Autosomal Dominant and Recessive
• Allelic heterogeneity with both dominant and recessive inheritance patterns
• Newborn screening
• Cultural sensitivity in counseling
Major Phenotypic Features
• Congenital deafness in the recessive form
• Progressive childhood deafness in the dominant form
History and Physical Findings
R.K. and J.K. are a couple referred to the genetics clinic by their ears, nose, and throat specialist because their 6-week-old daughter, B.K., was diagnosed with congenital hearing loss. The child was initially identified by routine neonatal hearing testing (evoked otoacoustic emissions testing) and then underwent formal auditory brainstem response (ABR) testing, which demonstrated moderate hearing impairment.
Both of B.K.'s parents are of European ancestry. Neither parent has a personal or family history of hearing difficulties in childhood, although the father thought that his aunt might have had some hearing difficulties in her old age. B.K. was the product of a full-term, uncomplicated pregnancy.
On examination, B.K. was nondysmorphic. There was no evidence of craniofacial malformation affecting the pinnae or external auditory canals. Tympanic membranes were visible and normal. Ophthalmoscope examination was limited because of the patient's age, but no abnormalities were seen. There was no goiter. Skin was normal.
Laboratory testing revealed a hearing loss of 60 dB bilaterally in the middle- and high-frequency ranges (500 to 2000 Hz and >2000 Hz). Electrocardiography results were normal. Computed tomography scans of petrous bone and cochlea were normal, without malformation or dilatation of the canals.
DNA from B.K. was examined for mutations in the GJB2 gene. She was found to be homozygous for the common frameshift mutation 35delG in the GJB2 gene.
Disease Etiology and Incidence
Approximately 1 in 500 to 1000 neonates has clinically significant congenital hearing impairment, which arises either from defects of the conductive apparatus in the middle ear or from neurological defects. It is estimated that approximately one third to one half of congenital deafness has a genetic etiology. Of the hereditary forms, approximately three quarters are nonsyndromic, characterized by deafness alone; one quarter is syndromic, that is, associated with other manifestations.
Among inherited forms of nonsyndromic deafness, mutations of GJB2 are among the more common causes, although mutations in several dozen other genes can also lead to nonsyndromic deafness. GJB2mutations cause DFNB1 (MIM 220290), which accounts for half of congenital nonsyndromic autosomal recessive deafness, as well as DFNA3 (MIM 601544), a rare form of childhood-onset, progressive, autosomal dominant deafness. The mutation 35delG accounts for approximately two thirds of identified autosomal recessive GJB2 mutations in white populations but not in other ethnic groups. Among the Chinese, for example, a different mutation—235delC—is the predominant mutation in GJB2 causing DFNB1.
The GJB2 gene encodes connexin 26, one of a family of proteins that form gap junctions. Gap junctions create pores between cells, allowing exchange of ions and passage of electrical currents between cells. Connexin 26 is highly expressed in the cochlea, the inner ear organ that transduces sound waves to electrical impulses. The failure to form functional gap junctions results in loss of cochlear function but does not affect the vestibular system or auditory nerve.
Phenotype and Natural History
Autosomal recessive deafness due to GJB2 mutations is congenital and may be mild to profound (Fig. C-13). Cognitive deficits are not a component of the disorder if the hearing impairment is detected early and the child is referred for proper management to allow the development of spoken or sign language.
FIGURE C-13 Profound hearing loss in a child homozygous for mutations in the GJB2 gene. X and O represent left and right ear, respectively. Normal hearing level is 0 to 20 dB throughout the frequency range. See Sources & Acknowledgments.
Autosomal dominant deafness due to GJB2 mutations also occurs. It has an early childhood onset and is associated with progressive, moderate to severe, high-frequency sensorineural hearing loss. Like the autosomal recessive disease, it also is not associated with cognitive deficits.
The diagnosis of congenital deafness is usually made through newborn screening. Newborn screening is carried out either by measuring otoacoustic emissions, which are sounds caused by internal vibrations from within a normal cochlea, or by automated ABR, which detects electrical signals in the brain generated in response to sound. With the introduction of universal newborn screening, the average age at diagnosis has fallen to 3 to 6 months, allowing early intervention with hearing aids and other forms of therapy. Infants in whom therapy is initiated before 6 months of age show improvement in language development compared with infants identified at an older age.
As soon as deafness is identified, the child needs to be referred for early intervention, regardless of the cause of the deafness. By consulting with professionals such as audiologists, cochlear implant teams, otolaryngologists, and speech pathologists about the benefits and the drawbacks of different options, parents can be helped to choose those that seem best for their families. Age-appropriate, intensive language therapy with sign language and spoken language with hearing assistance with hearing aids can be instituted as early as possible. Parents can be offered the option of an early cochlear implant, a device that bypasses the dysfunctioning cochlea. Use of cochlear implants before 3 years of age is associated with better oral speech and language outcomes than those in patients receiving an implant later in childhood.
During the newborn period, clinically distinguishing between some forms of syndromic deafness and nonsyndromic deafness is difficult because some syndromic features, such as the goiter in Pendred syndrome or the retinitis pigmentosa in any of the Usher syndromes, may have an onset late in childhood or adolescence. However, a definitive diagnosis is often important for prognosis, management, and counseling; therefore a careful family history and DNA analysis for mutations in the GJB2 gene as well as in other genes are key to such a diagnosis. Importantly, distinguishing among nonsyndromic forms of deafness is often critical for selecting proper therapy.
The form of severe congenital deafness caused by loss-of-function mutations in GJB2 (DFNB1) is inherited in a typical autosomal recessive manner. Unaffected parents are both carriers of one normal and one altered gene. Two carrier parents have one chance in four with each pregnancy of having a child with congenital deafness. Prenatal diagnosis by direct detection of the mutation in DNA is available.
Among families segregating nonsyndromic progressive deafness with childhood onset due to GJB2 mutations (DFNA3), inheritance is autosomal dominant, and the risk for an affected parent to have a deaf child is one in two for each pregnancy.
Questions for Small Group Discussion
1. Why might certain missense mutations in GJB2 cause dominant, progressive hearing loss, whereas another mutation (frameshift) results in recessive, nonprogressive hearing loss?
2. What special considerations and concerns might arise in providing genetic counseling to a deaf couple about the risk for their having a child with hearing loss? What is meant by the term deaf culture?
3. Mutation testing detects only 95% of the GJB2 mutations among white families known to have autosomal recessive deafness secondary to GJB2 defects. Also, many sequence variations have been detected in the GJB2 gene. If a couple with a congenitally deaf child presented to you and mutation analysis detected a GJB2 sequence variation, not previously associated with disease, in only one parent, how would you counsel them regarding recurrence risk and genetic etiology? Would your counseling be different if the sequence variation had been previously associated with disease, and what would constitute significant association? Would your counseling be different if the child had early childhood onset of progressive deafness?
4. Why might a child with a cochlear implant learn sign language in addition to spoken language?
5. Because mutations in many different genes can underlie recessive forms of nonsyndromic deafness, discuss various approaches to molecular diagnosis of the gene responsible in any given case: GJB2 testing, testing a panel of known genes, whole-exome sequencing, or whole-genome sequencing.
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