MENTAL RETARDATION AND DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 9: 109–119 (2003)

THE GENETICS OF DEAFNESS

Walter E. Nance* Department of Human Genetics,Virginia Commonwealth University, Richmond, Virginia

Deafness is an etiologically heterogeneous trait with many known argued about whether two, three, or perhaps four genes could genetic and environmental causes. Genetic factors account for at least half explain the inheritance of deafness, and whether these genes of all cases of profound congenital deafness, and can be classified by the mode of inheritance and the presence or absence of characteristic clinical were dominant or recessive. More than 120 independent genes features that may permit the diagnosis of a specific form of syndromic have been identified which can be the cause of hearing loss, and deafness. The identification of more than 120 independent genes for deaf- it now seems likely that this number may rise to include 1% of ness has provided profound new insights into the pathophysiology of hear- all human genes, or about 300. The goal of this review is to ing, as well as many unexpected surprises. Although a large number of genes can clearly cause deafness, recessive mutations at a single locus, GJB2 highlight some of the results and significance of this rapidly or Connexin 26, account for more than half of all genetic cases in some, but expanding body of knowledge, and to suggest some of the not all populations. The high frequency may well be related to the greatly directions that future research may take. improved social, educational, and economic circumstances of the deaf that began with the introduction of sign language 300–400 years ago, along with a high frequency of marriages among the deaf in many countries. GENETIC EPIDEMIOLOGY OF DEAFNESS Similar mechanisms may account for the rapid fixation of genes for speech Deafness has many recognized genetic and environmental after the first mutations appeared 50,000–100,000 years ago. Molecular causes. In this country, profound hearing loss occurs in about studies have shown that mutations involving several different loci may be the cause for the same form of syndromic deafness. Even within a single 0.8–1.0 per 1,000 births, but the incidence is known to vary locus, different mutations can have profoundly different effects, leading to with time and place. Many previous studies have suggested that a different pattern of inheritance in some cases, or isolated hearing loss about 50% of profound deafness is genetic in etiology. However, without the characteristic syndromic features in others. Most cases of ge- during the last rubella pandemic in 1964, the estimated propor- netic deafness result from mutations at a single locus, but an increasing number of examples are being recognized in which recessive mutations at tion of genetic cases fell to about 10%. Estimates of this type are two loci are involved. For example, digenic interactions are now known to obtained by the collection and analysis of the distribution of be an important cause of deafness in individuals who carry a single muta- affected relatives in the families of deaf probands, or index cases. tion at the Connexin 26 locus along with a deletion involving the function- The method of analysis involves the reasonable assumption that ally related Connexin 30 locus. This mechanism complicates genetic evalu- all nuclear families with more than one affected individual ation and counseling, but provides a satisfying explanation for Connexin 26 heterozygotes who, for previously unknown reasons, are deaf. A specific (“multiplex cases”) are genetic in origin. The task is then to genetic diagnosis can sometimes be of great clinical importance, as in the estimate what proportion of the “simplex cases” with only one case of the mitochondrial A1555G mutation which causes gene carriers to affected individual, are also genetically determined. We know be exquisitely sensitive to the ototoxic effects of aminoglycosides. This that simplex cases could represent true sporadic cases of envi- potentially preventable genetic-environmental interaction was the most common cause of genetic deafness in countries where these antibiotics ronmentally caused deafness in which the chance of another were used indiscriminately in the past. Advances in genetic knowledge affected child is very low. Alternatively, they could represent along with the use of cochlear implants have posed unique ethical dilem- “chance isolated genetic cases” in which, by chance, there is mas for society as well as the deaf community. Since most deaf children are only one affected child. The process of analysis is analogous to born to hearing parents, it seems likely that deaf culture, and intermarriages estimating the size of an iceberg from the part that is above water among those born with deafness will recede during this century. Will future critics view this as one of the medical triumphs of the 21st Century, or as an and knowledge of the density of ice and water. If only families egregious example of cultural genocide? On the other hand, genetics can with two or more affected children are considered to be genetic, provide empowering knowledge to the deaf community that for the first the true proportion will be underestimated. On the other hand, time can allow many deaf couples to know whether their children will be assuming that all simplex cases of deafness are caused by sporadic, hearing or deaf even before they are conceived. © 2003 Wiley-Liss, Inc. MRDD Research Reviews 2003;9:109–119. nongenetic factors would lead to the absurd conclusion that all deaf children in one-child families have nongenetic hearing loss. Data emerging from newborn hearing screening programs sug- Key Words: Alexander Graham Bell; syndromic deafness; nonsyndromic gest that for every child with profound hearing loss, one to two deafness; linguisitc homogamy; evolution of speech; ethical issues

Grant sponsor: National Institutes of Health; Grant numbers R01–DC02530 and R01–DC04293. *Correspondence to: Walter E. Nance, M.D., Ph.D., Department of Human Genetics, INTRODUCTION Virginia Commonwealth University, Richmond, VA 23298. E-mail: Astonishing success has been achieved during the past [email protected] decade in identifying genes for deafness so that any current Received 26 December 2002; Accepted 21 January 2003 Published online in Wiley InterScience (www.interscience.wiley.com). account of this research must be regarded as a “work in DOI: 10.1002/mrdd.10067 progress.” For the first half of the 20th Century, geneticists

© 2003 Wiley-Liss, Inc. are born with lesser, but clinically signif- or mixed hearing loss with persistent clinically from WS1 primarily by the ab- icant, degrees of hearing loss. Much less is branchial cleft fistulas, prehelical pits, sence or less frequent occurrence of the known about the contribution of genetic malformations of the pinna, deformities eyelid anomaly dystopia canthorum, and factors to this latter group of patients and of the inner ear which may include the a higher frequency of deafness and het- systematic studies of these cases are badly Mondini malformation and stapes fixa- erochromia [Hughes et al., 1994; Liu et needed. Although the genes that ulti- tion along with renal anomalies including al., 1995]. Some WS2A patients exhibit mately cause a child to be deaf are present dysplasia or adysplasia, polycystic kid- generalized hypopigmentation (albinoid- from the time of conception, not all neys, and malformations of the calyces ism) with or without freckling. This phe- forms of genetic deafness are necessarily [Melnick et al., 1976]. About 80% of notypic variant has been termed Tietz expressed at birth. Many families have gene carriers have some degree of hear- Syndrome. Additional dominantly inher- been observed in which the hearing loss ing loss, which can have a delayed onset. ited WS2 variants have been localized to appears to have been delayed in onset; The trait was mapped to band 13.3 on chromosomes 1p21–p13.3 (WS2B) and there are others in which there is a vari- the long (q) arm of chromosome 8 (i.e., 8p23 (WS2C). Mutations involving the able rate of progression. Genetic hearing 8q13.3), and later shown to result from vasoactive peptide endothelin–3 (END3) loss can be classified in many ways, in- mutations involving the EYE1 gene [Ab- on 20q13.2 or its receptor, ENDRB on cluding the mode of inheritance, the age delhak et al., 1997]. This gene is homol- 13q22, can also cause the features of WS, of onset, audiologic characteristics, pres- ogous to the Eya gene in Drosophila, commonly in association with Hirsch- ence or absence of vestibular dysfunc- which is required for the normal forma- sprung disease [McCallion and Chakra- tion, and the location and/or identity of tion of its compound eye by activating varti, 2001]. Homozygotes exhibit the the causal gene(s). The analysis of large downstream targets. These findings full syndrome, while heterozygotes may collections of family data have suggested prompted a closer examination of the only develop Hirschsprung disease. Sin- that at among genetic cases, approxi- eyes of human subjects with EYA1 mis- gle mutations involving the DNA bind- mately 77–88% are transmitted as auto- sense mutations and have revealed cata- ing SOX10 locus on 22q13 can also lead somal recessive traits, 10–20 % as domi- racts and anterior segment anomalies in to combined features. These phenotypic nants, and 1–2% as X-linked traits [Rose some cases. It is remarkable that knowl- variants have been designated WS4 or et al., 1977]. The frequency of mito- edge of the phenotype produced by Eya the Shah-Waardenburg syndrome. Fi- chondrial deafness is quite variable and in the fruit fly was of relevance to the nally, homozygous carriers of deletions can range from less than 1% to more than clinical findings in humans. The BOR involving the SLUG transcription factor 20% in some populations. Some forms of syndrome is transmitted as a dominant on 8q11 have a form of WS2 that shows genetic deafness have distinctive audio- trait such that an affected individual has a recessive transmission [Sanchez-Martin logic findings including conductive, low, 50% chance of transmitting the trait to et al., 2002] The gene product of MITF mid-tone, or high-frequency hearing each child. is also a DNA binding regulatory protein. losses, or evidence for vestibular dysfunc- Its downstream targets include SLUG tion. Finally, in 20–30% of cases, there Waardenburg Syndromes and the tyrosinase gene (TYR), which may be other associated clinical findings These disorders account for at least codes for the enzyme required for normal that permit the diagnosis of a specific 1–2% of individuals with profound hear- pigment formation that is deficient in form of syndromic deafness. ing loss. Bilateral or unilateral hearing one form of generalized albinism [Tachi- loss of variable severity occurs in associ- bana et al., 1994]. Families have been CLASSIFICATION OF GENETIC ation with defects in tissues and structures reported in which the digenic interaction DEAFNESS derived from neural crest cells. The most between a mutation at the MITF locus conspicuous findings are pigmentary ab- with a mild abnormality at the TYR Syndromic Deafness normalities which can include brilliant locus resulted in the features of WS2 Nearly 400 forms of deafness have blue eyes, complete or segmental hetero- along with ocular albinism [Morell et al., been identified in which the presence of chromia, lateral displacement of the inner 1997]. These important observations associated clinical findings permits the di- canthi of the eyes, a pinched nose, syno- show how pigment abnormalities are in- agnosis of a specific form of syndromic phorys, and variable patches of cutaneous corporated as a component of WS and deafness. In many of these syndromes, hyper- or hypopigmentation [Waarden- illustrate how phenotypic variation in a the hearing loss is a mild or inconstant burg, 1951]. Gastrointestinal symptoms syndrome can result from the effects of feature. Some other syndromes are quite such as chronic constipation, are com- modifier genes at other loci. It is tempt- rare. However there are several well- mon and some patients report symptoms ing to speculate that interactions of this characterized entities in which hearing of gastrointestinal dyskinesia or a history type could in part explain why only loss is a frequent or constant, and often of Hirschsprung disease. The incidence about 20–30% of those who carry a the most clinically significant, feature. A of neural tube defects is increased and PAX3 mutation develop profound bilat- few instructive examples of the later limb defects may be seen. The disorder is eral hearing loss [Pandya et al., 1996]. group are described below. More com- genetically heterogeneous, and mutations WS3 refers to the presence of limb de- prehensive reviews and up to date infor- involving at least eight loci can contrib- fects in association with other features of mation is available on several Internet ute to the phenotype. Waardenburg Syn- WS. It can result from homozygosity for sites and elsewhere [Gorlin et al., 1995; drome, Type 1 (WS1) can result from two PAX3 mutations; from particular Hereditary Hearing Loss Homepage, any one of more than 50 different muta- PAX3 mutations in single dose; or from 2000; Keats et al., 2002; Online Mende- tions involving the PAX3 gene on 2q35. small chromosomal deletions involving lian Inheritance in Man, 2002]. The PAX3 gene produces a DNA bind- the PAX3 locus. In the cochlea, neural ing protein that regulates the MITF locus crest cells are known to contribute to the The Branchio-Oto-Renal (BOR) Syndrome on 3q12, among other down stream tar- intermediate layer of the stria vascularis, The branchio-oto-renal syndrome gets. Mutations in MITF, in turn, give and it thus seems likely that the cause of refers to the association of sensori-neural rise to WS2A, which is distinguished deafness in WS may be related to a defect

110 MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE in the ability of the stria to maintain the of life, that is characteristic of Usher Syn- tered but the message can be drastically critical endocochlear potential that is re- drome Type 1 (USH1); 57% with USH2 edited to skip specific exons in particular quired for the hair cells to function nor- have a less severe hearing loss, with a later tissues resulting in the synthesis of pro- mally. The successful cloning of PAX3 onset of RP and can usually communi- teins that can differ in length. It is as if illustrates three powerful and comple- cate orally; in the remaining 3% with each article in a scientific journal had a mentary techniques that have been used USH3, the severity of the hearing loss is different editor who used different rules to map human genes. First, the gene was variable and can be progressive [Rosen- to determine whether an abstract, ac- localized to the long arm of chromosome berg et al., 1997]. To date, six genes for knowledgements, footnotes, references, 2 by testing Waardenburg families for USH1 have been mapped (USH1A-G), figures, or tables should be included in highly variable genetic marker genes lo- and of these, four have been identified, as the published version. This feature of cated throughout the genome. The goal has one of three USH2 loci and one gene expression greatly expands the dif- was to identify markers located close to USH3 locus. Mutations involving the ferent ways a single gene can be ex- the WS locus. A particular allele at this MYO7A gene have been shown to be pressed in different tissues or at different marker locus was always transmitted in the cause of USH1B. However, two times during development. Returning to the families along with the WS1 trait. forms of nonsyndromic deafness (NSD), the phenotypic differences in harmonin Markers in the 2q35 region met this cri- the dominantly inherited DFNA11 and mutations, in at least one subject with teria, and by invoking what might be the recessive DFNB2 also map to the isolated hearing loss (ie., DFNB18), the characterized as “guilt by association” the same region, 11q13.5, and have been mutation occurs in an exon of the gene approximate chromosomal location of shown to result from other alleles at the that is normally spliced out and not ex- the WS1 gene could be inferred The MYO7A locus. Another recessive form pressed in the retina [Ouyang et al., next important clue was the description of NSD, DFNB18, maps to 11p15.1, the 2002]. Any patient who is homozygous of a rare case of WS1 in a Japanese boy same location as USH1C, which codes or even a compound heterozygote for a who was found to have a small inverted mutation of this type would be expected segment on the long arm of chromosome to show deafness without RP, providing two. This knowledge effectively local- a satisfying explanation for at least some ized the gene to one of the two break “The information that is of the striking phenotypic differences points of the inversion. Finally, the rec- that can be seen between different mu- ognition that a coat color mutation in the emerging about the tations involving the same gene. mouse, known as “Splotch” mapped to intricate hierarchy of the homologous region of the mouse ge- Jervell, Lang-Neilsen Syndromes (JLNS) nome served to focus attention on the genes that determine the This syndrome refers to the associ- human homolog of Splotch as a candi- Waardenburg Syndromes ation of sensori-neural deafness and pro- date gene for WS1. The discovery that longation of the QT interval on the elec- pathologic mutations in PAX3 cosegre- is providing a dazzling trocardiogram, reflecting a defect in gated with the WS in many, but not all glimpse of the interacting cardiac repolarization. This in turn can families, confirmed the fact that PAX3 lead to recurrent attacks of syncope, ven- mutations can cause WS, and provided network of genes that tricular arrythmia, and sudden death. In the first clear indication that mutations at control the development some cases, syncopal attacks have been other loci might also cause similar syn- precipitated by fright. The syndrome is a dromes. The information that is emerg- and function of the ear.” rare recessive trait accounting for perhaps ing about the intricate hierarchy of genes one per thousand children with profound that determine the Waardenburg syn- deafness. However, when informed dromes is providing a dazzling glimpse of about this entity, many superintendants the interacting network of genes that for the protein harmonin. In this case, of schools for the deaf can recall having control the development and function of molecular studies have provided an inter- seen, during their careers, students who the ear. esting explanation for the differences be- died suddenly of unexplained causes. Pa- tween the mutations which cause tients with JLNS should be under the Usher Syndromes USH1C and those which only cause care of a knowledgeable cardiologist, This eponym refers to the syn- deafness (ie.,DFNB18). Although genes since treatment with beta-adrenergic dromic association of deafness with reti- are composed of linear sequences of nu- blockers or other drugs is effective in nitis pigmentosa (RP), a progressive de- cleotides at a particular site on a given most cases. In a second, much more fre- generation of the retina that leads to loss chromosome, typically, the sequences are quent condition, the Ward-Romano of night vision, restriction of the visual not continuous. Instead, the coding se- syndrome, prolongation of the QT inter- fields, and ultimately, blindness. The in- quence, which specifies the amino acid val, recurrent syncope, and sudden death cidence in this country has been esti- sequence of the protein product, is nor- can be seen in the absence of hearing loss. mated to be 4.4 per 100,000 [Boughman mally interrupted by noncoding se- It has been shown that in at least some et al., 1983], but the syndrome accounts quences known as introns. After the ge- cases, Ward-Romano patients are het- for 2–4% of all cases of profound deaf- netic message has been transcribed, these erozygous for genes that cause JLNS ness, and 50% of the deaf-blind popula- introns must be spliced out to form the when present in the homozygous state. tion. Usher syndrome is both phenotyp- mature messenger RNA. Expression of Thus, the parents and other hearing rel- ically and genetically heterogeneous. the enzymes required for this process can atives in the extended family of a JLNS Approximately 40% of affected patients vary from tissue to tissue such that some patient may be at risk for syncope and show a profound congenital hearing loss, exons (as well as introns) may also be sudden death. Mapping studies have with vestibular dysfunction and an early spliced out in some tissues but not in shown that the gene (KVLQT1), which onset of RP, often within the first decade others. The coding sequence is not al- causes JLNS1 and the Ward-Romano

MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE 111 syndrome, is a member of a large family progress to coma and death. If untreated, ers have been useful for mapping genes, of potassium channel genes, a discovery 75% of affected infants develop hearing and some are so variable that it is unusual that has provided a profound insight into loss, which may be profound, and persists for an individual to be homozygous for the physiology of hearing [Neyroud et despite the subsequent initiation of treat- exactly the same allele or variant. This al., 1997]. The transduction of sound ment [Wolf et al., 2002]. Since the symp- feature has been used to map genes for waves into a neural signal is initiated by toms of the disease, including the hearing rare recessive traits by “homozygosity the physical deflection of the hair cells of loss, can be completely prevented by pr- mapping.” We know that deaf individu- the cochlea, which mechanically opens esymptomatic diagnosis and the adminis- als who are the offspring of consanguin- ion channels in the hair cells and allows tration of supplemental biotin, this dis- eous matings carry two alleles for deaf- the passive inward flow of potassium ions ease has been included in many newborn ness that must be identical because they from the high potassium environment of screening programs throughout the are both copies of the same gene carried the surrounding endolymphatic fluid. world. The resulting data have shown by one of the common ancestors. To The high potassium concentration is in that the incidence of affected homozy- localize a gene, therefore, all we need to turn maintained by active transport gotes with severe enzyme deficiency is do is type a sample of consanguineous through potassium channels, such as about is about 1 in 60,000. Boitinidase probands for a large number of polymor- those involved in the JLNS syndromes, phic markers, and look for the chromo- deficiency is an example of a completely that are located in the stria vascularis at somal region where all of the affected preventable form of genetic deafness. the outer periphery of the coiled cochlear individuals are homozygous or “identical Some treatments for hearing loss, such as duct. Like a battery, this system stores by descent.” In the case of biotinidase potential energy in the high potassium hearing aides or cochlear implants, are deficiency, the analysis of data from 18 concentration of the endolymph for use generally effective for a wide range of consanguinious probands allowed the lo- by the hair cells during sound transduc- affected individuals regardless of the eti- calization of the gene to a very small tion [Davis, 1965]. One possible reason ology of their hearing loss. However, as region on 3p25 that was only about for this evolutionary adaptation may be illustrated by biotinidase deficiency, 0.036 % of the length of the entire ge- to avoid the need for active potassium nome [Blanton et al., 2000]. Many rare transport in the cilia. Decreasing the en- forms of recessive NSD have only been ergy requirements of the hair cells may observed in a single family and homozy- dramatically increase their sensitivity to “Imagine the cacophony gosity mapping has been of particular external sounds by allowing them to that would be produced if value for mapping these loci. function in a microenvironment that is devoid of turbulent blood flow. Imagine a capillary bed were Pendred Syndrome the cacophony that would be produced if required in the basal This autosomal recessive disorder is a capillary bed were required in the basal characterized by neuorsensory deafness, membrane that supports the hair cells, in membrane....to provide goiter, and malformation of the inner ear. order to provide the energy required for the energy required for It is probably the commonest form of active potassium transport in the cillia! In syndromic deafness and accounts for ap- addition to the JLNS1 locus on chromo- active potassium proximately 7.5% of all individuals with some 11p15.5, recessive mutations in- transport in the cilia! profound hearing loss [Fraser, 1965]. The volving another potassium channel gene, goiter results from a specific defect in the KCNE1, at the JLN2 locus on chromo- organification of iodine which may be some 21q22.1, can produce an identical demonstrated by the abnormal release of phenotype. The expression of another treatments that depend upon knowledge radioactive iodine trapped by the thyroid potassium channel gene, KCNQ4, is of the nature of the gene defect are likely after the administration of perchlorate. limited to the outer hair cells. Although to be very specific in their theraputic Unfortunately, this highly specific test is it does not contribute to homeostasis of relevance, even though they may be not widely available. The goiter may be the endolymph, mutations in the gene highly effective. Thus there is no indica- delayed in onset and clinically unappar- can cause a relatively common dominant ent, and is usually not associated with tion that supplemental biotin would im- form of progressive hearing loss hypothyroidism. A variety of malforma- prove the hearing of anyone other than (DFNA2) that typically begins in the first tions of the inner ear can be demon- the 1–1.5 % of hearing impaired infants two decades of life, initially involves the strated radiographically in 86% of cases, high frequencies, and progresses to be- estimated to have biotinidase deficiency. including Mondini malformation and come a profound loss within about a This disease also illustrates another im- malformations of the vestibular canals, decade. portant strategy that has been particularly but the most characteristic finding is di- useful for mapping human genes for lation of the vestibular acqueduct [Rear- Biotinidase Deficiency deafness. The term polymorphism refers don et al., 2000]. The hearing loss is This autosomal recessive trait re- to regions of the genome in which com- usually profound, but can be variable in sults from the deficiency of an enzyme mon sequence variations are found. Al- its onset, rapidly progressive, and even required for the normal recycling of the though some polymorphisms, such as the unilateral. The successful cloning of the vitamin biotin. Infants with severe defi- sickle cell gene, are maintained at high gene for Pendred Syndrome, SLC26A4, ciency are therefore entirely dependent frequency in the population by the selec- showed that it was a member of a family on dietary sources of the vitamin for their tive advantage they confer to heterozy- of genes involved in sulfate transport, but nutritional requirements and typically gous carriers, most polymorphisms have functional studies of pendrin, the protein develop skin rashes, seizures, hair loss, no detectable clinical effects and many product of the gene, suggest that it is hypotonia, vomiting, and acidosis within are not even located within the coding primarily involved in the transport of io- the first few months of life. This may sequences of genes. These genetic mark- dine and chloride ions. As in the case of

112 MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE Usher Syndrome, a form of nonsyn- or the other of three tissue specific size. Connexin 26 (also termed CX26 dromic deafness, DFNB4 can also result polypeptide subunits of collagen that are and GJB2), for example, has a molecular from mutations in the Pendred gene. encoded by the COL4A3, COL4A4, and weight of 26,000 Daltons. The different Cochlear abnormalities are also present in COL4A5 genes. The latter is determined Connexins vary in the tissues and devel- DFNB4, and it is not clear how many of by an X-linked gene at Xq22 while the opmental stages at which they are ex- these cases may have unapparent thyroid genes coding for the first two collagens pressed. Furthermore, some are capable disease, since testing with the perchlorate are located adjacent to each other on of forming heteromeric as well as homo- discharge test has not been reported in 2q35. Typically males with the X-linked meric connexins. Thus the clinical effects these patients. form of Alport syndrome are more se- of a mutation may well depend on the verely affected than females, who may degree of redundant expression of other Congenital Fixation of the Stapes Footplate never develop end stage renal disease. Connexins as well as its pattern of ex- With Perilymphatic Gusher The three collagen subunits are expressed pression within an organ or tissue. Seven Many examples of this association in the basilar membrane, spiral ligament, of these genes are either known to be the have been described, suggesting that it and basement membranes of the stria vas- cause of human deafness, or are expressed may be the commonest form of X-linked cularis. However, interpretation of the in the ear. More than 80 different deafness. Affected males can have either a molecular basis of the hearing loss is mutations of the CX26 gene have mixed or neurosensory deafness. In cases complicated by the fact that renal failure, been reported [The Connexin-Deafness with a conductive component, a congen- dialysis, and ototoxic drugs that may be Homepage, 2002]. Many are “private” ital fixation of the stapes footplate is used for treatment can all contribute to mutations, having been observed in only found at the time of surgery but attempts hearing loss. The overall incidence of one or a few pedigrees, but examples of to mobilize the footplate typically lead to Alport Syndrome is about 1 in 10,000, very common alleles have also been iden- a profuse flow of endolymphatic fluid, with the X-linked form being more tified in several populations including the which effectively prevents remediation common than both of the autosomal 35delG mutation in Caucasians, the [Nance et al., 1971]. Computerized to- variants. About 8,000 individuals with 167delT allele in Ashkenazi Jews, the mography shows dilation of the internal glomerulonephritis progress to end stage 235delC allele in Asian populations, and auditory meatus with an abnormal com- renal disease each year and make a sub- the R143W mutation in Ghana. Most munication between the subarachnoid stantial contribution to the 13,500 renal pathologic mutations are recessive, but at space and the cochlear endolymph which transplants that are performed annually. least six exhibit dominance. Similarly, accounts for the “gusher” at the time of Connexin deafness is usually not associ- stapes surgery. Carrier females may show Nonsyndromic Deafness ated with other features, but characteris- a mild hearing loss and less severe abnor- About 70–80% of genetic deafness tic dermatologic findings have been re- malities of the inner ear. After the locus is nonsyndromic. At least 33 recessive, 41 ported in association with specific was mapped to Xq21.1, affected males dominant, and five sex-linked loci have mutations, including palmoplantar hy- were found to carry mutations involving been mapped Among these, 31 of the perkeratosis in association with the dom- a DNA binding regulatory gene, causal genes have been identified. The inant G59A allele [Heathcoat et al., POU3F4 [de Kok et al., 1995]. In many dominant loci are identified by the sym- 2000], mutilating keratoderma (Vor- families, the mutation has been shown to bol and numbers DFNA1–41; the reces- winkle Syndrome) in association with the be a deletion, which can vary greatly in sive loci are designated DFNB1–33, and D66H allele [Maestrini et al., 1999], and size, and can sometimes involve nearby DFN1–5 refers to the X-linked loci. A three dominant alleles associated with the genes for mental retardation and choroi- current listing of the mapped genes and keratoderma-ichytheosis-deafness (KID) deremia. In such cases, symptoms of two identified loci, along with references, can syndrome [Richard et al., 2002]. In ad- or all three diseases may be present in be found at the Hereditary Hearing Loss dition, hearing loss occurs with dermato- affected family members, a phenomenon Homepage (http://dnalab-www.uia.ac. logic abnormalities in some mutations in- known as a contiguous gene syndrome. be/dnalab/hhh/ ). Several important ex- volving CX30 and CX31, and with amples of nonsyndromic deafness that neurologic abnormalities in X-linked Alport Syndromes have been identified to date are described Charcot-Marie–Tooth disease caused by Alport Syndrome refers to the as- in greater detail below. the CX32 gene. In most large studies, sociation of neurosensory hearing loss deaf probands are encountered who are with progressive nephritis. The latter be- Connexin Deafness apparent CX26 heterozygotes. Since the gins with hematuria and can lead to pro- In view of the large number of loci reported frequency of heterozygotes in gressive renal failure and death. About already identified, the knowledge that the general population has exceded 3% in 50% of affected individuals develop a most cases of genetic deafness are caused some studies, the heterozygosity could be progressive bilateral hearing loss, which by mutations involving a single gene in unrelated to the hearing loss. Alterna- usually begins in the second decade of many populations came as an astonishing tively, dominance or an unidentified sec- life, involves the high frequencies ini- surprise. The Connexins are a family of ond pathologic CX26 allele could be the tially, and may become incapacitating. genes that code for the subunits of gap explanation. Recently, it has been re- Ocular findings can include congenital junction proteins. Gap junctions form ported that a 342 kb deletion spanning cataracts, spherophakia, retinal flecks, and when the hexameric hemi-connexins on the CX30 locus can interact with a single anterior lenticonus. The latter two find- the surface of two adjacent cells “dock” recessive CX26 mutation to cause deaf- ings are seen in about 85% and 25% of to form a complete gap junction. The ness [del Castillo et al., 2002]. The CX26 affected individuals and are highly char- resulting channels permit the flow of ions and CX30 genes are located within about acteristic of the syndrome. Renal biopsy and small molecules between the cells. At 40 kb of each other on 13q11. Although shows irregular thickening of the glo- least 14 mammalian Connexins have the CX26 locus is not involved in the merular basement membranes. The dis- been identified, and are designated by deletion, it is still not clear whether the ease results from mutations involving one numbers that refer to their molecular deafness arises because the CX26 and

MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE 113 CX30 proteins interact, or whether the riage among the deaf, such as India and Mitochondrial A1555G mutation deletion itself perturbs the expression of Mongolia, CX26 mutations are present, The A1555G mutation in the mi- the adjacent normal CX26 gene. In but Connexin deafness occurs at a very low tochondrial 12S ribosomal RNA gene Spain, this deletion accounted for two frequency. The Bengkala village in Bali was first shown to be a cause of deafness thirds of 33 deaf probands who were provides a striking contrast. The frequency in a large Arab-Israeli pedigree with ma- apparent CX26 heterozygotes. In this of recessive DFNB3 deafness in the 2185 trilineal transmission of a severe to pro- country, 17 of 625 (2.7%) deaf probands villagers is 2%; 17% of the hearing subjects found hearing loss that typically began in were found to carry the CX30 deletion, are gene carriers, and all deaf by deaf mat- infancy or early childhood [Jabber et al., including one affected homozygote, and ings are noncomplementary as might be 1992]. Molecular testing revealed a ho- the deafness in 17.7% of deaf CX26 het- expected [Friedman et al., 1995]. The dra- moplastic substitution in the 12S ribo- erozygotes could be explained by this matic increase in the frequency of this gene somal RNA gene. Similar pedigrees with mechanism [Nance et al., 2002]. was accompanied by the development of the same mutation have been reported Why mutations involving the an indigenous sign language, now learned from Spain, where the mutation appears Connexins are such a common cause of to be a remarkably common cause of deafness is not clear. There is little to both by the deaf and hearing villagers. In deafness [Estivill et al., 1998], and from suggest they have a high mutation rate, many primitive populations, the genetic Italy, but the onset of hearing loss occurs or that there is a selective advantage for fitness of the deaf is close to zero. Although later in these families. In other countries connexin carriers, as in the case of “gene drift” undoubtedly played a role in sickle cell disease. Population bottle- the initial survival of the original DFNB3 such as the United States, China, South necks and founder effects can explain mutation, it is difficult to escape the con- Africa, and Mongolia, A1555G deafness why some genes have a high preva- clusion that the combination of improved has been virtually confined individuals lence, and could have contributed to fitness and assortative mating that followed who have been exposed to aminoglyco- the high frequency of the 167delT and the invention of a sign language, must also side antibiotics. The explanation for the R143W mutations in Ashkenazi Jews great variation in the phenotypic expres- and Ghana, but these effects are usually sion of this mutation is not known with associated with small or relatively certainty. Data support the idea that the closed populations. One interesting “...the combination of risk and expression of hearing loss in sub- possibility is that the high frequency improved...genetic jects who carry the A1555G substitution has resulted from the greatly can be strongly influenced, either by improved social and economic circum- fitness...and assortative other nuclear or mitochondrial genes or stances of the deaf combined with in- by environmental factors such as expo- tense assortative mating among the mating is a mechanism sure to aminoglycosides. In this country deaf. Both of these trends began with that will selectively where aminoglycosides are used selec- the introduction of sign language and tively, but often in high doses, only about the establishment of residential schools amplify the commonest 15% of all patients whose hearing loss is for the deaf about 300 years ago. An form(s) of recessive attributed to aminoglycosides are found analysis of a large nationwide collection to carry the A1555G mutation [Fischel- of pedigree data on deaf families col- deafness in the Ghodsian et al., 1997]. In contrast, in lected 100–200 years ago suggests that population...” Mongolia, where aminoglycosides were the relative frequency of connexin widely used in the past, the A1555G deafness in this country at that time mutation was the commonest identifiable cannot have been greater than about cause of deafness in a survey of students at 17% [Nance et al., 2000]. Contempo- have contributed to the dramatic increase the school for the deaf in Ulanbaatar in rary estimates suggest that this fre- in the frequency of deafness in the popu- 1997 [Pandya et al., 1997]. Other muta- quency may have doubled in the past lation. Clearly, this mechanism can increase tions in the same mitochondrial gene 200 years. Marriages between individ- the frequency of recessive genes for deaf- have been identified in patients with uals with precisely the same type of ness other than the Connexins. It also aminoglycoside ototoxicity who lack the recessive deafness can only have deaf seems likely that precisely the same forces A1555G substitution, including a offspring, and are termed “noncomple- led to the rapid fixation of genes for speech delT961Cn mutation [Casano et al., mentary matings.” Since the frequency [Lai et al., 2001] when they first arose in 1999], but little is known about their of these marriages is proportional to the the human species and subsequently con- fourth power of the respective gene prevalence. When a molecular diagnosis tributed to the explosive evolution of the frequency, only the commonest forms can be established, aminoglycoside oto- human brain that has occurred during the of deafness will make an appreciable toxicity is a trait with a high potential for contribution to these matings. Thus the past 50,000–100,000 years. The evolution- preventing the recurrence of deafness combination of improved fertility (i.e., ary biologist Stephen Gould popularized among matrilineal relatives. Whether all genetic fitness) and assortative mating is the idea that during specific periods the patients, or perhaps all Hispanic patients, a mechanism that will selectively am- pace of evolution has suddenly accelerated admitted to neonatal intensive care units plify the commonest form(s) of reces- [Gould and Eldredge, 1977]. The combi- should be screened for relevant mito- sive deafness in the population, along nation of intense assortative mating with chondrial mutations before the adminis- with “modifier genes”, such as the improved fitness associated with the acqui- tration of aminoglycosides is an issue that CX30, deletion which can interact sition of speech may be the mechanism would depend critically on the popula- with the major gene. [Nance et al., accounting for at least one such event in tion prevalence of the mutations. Unfor- 2002b]. In countries without a long human evolution [Nance and Pandya, tunately, these data represent an impor- tradition of sign language or intermar- 2002b]. tant gap in existing knowledge.

114 MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE Dominantly inherited low frequency hearing velopmental stage, tissues, and cells in which are thought to be involved in the loss (DFNA6, 14, & 38) which these genes are expressed, result- trafficking of intracellular organels. Otof- Dominantly inherited low fre- ing in an ever more detailed understand- erlin is located in the cytoplasm and an- quency hearing loss was first reported in ing of the molecular basis of hearing. chored to the cell membrane while the a large kindred whose impairment was Treacle protein is involved in nuclear- generally confined to frequencies less Transcription Factors cytoplasmic trafficking. TCOF1 is lo- than 2000 cps. A pseudolongitudinal Several large classes of proteins are cated on 5q31, and its mutations are the analysis of the audiologic findings within known which are typically required to cause of Treacher Collins Syndrome. the family provided little evidence for initiate the transcription of messenger Defects in OTOF cause a form of reces- progression with age. Affected family RNA (m-RNA). Some bind to specific sive NSD, DFNB9 on 2p23. members were not severely incapacitated sites within the promoter region of the and the children responded well to pref- gene, while others are involved in spe- Transmembrane Proteins erential classroom placement [VUHDSG, cific interactions with other proteins in 1968]. The gene in this family was the complete transcription complex. An Channelopathies mapped to 4p16.3 [Lesperance et al., abnormal phenotype can result from an Mutations involving at least three 1995]. Two other forms of dominantly abnormal base pair sequence in the pro- members of the Connexin family of gap inherited hearing loss, one of which ex- moter region or from a deficiency or junction proteins Cx26, Cx30, and Cx43 hibited progression, were subsequently abnormality in the transcription factor. are known to cause hearing loss. Two mapped to the same region and desig- Seven forms of deafness are known to be potassium channel genes, KVLQT1 and nated DFNA14 and DFNA38. How- the result of mutations of transcription KCNE1, are essential for maintaining the ever, when DFNA6 was found to arise factors. Defects in PAX3, MITF, and normal homeostasis of the cochlear en- from mutations in the Wolfram Syn- SOX10 cause three forms of Waarden- dolymph. Defects in these genes cause drome I gene (WFS1), DFNA14 and burg. Mutations involving the POU4F3 two forms of the recessive Jervelle, DFNA38 were shown to be the conse- and POU3F4 genes cause a dominant Lange-Nielsen Syndrome (JLN1 & 2). As quence of allelic mutations at the same form of progressive hearing loss noted previously, mutations in another locus [Bespalova, et al., 2001]. Mutations (DFNA15) and the X-linked syndrome potassium channel gene, KCNQ4, can involving this locus are now thought to of congenital fixation of the stapes foot- cause DFNA2 but do not contribute to explain most cases of dominantly inher- plate respectively. Finally, mutations in- homeostasis of the endolymph. One ited low frequency hearing loss. How- volving the EYA1 and EYA4 genes are other gene for deafness, SLC26A4, the ever, one additional gene, DFNA1, the cause of the Branchio-oto-renal syn- cause of Pendred Syndrome, is a mem- which led to a rapidly progressive hearing drome and a dominantly inherited form brane-bound protein that is involved in loss beginning in the low frequencies, of late onset hearing loss (DFNA10) re- ion transport, and the fixation of iodine was identified in a single large Costa spectively. Since these defective tran- in the thyroid gland. Prestin, the putative Rican kindred, mapped to 5q31, and scription factors act on both copies of a molecular motor protein of the outer hair later shown to result from a mutation in diploid target gene, all of these traits ex- cells, is a member of this same family of the human homolog of the diaphanous hibit dominant transmission. genes. A unique attribute of the outer gene in drosophila [Lynch, et al., 1997]. hair cells is their ability to change their Wolfram syndrome is a complex reces- Intracellular proteins length in response to sound stimuli. This sive trait. The hallmarks are diabetes mel- property is thought to greatly amplify and litus and insipidus, optic atrophy, and Atypical Myosins help resolve the transmission of sound deafness, but a variety of neuropsychiat- Mutations involving four different waves along the basal membrane. Muta- ric symptoms can also be seen including atypical myosins have been shown to be tions in this gene have been identified in seizures, ataxia, retardation, depression, the cause of deafness. Different mutations deaf probands, although the mode of in- violent behavior, and suicide in some in MYO7A can cause dominant or re- heritance is not yet clear [Liu et al., patient populations. Typically the hear- cessive NSD or Usher syndrome, type 2002]. ing loss in affected homozygotes has been 1B. Mutations involving MYO6 and progressive beginning with the high fre- MYH9 both lead to progressive forms of Cell Adhesion quencies. Diabetes mellitus and hearing dominant hearing loss (DFNA22 & Two genes for deafness involve loss have been shown to occur with DFNA17) while MYO15 defects under- genes that are required for normal cell higher frequency in heterozygous carri- lie a profound congenital form of reces- adhesion. CDH23, on 10q21, is a mem- ers. Carrier status does not appear to be a sive NSD (DFNB3). ber of a calcium dependant family of major risk factor for psychiatric disease genes, the cadherins, that mediate cell and suicide, but the possibility that some Structural Proteins adhesion. It is abnormal in USH1D as alleles have these effects has not been Two genes, DIAPH1 and STRC well as in families with recessive excluded [Crawford et al., 2002] are highly expressed in the hair cells DFNB12. The claudins are another a where they act to promote actin poly- large family of genes that form tight junc- MOLECULAR BASIS OF merization in the hair cells, and the pro- tions that bind homologous as well as HEARING AND DEAFNESS duction of Sterocilin, a component of the heterologous cells together. A mutation As new genes for deafness have microvillar proteins respectively. Defects in CLDN14 on 21q22.3 is responsible been mapped and cloned, analysis of their in the former result in the progressive for the recessive deafness in DFNB29. base pair sequence has frequently allowed dominantly inherited hearing loss of the structure and function of their pro- DFNA1 on 5q31, while the latter is as- Other transmembrane proteins tein products to be inferred. Molecular sociated with recessive deafness, The functions of the transmem- and histologic studies of m-RNA synthe- DFNB16 on 15q15. The OTOF and brane USH3 and TMC1 proteins that are sis have allowed determination of the de- TCOF1 are both intracellular proteins defective in USH3 on 3q21 and domi-

MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE 115 nant or recessive forms of NSD netic issues have been highlighted in a quency of deafness may well have been (DFNB7/11, DFNBA36) on 9q13 are number of recent surveys [Stern et al., correct. To avoid this effect, Bell advo- not as well established but TMPRSS3, 2002; Middleton et al., 1998]. Many deaf cated the closing of residential schools for which causes a recessive form of NSD on individuals reject the medical model of the deaf in favor of what is now called 21q22.3, codes for a transmembrane pro- deafness as a disability that needs to be mainstreaming. In this instance, he was tein with protease activity. “fixed.” Most express no preference for actually advocating more random mat- hearing or deaf children, but many ing, as opposed to the selective breeding Extracellular Proteins would prefer a deaf child and relatively commonly associated with eugenics. Ge- Mutations involving three collagen few express a preference for hearing chil- neticists have generally discounted Bell’s genes, COL2A1, COL11A2, and dren. The attitudes of the deaf commu- concerns about the mating structure of COL11A1 are the cause of the three rec- nity towards genetic testing and the use the deaf population believing that the ognized forms of Stickler Syndrome, of prenatal diagnosis, including the selec- effect would be negligible in view of the while mutations involving COL4A5, tive abortion of either deaf or hearing large number of genes involved in deaf- COL4A3, and COL4A4 cause the auto- fetuses, tend to be more polarized than ness. However, it now appears that this somal and sex linked forms of Alport those of hearing parents. In contrast, the mechanism may have contributed to an Syndrome. The gene that causes USH2A birth of a deaf child is often the supreme increase the frequency of the most com- codes for an extracellular matrix protein, tragedy in the lives of hearing parents, mon form of recessive deafness during while TECTA, the gene defective in who would do anything to restore the the last 200 years. Thus, Bell’s prediction DFNA8/12 on 11q22, codes for a com- child’s hearing. There are few other hu- forces us to consider what attitude we ponent of the tectorial membrane. should take towards the pattern of mar- Otoancorin, the product of the OTOA riages that may have contributed to this gene, is thought to anchor the apical increase. Assortative mating among the surface of the hair cells to the tectorial “Geneticists have deaf is not the only example in which the membrane, and is defective in DFNB22 marriage patterns of a population can on16p12.2. generally discounted Bell’s have a profound influence on the fre- quency of specific genetic diseases. The Energy Production concerns about the mating frequencies of Tay-Sachs disease and Both nuclear and cytoplasmic structure of the deaf Sickle Cell Anemia in this country are genes are active in the mitochondria, the much higher than they would be if mar- site of oxidative phosphorylation in the population.... However riages occurred at random, and unless we cell. Hearing loss can be a part of a large it now appears...this are also prepared to abolish racial and number of complex neurologic syn- ethnic homogamy, there would appear dromes that involve deletions in the mi- mechanism may have to be no rational genetic basis for pro- tochondrial DNA or point mutations in- contributed to an increase hibiting marriages among the deaf. It volving mitochondrial t-RNSs. The now seems likely that Bell’s goal will be A1555G substitution in the 12S mRNA in the frequency of the achieved not through the mainstreaming gene and the A7445G substitution in the of deaf children but because of the wide- t-RNA Ser(UNC) gene are examples of most common form of spread use of cochlear implants. This de- two mitochondrial mutations that can recessive deafness...” velopment almost certainly represents a lead to hearing loss alone. Finally, DDP much greater threat to deaf culture than the Deafness/Dystonia peptide is the genetic testing. Deaf culture may well product of a gene on Xq22 that is re- disappear in our country by the end of sponsible for the deafness, blindness, re- man traits for which such divergent atti- this century. If that does occur, who tardation, and dystonia seen in the tudes are held. among us can predict whether it will be Tranebjaerg syndrome. The protein viewed as one of the medical triumphs of product of this gene is normally trans- The Legacy of Alexander Graham the 21st Century, or as an egregious ex- ported into the mitochondria, but its pre- Bell ample of cultural genocide? cise function there has not been iden- Bell’s involvement with the Eu- tified. genics movement may have had a lasting Genetic Counseling SOCIAL AND ETHICAL influence on the attitudes of the deaf Genetic counselors are medical ASPECTS OF GENETIC community towards genetics. Bell was an specialists who are especially skilled in the DEAFNESS educator of the deaf who devoted most evaluation, diagnosis, and counseling of Advances in human genetics have of his professional career to promoting patients with certain genetic traits. In raised many ethical issues such as privacy, the welfare of deaf children. In 1883, 17 some cases, medical geneticists also be- autonomy, prenatal diagnosis, stem cell years before the rediscovery of Mendel’s come intimately involved in the treat- research, and the rights of children, that work, he published a Memoir of the Na- ment and long-term follow-up of pa- are just as applicable to deafness as they tional Academy of Sciences in which he tients with specific genetic diseases. In are to other genetic traits. In addition, speculated that the continued intermar- the case of hereditary deafness, geneticists there are issues that are particularly rele- riage among the deaf might someday re- can assist in the establishment of a specific vant, if not unique, to deafness. sult in the formation of a deaf variety of etiologic diagnosis. In some cases, this the human race [Bell, 1883]. Although may result in the diagnosis of a form of Attitudes of the Deaf and Hearing some of Bell’s genetic proposals cannot syndromic deafness for which specific Communities withstand modern criticism, his percep- treatments or diagnostic tests are indi- The contrasting attitudes of the tions about the effect of the mating struc- cated. The Jervelle, Lange-Neilsen Syn- deaf and hearing communities about ge- ture of the deaf population on the fre- dromes, Usher Syndromes, Branchio-

116 MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE oto-renal Syndrome, and Alport FUTURE DIRECTIONS she is 50 years old? One option would be Syndromes are examples of genetic forms In the recent past, the state of our to focus on forms of hearing loss that may of deafness in which serious complica- knowledge was such that we lumped not be expressed at birth and could there- tions involving other organ systems may many forms of nonsyndromic deafness fore be missed in current audiologic arise. Even when a diagnosis of nonsyn- together; assumed that each form of syn- newborn screening programs. Another dromic deafness is made, an increasing dromic deafness was caused by a single possible criterion would be to screen for number of genetic tests can diagnosis a gene; believed that dominance and reces- very common forms of deafness, or for specific form of NSD. These tests can be sivity were intrinsic properties of genes, forms that are associated with other seri- of particular value in confirming a ge- and had little insight into the heteroge- ous and/or preventable clinical compli- netic etiology in families where there is neity of mutations and the molecular cations. Examples of the former might only one affected child and no history of mechanisms involved in their effects. We include hearing loss resulting from CMV deafness in the family. Connexin testing used descriptive terms such as reduced infection or Pendred Syndrome. Exam- has rapidly become the standard of care penetrance variable expressivity, multi- ples in the latter group would include for the management of such cases. In the factorial transmission, and stochastic vari- Connexin deafness, the mitochondrial future, it will become increasingly useful ation to explain away examples of unex- A1555T mutation, genes for the JLN to establish a specific genetic etiology in pected gene expression. We are now syndrome, and possibly one or more order to provide prognostic information gaining a much more sophisticated un- forms of Usher Syndrome. Screening for about the natural history of deafness in a derstanding of genetic heterogeneity, and a limited array of traits such as these could family, and options for specific therapy. the factors which influence the expres- be performed with the newborn blood Some forms of nonsyndromic deafness sion of genes, their interactions with each spots that are already collected for exist- are progressive, while others are remark- other, and with the environment. In the ing metabolic screening programs. If pro- ably stable. Some have a conductive immediate future we can expect to see grams of this type are implemented in component that may be amenable to sur- this country, it would be highly desirable gical treatment. Finally, reliable informa- to collect pilot data on the frequency of tion about the chance that deafness will the traits and the sensitivity and specific- recur in the immediate family or in the “...information about ity of the tests. In this way, it should be children of the proband can only be pro- possible to incorporate the new tests into vided if the genetic form of deafness and the cause of a trait that existing screening programs. Programs of its mode of inheritance are known. If this has had such an this type should be viewed as a comple- knowledge is provided in a way that it ment to and not a substitute for existing can be understood and integrated by the important influence on newborn hearing screening programs. patient it can help dispel misconceptions their lives can be They would identify additional high-risk and feelings of guilt and allow the parents infants who deserve close follow-up, and to focus on planning for their child’s fu- empowering. In the past, accelerate an etiologic diagnosis in oth- ture. For deaf adults, information about deaf couples have never ers. In view of the complexities sur- the cause of a trait that has had such an rounding the interpretation of even the important influence on their lives can be known how, why, or simplest test results, it would not even be empowering. In the past, deaf couples whether their children possible to contemplate a newborn mo- have never known how, why, or even if lecular screening program without a pre- their children would be deaf, as they are, would be deaf” existing audiologic screening program. or hearing. For some, this uncertainty For example, some deaf individuals are must be like not knowing what race your found to carry only a single Cx26 muta- child will be. Increasingly, couples can tion. As noted previously, it is now receive answers to these questions pro- more of the same as additional genes for known that many of these individuals spectively. Much is known about the ge- deafness are discovered and we listen to also carry a deletion of the Cx30 gene. netics of profound deafness. In compari- the incredible stories they have to tell. However, others are undoubtedly simply son, much less is known about the causes The coincident development of the new- heterozygous carriers of a single Cx26 of lesser degrees of clinically significant born hearing movement (Karl White, mutation. Without evidence that a new- hearing loss. Many of these children may this volume) during this new era of ge- born infant has normal hearing, it would have one or the other of the several hun- netics provides an unparalleled opportu- be difficult to draw the conclusion that dred genetic syndromes that have been nity for synergistic interactions between the test result merely indicated heterozy- described in which hearing loss is a less these two streams of medical and scien- gosity with any degree of certainty. In conspicuous or inconstant feature. In tific progress. The time will come when view of the rapidly expanding body of many ways, these children are more in the application of existing “gene chip” relevant genetic knowledge about ge- need of the expertise in dysmorphology technologies or other methods currently netic deafness, the American College of that a geneticist brings to the evaluation under development, will make it possible Medical Genetics has recommended that of such children than those who have a to perform molecular genetic screening all infants with confirmed hearing losses clear cut diagnosis. Finally, as the training tests on blood samples from newborn who are identified in newborn screening of audiologists incorporates more knowl- infants at low cost for a virtually unlim- programs, should be referred to a genet- edge about genetics they should be in- ited number of gene mutations that can icist for clinical evaluation, the perfor- creasingly able to recognize families who cause deafness. The question then arises, mance of indicated genetic tests, and would benefit from genetic evaluation “What gene defects should we screen for counseling [Nance et al., 2000], and has and counseling, and to understand and and why?” Would it be important to developed detailed practice guidelines for reinforce information provided to their know that an infant has inherited a gene the evaluation of such infants [Genetic patients during counseling. that may cause hearing loss when he or Evaluation of Genetic Hearing Loss Ex-

MRDD RESEARCH REVIEWS ● GENETICS OF DEAFNESS ● NANCE 117 pert Panel, 2002]. Unfortunately, al- Davis H. 1965. A model for transducer action in the and diagnostic criteria. Am J Med Genet 55: though most states support genetic clinics cochlea. Cold Spring Harbor Symp Quant 95–100. Biol 30:181–189. Liu XZ, Ouyang XM, Xia XJ, et al. 2002. Prestin, and programs at their academic medical Casano RA, Johnson DF, Bykhovskaya Y, et al. a cochlear motor protein, is defective in non- centers, these genetic programs have not, 1999. Inherited susceptibility to aminoglyco- syndromic recessive deafness. Am J Hum in general, been incorporated as an inte- side ototoxicity: genetic heterogeneity and Genet 71( in press). gral part of the newborn hearing screen- clinical implications. 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