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DEAFNESS AND MYOPIA; DFNMYP

DEAFNESS AND MYOPIA; DFNMYP

In a survey of mental retardation in an inbred Amish community, Eldridge et al. (1968) observed 4 of 7 sibs in a family (2 males, 2 females) who also had deafnes...

In a survey of mental retardation in an inbred Amish community, Eldridge et al. (1968) observed 4 of 7 sibs in a family (2 males, 2 females) who also had deafness and myopia. The extent of intellectual impairment was difficult to evaluate. Sensory deprivation might have been a main factor.

Ohlsson (1963) described deafness and severe myopia in 3 boys in a sibship of 7. One was stated to be of somewhat low intelligence. All 3 plus 3 other sibs and the mother had albuminuria or hematuria. Ohlsson (1963) concluded that the family did not have Alport syndrome (104200).

Tekin et al. (2013) studied 2 families with deafness and high myopia. One was a consanguineous Old Order Amish family in which 3 sibs had congenital high myopia, with refraction error ranging from -7.25 to -10.25 diopters corrected by glasses, and prelingual-onset moderate to severe bilateral sensorineural hearing loss necessitating hearing aids. Their parents had low myopia with onset in their youth, and normal hearing. The second family was a consanguineous Turkish family in which 4 sibs had high myopia, with refraction error ranging from -6.0 to -11.0 diopters, and prelingual-onset moderate to profound sensorineural hearing loss. Their parents and 2 unaffected sibs did not have hearing loss; the father and 2 unaffected sibs had mild adult-onset myopia of less than -2 diopters. Affected individuals in both families did not exhibit delays in gross motor development, and none had balance problems, vertigo, dizziness, or spontaneous or positional nystagmus. CT scan of the temporal bone was normal in 1 affected individual from each family. Clinical examination confirmed the absence of additional findings, with normal facial appearance and normal neurologic, connective tissue, and ocular manifestations. None of the affected individuals had retinitis pigmentosa.

Morlet et al. (2014) provided a longitudinal description of the auditory phenotype in 9 patients from an Old Order Amish community with deafness and myopia who were homozygous for the Q414X mutation in the SLITRK6 gene (609681.0001). The patients ranged in age from 4 months to 36 years. The 4 oldest patients, who were in the second to fourth decade of life, had absent ipsilateral middle ear muscle reflexes. Distortion product otoacoustic emissions (OAEs) were absent in all ears tested; the cochlear microphonic (CM) was increased in amplitude and duration in young patients but absent in the 2 oldest subjects. Auditory brainstem responses were dyssynchronized bilaterally with no reproducible waves I, III, or V at high intensities. Hearing loss and speech reception thresholds deteriorated symmetrically with age, which resulted in severe to profound hearing impairment by early adulthood. Vestibular evoked myogenic potentials were normal in 3 ears and absent in 1. Noting the absence of OAEs with large CMs and wave I recordings at high intensities, Morlet et al. (2014) suggested that inner hair cell function is relatively preserved in these patients. The authors concluded that homozygosity for the SLITRK6 Q414X mutation is associated with high myopia, cochlear dysfunction attributable to outer hair cell disease, and progressive auditory neuropathy.

▼ Mapping
In a consanguineous Old Order Amish family segregating autosomal recessive high myopia and deafness, Tekin et al. (2013) performed genomewide SNP analysis and identified a single 12.2-Mb homozygous region shared among all affected individuals on chromosome 13q31.1-q31.3, delimited by the recombinant SNP markers rs1333404 and rs9584101. Autozygosity across the interval was corroborated by microsatellite marker analysis in all family members, which defined a haplotype that cosegregated with the disease phenotype.

Using DNA samples from 3 affected sibs from an Old Order Amish community, Morlet et al. (2014) mapped a locus for deafness and myopia to chromosome 13q31 between SNP markers rs722023 and rs958373.

▼ Molecular Genetics
In a consanguineous Old Order Amish family in Ohio with deafness and myopia mapping to chromosome 13q31, Tekin et al. (2013) analyzed candidate genes as well as microRNAs and other potentially functional molecules within the disease interval, and identified a nonsense mutation in the SLITRK6 gene (Q414X; 609681.0001) that segregated with disease in the family. The mutation was not found in the dbSNP (build 135) or 1000 Genomes Project databases or in 450 controls of European ancestry; only a single heterozygous carrier was detected in 80 Amish controls. In parallel, whole-exome sequencing was performed in 2 affected individuals from a consanguineous Turkish family with deafness and myopia, which revealed homozygosity for a different nonsense mutation in SLITRK6 (S297X; 609681.0002) that cosegregated with disease in the family and was not found in 330 Turkish controls. Analysis of the SLITRK6 gene in 177 multiplex families with nonsyndromic autosomal recessive deafness, in some of which myopia was also present, identified a Greek family with 2 affected brothers who were homozygous for a third nonsense mutation (R181X; 609681.0003); the parents were heterozygous for the mutation, which was not found in 300 Greek controls. Screening for the R181X and S297X mutations in 370 probands from the United States with nonsyndromic sensorineural hearing loss identified no sequence variants.

In affected individuals from an Old Order Amish community in Pennsylvania with deafness and myopia mapping to chromosome 13q31, Morlet et al. (2014) performed Sanger sequencing of the candidate gene SLITRK6 and identified homozygosity for the Q414X mutation. Genotyping of 571 Old Order Amish control samples by high-resolution melt analysis revealed 27 carriers of the mutation (4.7% carrier frequency).

▼ Animal Model
Using high-resolution small-animal MRI scanning, Tekin et al. (2013) studied 10- to 12-month-old Slitrk6 -/- mice and observed a significant increase in axial length, but not lens thickness, in mutant mice compared to controls. The size difference in axial length was not apparent in newborn mice, indicating that SLITRK6 regulates eye growth after birth. Tekin et al. (2013) concluded that Slitrk6 knockout mice appeared to closely mimic the human myopia phenotype, in association with previously documented deafness in Slitrk6-null mice (Matsumoto et al., 2011).

Tags: 13q31.1