney
structure or function
development, genital abnormalities
Premature fusion of skull bones AD FGFR1, FGFR2, FGFR3
Heart arrhythmia, long QT syndrome, fainting spells AR KCNE1, KCNQ1
vomiting
arthritis, cleft palate, attened facial appearance, large
tongue, small lower jaw
ear canals, down-slanting eyes, dental problems, notched
lower eyelids, missing eyelashes, and small jaw
two dierent colors in the same eye; wide-spaced eyes;
pigmentary anomalies; gastrointestinal disturbances
Low-frequency, progressive sensorineural hearing loss,
diabetes insipidus, diabetes mellitus, optic atrophy
36
and OMIM,20 September 2016.
15% AR
5% AD
AR BTD
AD EYA1, SIX1, SIX5
AD CHD7, SEMA3E
Mitochondrial Most common: c.3243A in MTTL1.
AD COL2A1, COL11A1, COL11A2,
AD
Less common: AR
AD Type 1: PAX3
AR WFS1, CISD2
X-linked: COL4A5
AR: COL4A4
AR/AD: COL4A3
Other genes include: MTTQ, MTTH,
MTTK, MTTC, MTTS1, MTND6.
MTTS2, MTND1, MTND5, MTTL1
MTTS2, MTTF, MTND5
COL9A1, COL9A2
TCOF1, POLR1D, POLR1C
PCDH15, SANS, CIB2
Type 2: USH2A, GPR98, PDZD7,
VLGR1, ADGRV1, WHRN
Type 3: CLRN1, HARS
Type 2: MITF, SNA12, SOX10
Type 3: PAX3
Type 4: EDNRB, EDN3, SOX10
individuals and is associated with the genes EYA1, SIX1, and SIX5.
Approximately 10% of cases of BOR are due to new variants.
45
70% of individuals who meet clinical criteria for CHARGE
syndrome.
48
3.7.5 CHARGE Syndrome
CHARGE syndrome is characterized by features abbreviated in
its name: coloboma (malformation in the eye), heart defects,
choanal atresia, retarded growth and development, genital
abnormalities, and ear anomalies. This disorder is inherited in
an autosomal dominant pattern with an incidence of 1 in 12,000
babies46 and most cases being due to new variants. The hearing
loss associated with CHARGE can be conductive, sensorineural,
or mixed; may vary from mild to profound; and may progress
over time. Temporal bone abnormalities are a hallmark of this
condition, specifically semicircular canal hypoplasia/aplasia.47
Pathogenic variants in the gene CHD7 are responsible for over
3.7.6 Jervell and Lange-Nielsen Syndrome
and Other Syndromes Related to
Cardiac Function
Jervell and Lange-Nielsen is an autosomal recessive disorder
characterized by heart arrhythmia, long QT syndrome, fainting
spells, and profound congenital hearing loss. Approximately one
in every 200,000 individuals in northern Europe is aected by
Jervell and Lange-Nielsen syndrome.
terized by a high risk of sudden death but, if identified early, can
be clinically managed.
49
This syndrome is charac-
35
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
Other forms of genetic hearing loss associated with cardiac abnormalities include sinoatrial node dysfunction and deafness (SANDD)
and 22q11.2 deletion syndrome. SANDD disorder is characterized
by bradycardia (an abnormally low heart rate, less than 60 beats per
minute) and congenital severe to profound sensorineural hearing
loss. SANDD is an autosomal recessive disorder, and, in contrast
to Jervell and Lange-Nielsen syndrome, QT intervals are not prolonged.50 The disorder of 22q11.2 deletion syndrome, also known
as DiGeorge syndrome or velocardiofacial syndrome, is related to
a constellation of cardiac and craniofacial abnormalities, including
an autosomal dominant unilateral or bilateral hearing loss in 78%
of individuals.51 Those with 22q11.2 deletion have structural heart
disease rather than cardiac rhythm defects.
3.8 Chromosome Disorders
It is estimated that 1% of the general population has a chromosome abnormality;52 however, very few conditions exist where
an entire chromosome is added or deleted. More often, small
portions of chromosomes are missing or duplicated.
3.8.1 Down Syndrome
The most common chromosome abnormality associated with
hearing loss is Down syndrome. The incidence of Down syndrome is 1/600 live births, making it the most common chromosome condition in humans. Hearing loss is reported in over
80% of children with Down syndrome53 and may be conductive,
mixed, or sensorineural, potentially involving stapes malformations, stenotic ear canals, dysfunctional eustachian tubes, and/or
middle ear infections.
For children with Down syndrome who also have hearing loss,
one should not assume that Down syndrome is the sole cause
of hearing loss. A case has been reported of a child with Down
syndrome also having GJB2-related hearing loss.54 The incidence
of co-occurring syndromic and nonsyndromic genetic diagnoses
may be higher than previously estimated.
3.8.2 Microdeletions
Even submicroscopic regions of chromosomes can encode dozens
of genes, and current genetic testing techniques can detect
microdeletions through microarray. Microdeletions are characterized by dominant inheritance pattern in which one chromosome version is deleted and the other chromosome remains
intact. The online parent support resource Unique55 can provide
information for families regarding previously undescribed disorders. Williams syndrome and 22q11.2 deletion are examples of
microdeletion disorders with associated hearing loss.
8,51
Features of ANSD include uctuating hearing, diculty listening
in noise, and speech perception abilities that are worse than
would be predicted with cochlear hearing loss. The underlying
deficit is likely impaired inner hair cells, inner hair cell ribbon
synapses, or spiral ganglion neurons.
Approximately 40% of ANSD is genetic in origin, with both
syndromic and nonsyndromic findings,57 and inheritance patterns
that include autosomal dominant, autosomal recessive, X-linked,
and mitochondrial modes. ANSD in its syndromic form may be
seen as a component in degenerative neuropathies such as CMT
disease or Friedreich ataxia, and auditory neuropathy may develop
after the onset of the peripheral neuropathy. A mitochondrial
form of auditory neuropathy has been associated with Leber’s
hereditary optic neuropathy.
Nonsyndromic auditory neuropathy is most often autosomal
recessive.59 The two genes frequently implicated are OTOF (DFNB9)
and DFNB59. The OTOF gene codes for the protein otoferlin, which
is known to have an impact on inner hair cell function. Variants
in OTOF have been implicated in temperature-sensitive ANSD.60
DFNB59 codes for the protein pejvakin, which is associated with
auditory nerve function, with some variants causing the ANSD
phenotype,61 although this is controversial. Interestingly, GJB2
variants may also potentially cause ANSD.
The nonsyndromic autosomal dominant auditory neuropathy 1
(AUNA1) locus relates to pathogenic variants in the DIAPH3 gene.
The X-linked locus, AUNX1, is characterized by childhood onset of
auditory neuropathy and later-onset peripheral sensory neuropa-
thy and was recently identified to be AIFM1.
58
56
62
33
3.10 Genetic Evaluation of
Individuals with Hearing Loss
Only a few years ago, genetic testing for a child with apparently
nonsyndromic hearing loss was limited to testing one gene at a
time at a cost of nearly US $1,000 per gene. For a condition like
hearing loss, where any one of over 100 genes could be the cause
of hearing loss, exhaustive genetic testing was prohibitively
expensive with limited availability. Combining this with months
of eort to sequence each gene, it could take years before the
reason for a child’s hearing loss could be identified, if ever. The
list of individual genes that could be tested was quite short
and consisted of sequencing GJB2, deletion detection in GJB6,
sequencing SLC26A4, and possibly sequencing M YO7A . Although
GJB2 sequence variants and GJB6 deletions account for 25% of sen-
sorineural hearing loss in North American populations,24 limiting
testing to this gene identified only a small number of aected
children. To overcome this limitation, nearly all confirmed hearing loss genes are now sequenced simultaneously through NGS.
3.9 Auditory Neuropathy
Spectrum Disorder
Auditory neuropathy spectrum disorder (ANSD) is diagnosed
based on absent or abnormal auditory neural function reected
in the auditory brainstem response, with present cochlear
microphonic or outer hair cell responses (otoacoustic emissions).
Special Consideration
Parents may feel guilty if a genetic basis of hearing loss is discovered through genetic testing. Audiologists can reassure parents
that they are not at fault for the child’s hearing loss, and this
message can be supported by the understanding of how genetic
traits are inherited and how new traits develop.
36
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
3.10.1 NGS and Sequence Variant
Nomenclature
NGS was developed in the 2000s and was first applied to hearing
loss in 2010 by Richard Smith and colleagues at the University of
Iowa.63 NGS has also been called massively parallel sequencing.
Sequencing can include the whole genome or subsets of the
genome. For a patient with hearing loss, sequencing is targeted
to genes that are associated with hearing loss. Hearing loss
gene panels are designed to be comprehensive, because it is
nearly impossible to determine clinically whether a child has
syndromic or nonsyndromic hearing loss just by the audiogram.
Furthermore, while most recessive forms of hearing loss present
in infancy and most dominant forms present later on, this may
not always be true. Thus, it is better to test comprehensively
using a panel that includes dominant, recessive, and X-linked
genes, given that sometimes inheritance patterns and hearing
loss phenotypes may be misleading.
NGS requires a blood draw to obtain nucleated cells from
a whole blood sample. In some less common circumstances,
cheek cells, obtained by scraping the inside of the cheek with a
brush, are acceptable. Genomic DNA is isolated and broken into
fragments. The fragments are captured to enrich the DNA for only
those fragments that correspond to genes targeted to hearing loss.
The fragments are labeled and are injected into a microuidic cell,
where each fragment is then sequenced multiple times over. In
this manner, sequences are accumulated from multiple genes at
once and each area of the genome is sequenced many times over
to ensure a quality sequence read for each nucleotide.
Bioinformatic approaches are used to map the sequence back to
a reference genome, and the sequence is both computationally and
manually curated for sequence variants. Sequence variants are then
evaluated and given a designator. Furthermore, knowing whether or
not a gene causes dominant or recessive hearing loss is taken into
consideration as part of the interpretation. For example, if a child has
only one variant in a hearing loss–associated gene that is typically
inherited as a recessive, this variant alone may not be the cause of
hearing loss. In addition to small genomic variants, larger variants,
called copy number variants (CNVs), may be identified, where a loss
or gain of a large genomic segment may remove a hearing loss gene.
Support of a clinical geneticist and genetic counselor is almost
always needed to assist in interpretation of the sequencing report,
much in the way a radiologist is needed to read an X-ray image.
There are three possible outcomes with an NGS result: negative,
positive, and variant of uncertain significance (VUS).
64
loss is autosomal recessive, autosomal dominant, X-linked, or
mitochondrial in origin.
VUS
VUS means that a change in the DNA sequence of a particular
gene was detected, but it is not known whether the change
explains the hearing loss. If a VUS is detected, the laboratory
may request a blood sample from both parents to help clarify
the child’s results and to help determine whether the VUS is
benign (normal variant) or pathogenic. It is important that
the parents understand that their samples may be needed for
complete interpretation of their child’s results. Sometimes, even
after parental testing, a variant may still be classified as being of
uncertain significance.
Advantages of NGS
NGS is advantageous because many genes can be sequenced
at one time and the process of finding the right gene is accelerated. NGS is particularly helpful for such conditions as Usher
syndrome, where the diagnosis typically does not become obvious until a child has reached the teenage years65 yet decisions
regarding habilitation, especially cochlear implantation, need to
be made in infancy.
NGS hearing loss panels typically include between 70 and
120 genes and can be obtained through Clinical Laboratory
Improvement Act (CLIA)-certified molecular diagnostic laboratories. Laboratory choice can be based on local provider or institutional preference, insurance coverage, timeliness, and readability
of reports. Examples of commonly used NGS panels include the
OtoGenome Test (performed at Harvard Partners Laboratory for
Molecular Medicine) and the OtoScope Test (performed at the
Molecular Otolaryngology and Renal Research Laboratories,
University of Iowa). Additional laboratories oer targeted NGS
tests as well.
Pearl
Genetic testing by targeted NGS has become the standard of
care for children with hearing loss. A panel of hearing loss genes
(approximately 100) should be tested at one time rather than
sequential testing of single genes. Dominant and recessive genes
as well as genes for syndromic and nonsyndromic hearing loss
should be tested.
Negative
No variants were identified in the genes that were tested/
sequenced. This does not rule out a genetic cause for an individual’s hearing loss. Additional testing can be considered in the
f
uture as new hearing loss genes are discovered and added to
testing panels.
3.10.2 Genetic Testing for Hearing
Loss: Standard of Care and Cost-
Eective
Positive
A likely pathogenic or known pathogenic variant is identified.
This gives the individual a genetic or molecular diagnosis and
answers the question of “how did this happen?” Identification
of a pathogenic variant also determines whether the hearing
Genetic evaluation, genetic testing, and genetic counseling are
standard of care for children who are deaf or hard of hearing. The
emerging standard is to perform NGS as a first-line test.2 Studies
are showing that a hearing loss diagnosis can be made, on aver-
age, 41% of the time depending on the populations studied and
37
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
the family structure.66 It has recently been shown that genetic
testing for hearing loss has value and is a cost-eective tool in
providing care for children who are deaf or hard of hearing.
67
3.11 Genetic Counseling for Hearing
Loss
At the initial visit, t he genetic counselor will meet with the fa mily
to review the family medical history and to construct a three- to
four-generation pedig ree, discuss genetic testing options (includ-
ing the benefits and limitations of testing), and obtain informed
consent for testing. After the results return from a child’s testing,
the genetic counselor provides interpretation and explanations
to the family. This potentially leads to a review of a new diagnosis, combined with a discussion of inheritance and associated
recurrence chance for future children. If a VUS is identified on
testing, the genetic counselor will coordinate parental testing
when necessary. If there is a negative/normal result, a genetic
cause for a child’s hearing loss has not been ruled out. Therefore,
posttest counseling could include a discussion of further testing
in the future as new hearing loss genes are discovered.
Constructing a pedigree is an ecient way to record the family
medical history information and can illustrate a possible mode of
inheritance for the hearing loss. When obtaining this information,
the genetic counselor will focus on hearing loss history in the
family as well as additional history of vision loss, kidney disease,
cardiac disease (or sudden death), developmental disabilities, and
birth defects. Once a genetic cause for hearing loss is identified in
a family, the genetic counselor can facilitate testing for relatives
who are at risk for hearing loss or for relatives that could be carriers of a pathogenic variant.
3.12 Incorporating Genetic Testing
as Part of Newborn Hearing
Screening Programs
The cost of genetic testing has decreased considerably through
the use of NGS panels, and it is feasible to consider oering
genetic testing following initial referral on a newborn hearing
screening rather than later in life.
While newborn hearing screening programs can identify
hearing loss caused by a number of genetic variants at birth,
if hearing loss is not present at birth or if it presents as a sub-
clinical finding (not detected by newborn hearing screening),
the cause of the hearing loss will continue to be unknown until
genetic testing is completed. It is estimated that if a newborn
can be screened for sequence variants in GJB2, SLC26A4, and
the mitochondrial allele m.A1555G, in addition to being tested
for congenital cytomegalovirus (cCMV), up to 60% of all infants
who will be aected by late-onset, prelingual hearing loss can be
identified at birth.
34
Special Consideration
Genetic testing is not an attempt to change an individual’s Deaf
identity or self-identication with the Deaf community.
3.13 Future Perspectives and Hope
for the Future of Genetic
Medicine
To date, there have been a number of ex amples where investigators
have taken a gene that is missing or defective in mouse models of
human deafness and have restored hearing by reintroducing the
gene via inserting a functioning copy of the gene into the inner
ear through a viral vector. This technique of replacing a variant
gene copy with a functioning copy to restore hearing is called
gene therapy. Present research findings provide hope that in the
future, genetic testing will be used to identify the cause of hearing
loss and, thus, enable selection of the precise therapies that may
restore hearing in individuals who are deaf or hard of hearing.
Pearl
Ongoing follow-up is needed for individuals with hearing loss as
technologies for genetic testing improve and new genomic discoveries are made. If, for example, an individual was initially tested
only for GJB2 and no pathogenic variation was identied, an audiologist can suggest additional follow-up with genetics professionals
to further investigate the etiology of the hearing loss.
3.14 Conclusion
Audiologists are often among the first professionals to discuss
the importance of a genetics referral to a family whose child
has a hearing loss, and interprofessional collaboration between
audiologists and genetics professionals is key to serving families.
As the knowledge surrounding the genetics of hearing loss grows
over time, well-informed audiologists will provide the link
between new applications of scientific breakthroughs and the
individual who might benefit from such discoveries.
Pitfall
If genetic testing comes back negative, never assume that that
there is not a genetic cause behind an individual’s hearing loss.
The pathogenic variant associated with hearing loss may not
yet be identied, or multiple gene interactions that are not yet
understood may produce hearing loss.
Discussion Questions
1. What information from the audiology case history can be
used by genetics professionals?
2. What is the recurrence rate for a recessive hearing loss with
each birth? What is the recurrence rate for a dominant hearing loss with each birth?
3. What other medical evaluations or tests are typically recom-
mended following a hearing loss identication, and how do these
sults help in determining the genetic cause of hearing loss?
re
4. A child has a normal/negative genetic test result. Has this
ruled out a genetic cause for the child’s hearing loss?
38
3 Genetics of Hearing Loss
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
References
[1] Centers for Disease Control and Prevention. Summary of 2013 National CDC
EHDI Data. http://www.cdc.gov/ncbddd/hearingloss/2013-data/2013_EHDI_
HSFS_summary_E.pdf. Published 2016. Accessed December 1, 2017
[2] Alford RL, Arnos KS, Fox M, et al; ACMG Working Group on Update of Genetics
Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss;
Professional Practice and Guidelines Committee. American College of Medical
Genetics and Genomics guideline for the clinical evaluation and etiologic diagno-
sis of hearing loss. Genet Med 2014;16(4):347–355
[3] Joint Committee on Infant Hearing (JCIH). Year 2007 position statement:
principles and guidelines for early hearing detection and intervention programs.
Pediatrics 2007;120(4):898–921
[4] Palmer CG, Martinez A, Fox M, Zhou J, Shapiro N, Sininger Y, et al. A prospective,
longitudinal study of the impact of GJB2/GJB6 genetic testing on the beliefs and
attitudes of parents of deaf and hard-of-hearing infants. Am J Med Genet A. 2009
Jun;149A(6):1169-82
[5] Wang T, Birsoy K, Hughes NW, et al. Identification and characterization of essen-
tial genes in the human genome. Science 2015;350(6264):1096–1101
[6] Arnos KS, Welch KO, Pandya A. Epidemiology, etiology, genetic mechanisms, and
genetic counseling. In: Toriello H, Smith SD, eds. Hereditary Hearing Loss and Its
Syndromes. 3rd ed. Oxford, UK: Oxford University Press; 2013:4–12
[7] Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal mi-
croarray is a first-tier clinical diagnostic test for individuals with developmental
disabilities or congenital anomalies. Am J Hum Genet 2010;86(5):749–764
[8] Marler JA, Sitcovsky JL, Mervis CB, Kistler DJ, Wightman FL. Auditory function
and hearing loss in children and adults with Williams syndrome: cochlear impairment in individuals with otherwise normal hearing. Am J Med Genet C Semin
Med Genet 2010;154C(2):249–265
[9] Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 6th ed. New York,
NY: Garland Science; 2015
[10] Richards S, Aziz N, Bale S, et al; ACMG Laboratory Quality Assurance Commit-
tee. Standards and guidelines for the interpretation of sequence variants: a
joint consensus recommendation of the American College of Medical Genetics
and Genomics and the Association for Molecular Pathology. Genet Med
2015;17(5):405–424
[11] Prasad S, Cucci RA, Green GE, Smith RJH. Genetic testing for hereditary hearing
loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat 2000;16(6):502–508
[12] Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis, and
strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci 2008;1142:133–158
[13] Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNA muta-
tion associated with both antibiotic-induced and non-syndromic deafness. Nat
Genet 1993;4(3):289–294
[14] Yelverton JC, Arnos K, Xia X-J, Nance WE, Pandya A, Dodson KM. The clinical and
audiologic features of hearing loss due to mitochondrial mutations. Otolaryngol
Head Neck Surg 2013;148(6):1017–1022
[15] Pandya A. Nonsyndromic hearing loss and deafness, Mitochondrial. 2004 Oct
22 [Updated 2014 Jul 3]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors.
GeneReviews© [Internet]. Seattle (WA): University of Washington, Seattle;
199302016. Accessed September 3, 2016.
[16] Schimmenti LA, Steyermark J, Bower M. Genetic testing for deaf and hard of
hearing individuals: genetic counseling. Curr Genet Med Rep 2016;4:27–34
[17] Smith RJH, Shearer AE, Hildebrand MS, et al. Hereditary hearing loss and deaf-
ness overview. GeneReviews [Internet]. http://www.ncbi.nlm.nih.gov/books/
NBK1434/. Updated July 27, 2017. Accessed December 2, 2017
[18] Denoyelle F, Lina-Granade G, Plauchu H, et al. Connexin 26 gene linked to a
dominant deafness. Nature 1998;393(6683):319–320
[19] Van Camp G, Smith R. Hereditary Hearing Loss Homepage. http://hereditary-
hearingloss.org/. Updated October 5, 2017. Accessed December 3, 2017
Online Mendelian Inheritance in Man (OMIM). McKusick-Nathans Institute for
[20]
Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD).
ht
tp://omim.org. Updated December 1, 2017. Accessed December 3, 2017
[21] Takada Y, Beyer LA, Swiderski DL, et al. Connexin 26 null mice exhibit spiral
ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res
2014;309:124–135
[22] Snoeckx RL, Huygen PLM, Feldmann D, et al. GJB2 mutations and degree of hear-
ing loss: a multicenter study. Am J Hum Genet 2005;77(6):945–957
[23] Kenna MA, Feldman HA, Neault MW, et al. Audiologic phenotype and pro-
gression in GJB2 (Connexin 26) hearing loss. Arch Otolaryngol Head Neck Surg
2010;
136(1):81–87
[24] Schimmenti LA, Martinez A, Telatar M, et al. Infant hearing loss and connexin
testing in a diverse population. Genet Med 2008;10(7):517–524
[25] Pandya A, Arnos KS, Xia XJ, et al. Frequency and distribution of GJB2 (connexin
26) and GJB6 (connexin 30) mutations in a large North American repository of
deaf probands. Genet Med 2003;5(4):295–303
[26] Chu CW, Chen YJ, Lee YH, Jaung SJ, Lee FP, Huang HM. Government-funded uni-
versal newborn hearing screening and genetic analyses of deafness predisposing
g
enes in Taiwan. Int J Pediatr Otorhinolaryngol 2015;79(4):584–590
[27] Kabahuma RI, Ouyang X, Du LL, et al. Absence of GJB2 gene mutations, the
GJB6 deletion (GJB6-D13S1830) and four common mitochondrial mutations in
nonsyndromic genetic hearing loss in a South African population. Int J Pediatr
Otorhinolaryngol 2011;75(5):611–617
[28] Iossa S, Marciano E, Franzé A. GJB2 gene mutations in syndromic skin diseases
with sensorineural hearing loss. Curr Genomics 2011;12(7):475–785
[29] Kelsell DP, Dunlop J, Stevens HP, et al. Connexin 26 mutations in hereditary
non-syndromic sensorineural deafness. Nature 1997;387(6628):80–83
[30] de Kok YJ, van der Maarel SM, Bitner-Glindzicz M, et al. Association between
X-linked mixed deafness and mutations in the POU domain gene POU3F4. Science
1995;267(5198):685–688.
[31] Rost S, Bach E, Neuner C, et al. Novel form of X-linked nonsyndromic hearing loss
with cochlear malformation caused by a mutation in the type IV collagen gene
COL4A6. Eur J Hum Genet 2014;22(2):208–215
[32] Huebner AK, Gandia M, Frommolt P, et al. Nonsense mutations in SMPX, encod-
ing a protein responsive to physical force, result in X-chromosomal hearing loss.
Am J Hum G
[33] Zong L, Guan J, Ealy M, et al. Mutations in apoptosis-inducing factor cause
X-linked recessive auditory neuropathy spectrum disorder. J Med Genet
2015;52(8):523–531
[34] Morton CC, Nance WE. Newborn hearing screening—a silent revolution. N Engl J
Med 2006;354(20):2151–2164
[35] del Castillo FJ, Rodríguez-Ballesteros M, Martín Y, et al. Heteroplasmy for the
1555A>G mutation in the mitochondrial 12S rRNA gene in six Spanish families
with non-syndromic hearing loss. J Med Genet 2003;40(8):632–636 AccessedJuly312016
[36]
National Library of Medicine (US). Genetics Home Reference. https://ghr.nlm.nih.
gov/. Updated November 28, 2017. Accessed December 2, 2017
[37] Toriello HV, Smith SD. Hereditary Hearing Loss and Its Syndromes. 3rd ed.
Oxford, UK: Oxford University Press; 2013
[38] Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of
prevalence from two high-risk populations. J Chronic Dis 1983;36(8):595–603
[39] Reardon W, OMahoney CF, Trembath R, Jan H, Phelps PD. Enlarged vestibular
aqueduct: a radiological marker of pendred syndrome, and mutation of the PDS
gene. QJM 2000;93(2):99–104
[40] Phelps PD, Coey RA, Trembath RC, et al. Radiological malformations of the ear
in Pendred syndrome. Clin Radiol 1998;53(4):268–273
[41] Smith RJH, Bale JF Jr, White KR. Sensorineural hearing loss in children. Lancet
2005;365(9462):879–890
[42] Pryor SP, Madeo AC, Reynolds JC, et al. SLC26A4/PDS genotype-phenotype
correlation in hearing loss with enlargement of the vestibular aqueduct (EVA):
evidence that Pendred syndrome and non-syndromic EVA are distinct clinical
and genetic entities. J Med Genet 2005;42(2):159–165
[43] Milunsky JM. Waardenburg syndrome type 1. GeneReviews [Internet]. https://
www.ncbi.nlm.nih.gov/books/NBK1531/. Updated May 4, 2017. Accessed
December 3, 2017
[44] Fraser FC, Sproule JR, Halal F. Frequency of the branchio-oto-renal (BOR) syn-
drome in children with profound hearing loss. Am J Med Genet 1980;7(3):341–
349
Chang EH, Menezes M, Meyer NC, et al. Branchio-oto-renal syndrome: the
[45]
mutation spectrum in EYA1 and its phenotypic consequences. Hum Mutat
2004;23(6):582–589
[46] Källén K, Robert E, Mastroiacovo P, Castilla EE, Källén B. CHARGE association in
newborns: a registry-based study. Teratology 1999;60(6):334–343
[47] Amiel J, Attieé-Bitach T, Marianowski R, et al. Temporal bone anomaly pro-
posed as a major criteria for diagnosis of CHARGE syndrome. Am J Med Genet
2001;
[48] Vissers LELM, van Ravenswaaij CMA, Admiraal R, et al. Mutations in a new
member of the chromodomain gene family cause CHARGE syndrome. Nat Genet
2004;36(9):955–957
enet 2011;88(5):621–627
99(2):124–127
39
I Hearing Loss: Essential Information
Madell et al., Pediatric Audiology: Diagnosis, Technology, and Management, 3rd Ed. (ISBN 978-1-62623-401-7),
copyright © 2019 Thieme Medical Publishers. All rights reserved. Usage subject to terms and conditions of license.
[49] Tranebjaerg L, Bathen J, Tyson J, Bitner-Glindzicz M. Jervell and Lange-Nielsen
syndrome: a Norwegian perspective. Am J Med Genet 1999;89(3):137–146
[50] Baig SM, Koschak A, Lieb A, et al. Loss of Ca(v)1.3 (CACNA1D) function in a
human channelopathy with bradycardia and congenital deafness. Nat Neurosci
2011;14(1):77–84
[51] Van Eynde C, Swillen A, Lambeens E, et al. Prevalence and nature of hearing loss
in 22q11.2 deletion syndrome. J Speech Lang Hear Res 2016;59(3):583–589
[52] Morton CC, Giersch AB. Genetic hearing loss associated with chromosome disor-
ders. In: Toriello H V., Smith SD, eds. Hereditary Hearing Loss and Its Syndromes.
3r
d ed. Oxford, UK: Oxford University Press; 2013:700–718
[53] Manickam V, Shott GS, Heithaus D, Shott SR. Hearing loss in Down syndrome
revisited—15 years later. Int J Pediatr Otorhinolaryngol 2016;88:203–207
[54] Venail F, Roux AF, Pallares-Ruiz N, et al. Nonsyndromic 35 delG mutation of the
connexin 26 gene associated with deafness in syndromic children: two case
reports. Laryngoscope 2004;114(3):566–569
[55] Searle B; The Rare Chromosome Disorder Support Group. Unique. http://www.
rarechromo.org/html/home.asp. 1996–2017. Accessed December 2, 2017
[56] Moser T, Starr A. Auditory neuropathy--neural and synaptic mechanisms. Nat
Rev Neurol 2016;12(3):135–149
[57] Sininger YS. Identification of auditory neuropathy in infants and children. Semin
Hear 2002;23(3):193–200
[58] Ceranić B, Luxon LM. Progressive auditory neuropathy in patients with Leber’s
hereditary optic neuropathy. J Neurol Neurosurg Psychiatry 2004;75(4):626–630
[59] Rodríguez-Ballesteros M, Reynoso R, Olarte M, et al. A multicenter study on the
prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects
with nonsyndromic hearing impairment and auditory neuropathy. Hum Mutat
2008;29(6):823–831
[60] Starr A, Sininger Y, Winter M, Derebery MJ, Oba S, Michalewski HJ. Tran-
sient deafness due to temperature-sensitive auditory neuropathy. Ear Hear
1998;19(3):169–179
[61] Delmaghani S, del Castillo FJ, Michel V, et al. Mutations in the gene encoding pej-
vakin, a newly identified protein of the aerent auditory pathway, cause DFNB59
auditory neuropathy. Nat Genet 2006;38(7):770–778
[62] Cheng X, Li L, Brashears S, et al. Connexin 26 variants and auditory neuropa-
thy/dys-synchrony among children in schools for the deaf. Am J Med Genet A
2005;139(1):13–18
[63] Shearer AE, DeLuca AP, Hildebrand MS, et al. Comprehensive genetic testing for
hereditary hearing loss using massively parallel sequencing. Proc Natl Acad Sci U
S A 2010;107(49):21104–21109
[64] Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N
Engl J Med 2014;370(25):2418–2425
[65] Aparisi MJ, Aller E, Fuster-García C, et al. Targeted next generation sequencing for
molecular diagnosis of Usher syndrome. Orphanet J Rare Dis 2014;9:168
[66] Shearer AE, Smith RJH. Massively parallel sequencing for genetic diagno-
sis of hearing loss: the new standard of care. Otolaryngol Head Neck Surg
2015;153(2):175–182
[67] Sabatini LM, Mathews C, Ptak D, et al. Genomic sequencing procedure microcost-
ing analysis and health economic cost-impact analysis: a report of the Association for Molecular Pathology. J Mol Diagn 2016;18(3):319–328
40
Соседние файлы в папке Библиотека им академика М.И. Перельмана