Usher Syndrome

The eye and the ear are the sensory organs responsible for vision, balance, and hearing in mammals. These organs are essential for both communication and environmental perception. Diseases affecting the inner ear and retina of the eye can cause major impairments for human communication systems. Syndromes that include symptoms of both blindness and hearing impairment are widely known. In humans, there are approximately 40 syndromes that include both impairments; about half of the affected cases are caused by mutations attributed to Usher syndrome. Usher syndrome is an autosomal recessive genetic disease with clinically and genetically heterogeneous characteristics. In humans, it is defined by congenital, bilateral deafness and a later onset of vision impairment caused by retinitis pigmentosa. Epidemiologic studies have estimated that the prevalence of Usher syndrome ranges from 1 per 6000 to 1 per 10,000. Usher syndrome is subclassified into 3 clinical types, USH1, USH2, and USH3, based on the severity of the sensorineural HL (SNHL), the presence or absence of vestibular dysfunction, and the age at onset of retinitis pigmentosa. Patients with USH1 have severe to profound congenital bilateral HL accompanied by congenital vestibular dysfunction. In terms of retinitis pigmentosa symptoms, night blindness may be detected during childhood, followed by a narrowing of the visual field, which progresses to severe blindness. Patients with USH2 have moderate to severe congenital HL with no vestibular abnormalities. Retinitis pigmentosa is usually diagnosed between 10 and 40 years of age. In patients with USH3, hearing impairment begins before the third decade of life and is characterized by variable progression. In most cases, patients eventually become profoundly deaf. Vestibular defects are variable, and retinitis pigmentosa usually begins from 20 years of age. Early symptoms of retinitis pigmentosa are night blindness and loss of peripheral vision. This form of Usher syndrome is the least common in the general population but is more prevalent in the Finnish and Ashkenazi Jewish populations.

To date, 16 independent loci on different chromosomes are known to be associated with Usher syndrome. These loci are further divided into USH1A-G , USH2A-C , and USH3A . Moreover, 13 genes have been identified. The USH1 genes are MYO7A for the USH1B locus, encoding the motor protein myosin VIIA. USH1C encodes harmonin and USH1G encodes SANS, both of which are scaffold proteins. CDH23 mutations are responsible for USH1D, which encodes cadherin 23, PCDH15 mutations lead to USH1F and encodes protocadherin 15, both of which are cell adhesion molecules. CIB2 mutations are the cause of USH1J, which encodes calcium and integrin-binding protein 2. The USH2 genes are USH2A , encoding usherin and ADGRV1 for USH2C, encoding adhesion G protein–coupled receptor VI, also referred to as GPCR98 or VLGR1 . Both genes are transmembrane proteins that are involved in signaling. Another gene associated with USH2 is WHRN , encoding whirlin for USH2D. The USH3 genes are CLRN1 for USH3A, encoding clarin 1, and HARS (histidyl tRNA synthetase). Moreover, another 2 Usher syndrome genes have recently been identified. PDZD7 encodes the protein PDZ domain containing 7 and CEP250 encodes centrosome-associated protein 250. Usher syndrome has recently been proposed to be an oligogenic disease because of the digenic inheritance of PDZD7 and USH2A or ADGRV1 in patients with Usher syndrome. Two genes have been proposed to lead to variable phenotypes of Usher syndrome, depending on the dosage. CEP250 is associated with early onset HL and severe retinitis pigmentosa in conjunction with 2 mutant alleles of C2orf71 . The patients have mild HL and retinal degeneration with one mutant allele of C2or71 . C2orf71 mutations are associated with retinitis pigmentosa and proposed to encode a ciliary protein. Importantly, many of the genes listed earlier have been reported to cause NSHL (see Fig. 1 ). For example, different mutations in MYO7A are known to cause recessive deafness DFNB2 and dominant deafness DFNA11.

Waardenburg Syndrome

Waardenburg syndrome was considered to be an autosomal dominant inherited disease of the neural crest cells, but this syndrome is more clinically and genetically heterogeneous than originally known. Waardenburg syndrome is characterized mostly by SNHL and pigmentation abnormalities that can occur in the eyes, hair, skin, and the cochlear stria vascularis. Other features can be found in a subset of patients. These features are used for clinical classification of the syndrome. Waardenburg syndrome is estimated to have a prevalence of 1 per 42,000 and is responsible for 1% to 3% of all congenital HL cases. During embryonic development, the pluripotent neural crest cells migrate from the neural tube and give rise to different cell types, among them, melanocytes of the skin and inner ear, glia, neurons of the peripheral and enteric nervous systems, and some of the skeletal tissue. The symptoms associated with Waardenburg syndrome result from an abnormal proliferation, survival, and migration or differentiation of neural crest-derived melanocytes. Waardenburg syndrome is subdivided into 4 subtypes, WS1, WS2, WS3, and WS4, by the presence or absence of additional symptoms. WS1 is further characterized by dystopia canthorum, an appearance of wide-set eyes caused by a prominent broad nasal root, whereas WS2 has no further significant features. WS1 and WS2 are the most frequent among the 4 subtypes. WS3 is further characterized by dystopia canthorum and musculoskeletal abnormalities of the upper limbs. WS4 is associated with Hirschsprung disease, characterized by a blockage of the large intestine caused by improper muscular bowel movement and neurologic defects. Neurologic features were also observed in a subset of patients with WS2. Among the symptoms of this syndrome, the SNHL is the most frequent one, with 60% in WS1 to 90% in WS2. Six genes are associated with this syndrome: paired box 3 ( PAX3 ), microphthalmia-associated transcription factor ( MITF ), endothelin receptor type B ( EDNBR ), endothelin 3 ( EDN3 ), SRY box10 ( SOX10 ), and snail homolog 2 ( SNAI2 ). These genes are known to be involved in the regulation of melanocyte differentiation. A database for the Waardenburg syndrome–associated genes can be found at the Leiden Open Variation Database (see Table 1 ).

Pendred Syndrome

Pendred syndrome is one of the most common autosomal recessive syndromic causes of HL. The audiological phenotype is quite broad, ranging from mild to profound, and can be congenital or with a later onset and be progressive. A common feature among patients is an enlarged vestibular aqueduct, a common radiological malformation of the inner ear. In addition to SNHL, patients who have this syndrome also show features of congenital and severe to profound temporal bone abnormalities, in addition to goiter partial iodine organification defects resulting in a positive perchlorate discharge test from the goiter, usually in late childhood to early adulthood. Pendred syndrome also features thyroid dysfunction, ranging from euthyroid to hypothyroidism, and vestibular dysfunction, demonstrated in approximately 65% of affected individuals. The vestibular dysfunction can range from mild unilateral canal paresis to gross bilateral absence of function.

The estimated prevalence of Pendred syndrome is 7.5 per 100,000 newborns and it accounts for approximately 1% to 8% of the cases of congenital deafness. Approximately half of the Pendred syndrome cases are caused by a mutation in one of 3 genes. SLC26A4 , encoding the protein pendrin, is an iodide-chloride transporter. Mutations in this gene are responsible for both Pendred syndrome and DFNB4, a form of NSHL. Pendrin is expressed in the kidneys, the inner ear, and thyroid. Approximately 50% Pendred syndrome–affected individuals have a mutation in this gene (Genetics Home Reference, see Table 1 ). Less than 2% of the rest of the affected individuals have mutations in FOXI1 encoding Forkhead box protein I1 or KCNJ10 encoding the ATP-sensitive inward rectifier potassium channel 10. More than 280 SLC26A4 -Pendred syndrome and DFNB4-causing mutations have been identified; but in different ethnic groups, unique pathogenic alleles are found more frequently than others, reflecting a few prevalent founder mutations.

Additional Syndromes

In addition to the aforementioned syndromes, there are more than 700 genetic syndromes that have been described with features of hearing impairment. Alport syndrome is characterized by renal defects, SNHL, and ocular abnormalities with a prevalence of 1 in 50,000 (Genetics Home Reference). Three genes are associated with this syndrome: COL4A3 encoding collagen, type IV, alpha 3, and COL4A4 encoding collagen, type IV, alpha 4 for the autosomal inherited types and COL4A5 encoding collagen, type IV, alpha 5 for the X-linked type.

Branchio-oto-renal (BOR) syndrome is an autosomal dominant disease, characterized by defects in the development of the tissues in the neck and malformations of the ear and kidney. It is estimated that the prevalence of this syndrome is 1 in 40,000 (Genetics Home Reference). Approximately 40% of the individuals affected test positive for mutations in the EYA1 gene encoding the eyes absent homolog 1. An additional 5% and 4% of affected individuals have a mutation in SIX5 encoding the homeobox protein SIX5 and SIX1 encoding the homeobox protein SIX1, respectively.

CHARGE syndrome is an autosomal dominant syndrome that features coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness. It is estimated that the prevalence of CHARGE syndrome is 1 in 8500 to 10,000 individuals (Genetics Home Reference). This syndrome is mostly caused by mutations in the CHD7 gene encoding Chromodomain-helicase-DNA-binding protein 7, an ATP-dependent chromatin remodeling protein.

Jervell and Lange-Nielsen syndrome is an autosomal recessive disease with features of arrhythmia, SNHL, and a significantly higher risk of fainting and sudden death as a result of prolongation of the corrected QT interval. This syndrome is estimated to affect 1.6 to 6.0 per 1,000,000 people worldwide, with a higher frequency in Denmark (Genetics Home Reference; see Table 1 ). The genes associated with this syndrome are KCNQ1 encoding the potassium channel, voltage-gated KQT-like subfamily Q, member 1 and KCNE1 encoding potassium channel, and voltage-gated subfamily E regulatory beta subunit 1. Approximately 90% of the cases are caused by a mutation in the KCNQ1 gene, with the rest of the cases caused by mutations in KCNE1 .

Norrie disease is characterized by a spectrum of fibrous vascular changes of the retina at birth that progresses to visual impairment with age. About 30 to 50% of males with Norrie disease have developmental delays or other forms of intellectual disability, behavioral abnormalities, or psychoticlike features. Moreover, most of the males also develop HL. This syndrome is X-linked, recessively inherited, and caused by mutations in the NDP gene encoding the norrin protein. Mutations in this gene are responsible for about 95% of the affected individuals. The prevalence of this syndrome is unknown, and it is not associated with any racial or ethnic group (Genetics Home Reference, see Table 1 ).

Stickler syndrome can be both dominant and recessive and is characterized by ocular, skeletal, orofacial, and auditory abnormalities. The prevalence of this syndrome is about 1 in 7500 to 1 in 9000 newborns (Genetics Home Reference; see Table 1 ). Stickler syndrome is subdivided into 5 subtypes based on its underlying genetic collagen defect. For the autosomal dominant form of Stickler syndrome, 3 genes have been identified. Type I Stickler syndrome (STL1) is associated with mutations in COL2A1 encoding collagen, type II, alpha-1. Moreover, mutations in COL11A1 encoding collagen, type XI, alpha-1 are associated with type II (STL2) and mutations in COL11A2 encoding collagen, type XI, alpha-2 are associated with type III (STL3). The autosomal recessive forms of Stickler syndrome are STL4 and STL5; their identified related genes are COL9A1 encoding collagen, type IX, alpha-1 and COL9A2 encoding collagen, type IX, alpha-2, respectively. There is a degree of variability in HL frequency and severity in the different types of this syndrome, even within the same family.

Treacher-Collins syndrome is usually an autosomal dominant syndrome that affects the development of the bones and other tissues of the face. These abnormalities contribute to speech and language difficulties, visual impairment, conductive HL, and breathing difficulties. The symptoms of this syndrome can range from undetectable to severe. Half of the affected individuals have HL caused by defects of the 3 bones of the middle ear or defects in the development of the ear canal. One in 50,000 people will have this syndrome (Genetics Home Reference; see Table 1 ), caused by mutations in 3 genes: TCOF1 encoding the treacle protein, POLR1C encoding polymerase I polypeptide C, and POLR1D encoding polymerase I polypeptide D. Most patients have a mutation in TCOF1 , with 1% of the cases caused by a recessive form of this syndrome, with mutations in POLR1C .

Perrault syndrome is an autosomal recessive disease characterized by SNHL in both sexes and ovarian dysfunction in females. The HL symptoms are bilateral and range from moderate with early childhood onset to profound at birth. Moreover, the early childhood form can be progressive. The ovarian dysfunction symptoms can also vary; affected females also show, in some cases, neurologic features, such as developmental delay and cerebellar ataxia. Less than 100 affected individuals have been documented (Genetics Home Reference; see Table 1 ), most probably because of the difficulties in diagnosis. Four genes have been associated with this syndrome: HARS2 encoding histidyl-tRNA synthetase 2, HSD17B4 encoding hydroxysteroid (17-beta) dehydrogenase 4, LARS2 encoding leucyl-tRNA synthetase 2, and CLPP encoding the caseinolytic mitochondrial matrix peptidase proteolytic subunit. This syndrome is subdivided into 4 types: type I, II, III, and IV, also called PRLTS1, 2, 3, and 4, respectively. The classification of the subtypes is determined according to the neurologic involvement and its state, progressive or nonprogressive. This classification is now being reconsidered, as mutations in CLPP were found to include both types of cases, with or without neurologic symptoms. The clinical features and the molecular genetic information of these syndromes are comprehensively described in the Online Mendelian Inheritance in Man (OMIM) database (see Table 1 ).