Summary
Hereditary hearing loss and deafness may be conductive, sensorineural, or a combination of both; syndromic (associated with malformations of the external ear or other organs or with medical problems involving other organ systems), or nonsyndromic (no other visible abnormalities of the external ear or any related medical problem); and prelingual (before language develops) or postlingual (after language development). Molecular genetic testing plays a prominent role in diagnosis and genetic counseling.
Panel testing recommended at Breda Genetics for hereditary hearing loss:
or
Detailed clinical description
Based on pathogenesis, there are four types of hearing loss:
- Conductive hearing loss results from abnormalities of the external ear and/or the ossicles of the middle ear.
- Sensorineural hearing loss results from malfunction of inner ear structures (i.e., cochlea).
- Mixed hearing loss is a combination of conductive and sensorineural hearing loss.
- Central hearing loss (central auditory dysfunction) results from damage or dysfunction at the level of the eighth cranial nerve, auditory brain stem, or cerebral cortex. Central hearing loss is very rare.
Onset of deafness / hearing loss can be prelingual (hearing loss is present before speech develops), or postlingual (hearing loss occurs after the development of normal speech).
Terminology: “hearing impairment” and “hearing loss” are often used interchangeably by healthcare professionals to refer generically to a decrease in hearing capabilities, whereas “deafness” is a term that usually implies hearing thresholds in the severe-to-profound range by audiometry.
Hearing is measured in decibels (dB). The severity of hearing loss is classified according to the following hearing threshold in decibels: mild (26-40 dB), mderate (41-55 dB), moderately severe (56-70 dB), severe (71-90 dB), profound (90 dB).
Molecular genetic testing plays a prominent role in diagnosis and genetic counseling. However, before genetic testing is performed, patients usually undergo several other diagnostic steps, including auditory brain stem response testing, auditory steady-state response testing, evoked otoacoustic emissions, immittance testing (tympanometry, acoustic reflex thresholds, acoustic reflex decay), audiometry (behavioral testing, pure-tone audiometry, air conduction audiometry, bone conduction audiometry, conditioned play audiometry, conventional audiometry, audioprofile).
Autosomal recessively inherited hearing loss is severe to profound and almost invariably prelingual (with the exception of DFNB8 and some instances of DFNB2 and DFNB4, which are post-lingual). Most autosomal dominant loci cause postlingual hearing impairment, with some exceptions such as DFNA3, DFNA8, DFNA12, and DFNA19. X-linked nonsyndromic hearing loss can be either pre- or postlingual or mixed (DFNX3, for instance, is a mixed form).
Most cases of autosomal recessive hearing loss are clinically stable, whereas some subtypes are progressive. By contrast, autosomal dominant forms are mainly progressive. Audioprofiling can be used to prognosticate the rate of hearing loss per year and can be useful in developing an evaluation strategy for molecular genetic testing, since the audioprofile in autosomal dominant nonsyndromic hearing loss can be distinctive.
Prevalence
Congenital hearing impairment is the most common birth defect in developed countries, affecting nearly 1 in every 1000 live births. Congenital hearing loss is therefore a condition that greatly impacts global health.
More than 50% of prelingual deafness is genetic. The carrier rate of the most common form of genetic hearing loss in the general population (DFNB1, caused by GJB2 mutations) is approximately 1 in 33.
Molecular genetics
More than 50% of prelingual deafness is genetic. More than 70% of genetic hearing loss is nonsyndromic (75-80% autosomal recessive, 20-25% autosomal dominant, 1-1.5% X-linked, up to 4% mitochondrial).
Autosomal recessive and autosomal dominant colocalizations as well as nonsyndromic and syndromic colocalizations on the same gene are possible (see for instance MYO7A gene mutations causing either DFNB2 or DFNA11 and SLC26A4 gene mutations causing either Pendred syndrome or DFNB4).
DFN is the abbreviation used to indicate nonsyndromic hearing impairment in genetic databases: DFNA indicates any form of nonsyndromic autosomal dominant hearing loss, DFNB indicates any form of nonsyndromic autosomal recessive hearing loss, and DFNX indicates any form of nonsyndromic X-linked inherited hearing loss. The number following DFNA, DFNB or DFNX reflects the order of gene mapping and/or discovery. No abbreviation is used for the mitochondrial forms.
Autosomal recessive nonsyndromic hearing loss
DFNB is caused in most cases by a mutation in the GJB2 gene, which codes for a protein called connexin 26. GJB2-related hearing loss has been designated as DFNB1 and represent 50% of all cases of nonsyndromic autosomal recessive hearing loss. DFNB1 can be either bilateral or unilateral. c.35delG is the most frequent GJB2 mutation. Of note, there’s some debate about the molecular etiology of nonsyndromic sensorineural hearing loss in subjects with only one detectable GJB2 mutation. A minority of such cases is explained by digenic etiology of GJB2 with GJB3 or GJB6. Digenic inheritance was hypothesizes also for GJB2 and MITF. However, is some patients the contribution of a single GJB2 mutation remains unclear.
Another relatively frequent recessive form is DFNB4 (also known as large vestibular aqueduct syndrome), which is caused by SLC26A4 gene mutations. The rest of the cases is caused by mutations in several other genes, which sometimes have been identified in just one family or two.
Some genes of which mutations cause nonsyndromic autosomal recessive hearing loss are CDH23, CLDN14, COL11A2, DFNB59 (also known as PJVK), ESPN, ESRRB, GJB2, GJB6, GPSM2, GRXCR1, HGF, MARVELD2, MYO15A, MYO3A, MYO6, MYO7A, OTOA, OTOF, PCDH15, RAI1, RDX, SLC26A4, STRC, TECTA, TMC1, TMIE, TMPRSS3, TRIOBP, USH1C, and WHRN.
Autosomal dominant nonsyndromic hearing loss
No gene predominates on the others in term of prevalence. Mutations can be identified in several different genes. Some genes relating to autosomal dominant hearing loss are ACTG1, CCDC50, COCH, COL11A2, DFNA5, DIAPH1, DMXL2, DSPP, EYA4, GJB2, GJB3, GJB6, GRHL2, KCNQ4, MIR96, MYH14, MYH9, MYO1A, MYO6, MYO7A, P2RX2, POU4F3, SIX1, SLC17A8, TECTA, TJP2, FAM189A2, TMC1, TMTC2, and WFS1. An interesting form of autosomal dominant, nonsyndromic (or let’s say non-dysmorphic) is Muckle-Wells syndrome, caused by heterozygous mutation in the NLRP3 gene. Muckle-Wells syndrome is characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis.
X-linked nonsyndromic hearing loss
X-linked hearing loss is relatively rare. Few genes have been so far identified: PRPS1, POU3F4, SMPX, and AIFM1. X-linked hearing loss may be prelingual or postlingual or mixed (like in DFNX3). A mutation has been identified in COL4A6 in one family.
Mitochondrial nonsyndromic hearing loss
Variants in a subset of genes of the mitochondrial DNA (mtDNA), mainly MT-RNR1 and MT-TS1, cause nonsyndromic hearing loss by a currently unknown mechanism. In particular, mutations of the MT-RNR1 gene, which encodes for the mitochondrial 12S ribosomal RNA, have been found with a carrier frequency of up to 4%. Additional mtDNA genes involved in nonsyndromic hearing loss are MT-CO1, MT-TH, MT-ND1, and MT-TI.
Matrilineal relatives within and among families carrying certain pathogenic mitochondrial mutations exhibit a wide range of penetrance, severity, and age of onset of hearing loss, indicating that the mitochondrial mutations by themselves are not sufficient to produce a deafness phenotype. Modifier factors, such as nuclear and mitochondrial genes, or environmental factors, such as exposure to aminoglycosides, appear to modulate the phenotypic manifestations.
Differential Diagnosis
In children with delayed speech development, the auditory system should be assessed. In the presence of normal audiometry associated with progressive loss of speech and temporal lobe seizures, the diagnosis of Landau-Kleffner syndrome (GRIN2A gene mutations) should be considered.
Delayed speech suggesting possible hearing loss can also be seen in young children with autism.
Acquired hearing loss in children commonly results from prenatal infections from “TORCH” organisms (i.e., toxoplasmosis, rubella, cytomegalic virus, and herpes), or postnatal infections, particularly bacterial meningitis caused by Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, or many other organisms. In developed countries congenital cytomegalovirus (CMV) infection is the most frequent non-genetic cause of hearing loss. Its overall birth prevalence is approximately 0.64%; 10% of this number have symptomatic CMV. Of asymptomatic cases, up to 4.4% develop unilateral or bilateral hearing lossbefore primary school, although there is marked ethnic variation.
Age-related and noise-induced hearing losses are the most frequent examples of complex ‘environmental-genetic’ hearing loss in adults.
Genetic testing strategy
Hereditary deafness is one of the most genetically heterogeneous conditions known to date. It has been estimated that at least 1% of human genes may be involved in the pathogenesis of some form of hereditary hearing loss. For several genetic subtypes of deafness the locus has been mapped on a defined chromosomal region, yet the gene remains unknown. In one study, about 15% of patients with non-syndromic hearing loss have been found to carry at least one copy number variation in a known deafness gene (mostly large deletions, but also gene conversions and large duplications).
Because of the aforementioned reasons, next generation sequencing by doing clinical exome sequencing, whole exome sequencing (20,000 genes) or even whole genome sequencing is the gold standard. Breda Genetics offers exome-based panels for hereditary hearing loss testing. If the panel is negative, one may proceed to add-on panels to test the genes included in the differential diagnosis or to the upgrade of the analysis of all data from exome or genome sequencing. The mutation detection rate of exome sequencing in hearing loss testing is reportedly above 70%.
Large deletions/duplications testing is available by sequencing, array-CGH (genome-wide), and by MLPA (for single genes or group of genes). Patients and professionals can send an inquiry to info@bredagenetics.com.
Panel testing recommended at Breda Genetics for hereditary hearing loss:
or
References:
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OMIM: 561000
