Deafness, Autosomal Recessive 57

A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-57 (DFNB57) is caused by homozygous or compound heterozygous mutation in the PDZD7 gene (612971) on chromosome 10q24.

Description

Autosomal recessive deafness-57 is characterized by symmetric bilateral moderate to severe hearing loss, represented by gently downward-sloping audiograms. The hearing loss may be mildly progressive (Guan et al., 2018).

Clinical Features

Booth et al. (2015) studied 4 unrelated Iranian families, 2 from the north (L-445 and L-8900092), 1 from the central part (L-755), and 1 from the northwest (L-8600482), with nonsyndromic hearing loss. Physical examination revealed only hearing loss; funduscopy showed no abnormalities. In 2 families, L-445 and L-755, audiologic testing demonstrated prelingual mild to moderate downsloping to severe hearing loss in high frequencies. In family L-8900092, patients reported prelingual severe to profound hearing loss across all frequencies. However, in family L-8600482, 2 different phenotypes were observed: the proband had severe to profound hearing loss, whereas his sister had mild to moderate downsloping to severe hearing loss in high frequencies, similar to the phenotype in families L-445 and L-755.

Vona et al. (2016) reported a German girl with nonsyndromic hearing loss. At birth, otoacoustic emissions testing showed a deficit, but a follow-up auditory brainstem response (ABR) analysis was normal. At age 3 years, her parents noticed decreased hearing comprehension, and at age 4 years, ABR revealed bilateral mild to moderate sensorineural hearing loss that was ameliorated by hearing aids. Over the next 5 years, she underwent progression to severe sensorineural hearing loss, particularly at 4,000, 6,000, and 8,000 Hz. Ophthalmologic evaluation at age 12 years showed healthy retinas, with normal funduscopy, fundus autofluorescence, electroretinograms (ERGs), and optical coherence tomography (OCT) results. Vona et al. (2016) also provided follow-up on a boy with nonsyndromic deafness and a homozygous reciprocal translocation involving the PDZD7 gene (see CYTOGENETICS), who was originally reported by Schneider et al. (2009). Audiologic testing through age 15 years showed stable sloping sensorineural hearing loss. He had no problems with night vision, and thorough ophthalmologic evaluation at age 15.5 years, including funduscopy, fundus autofluorescence, ERGs, OCT, and color vision analysis, showed no signs of retinal degeneration.

Guan et al. (2018) studied 2 unrelated Chinese families segregating autosomal recessive nonsyndromic hearing loss, with age of onset between 11 months and 5 years. In the first family (CN-1507352), a 12-year-old girl and her 5-year-old brother had symmetric bilateral mild hearing loss at 250 Hz and moderate to severe hearing loss between 500 Hz and 8,000 Hz. The hearing loss had remained stable over the 2 years since their initial testing. Funduscopy, visual field testing, and ERGs were normal in both sibs, and the sister also underwent vestibular testing with normal results. In the second family (CN-0501754), evaluation of 2 affected sibs at 11 years and 8 years of age showed results similar to those of the first family, with symmetric bilateral mild hearing loss at 250 Hz and moderate hearing loss between 500 Hz and 8,000 Hz. Upon telephone follow-up at ages 22 and 19 years, the patients reported no vestibular symptoms and no progression in hearing loss, and neither sib had experienced night blindness or reduction in visual fields. The authors noted that in both families, the older sib had slightly worse hearing thresholds than their younger sib, suggesting that the hearing loss was mildly progressive.

Mapping

By linkage analysis in a consanguineous Iranian family (L-445) in which 4 sibs had nonsyndromic hearing loss, Booth et al. (2015) identified a single 60-Mb region of homozygosity by descent that segregated with the phenotype at chromosome 10q21.2-q26.13 between markers D10S1652 and D10S587. The interval was refined to a 34-Mb region between markers D10S1686 and D10S1693, overlapping the previously designated deafness locus DFNB57. In another Iranian family with nonsyndromic deafness (L-755), 3 affected sibs shared haplotypes between D10S185 and D10S597.

Cytogenetics

In a boy with nonsyndromic congenital sensorineural hearing impairment, born of consanguineous parents, Schneider et al. (2009) identified a homozygous reciprocal 46,XY t(10;11),t(10;11) translocation. Examination did not show any signs of retinitis pigmentosa or vestibular dysfunction at age 8 years. Both parents and their 4 other children were heterozygous translocation carriers. FISH analysis localized the breakpoints to chromosome 10q24.3 in intron 10 of the PDZD7 gene and to chromosome 11q23.3 in close proximity (less than 5 Mb) to 2 other nonsyndromic deafness genes, RDX (179410) and TECTA (602574). The 10q24.3 breakpoint would disrupt the open reading frame of the C and D isoforms of PDZD7. Schneider et al. (2009) suggested that the PDZD7 gene can cause nonsyndromic autosomal recessive deafness and is also a prime candidate gene for Usher syndrome (see 276900).

Molecular Genetics

By targeted genomic enrichment and massively parallel sequencing in 4 unrelated Iranian families segregating autosomal recessive nonsyndromic hearing loss, Booth et al. (2015) identified homozygosity or compound heterozygosity for mutations in the PDZD7 gene (612971.0003-612971.0007) that segregated fully with disease in each family and were not found in 300 ethnically matched controls.

In a 12-year-old German girl with nonsyndromic progressive sensorineural deafness, who was negative for mutation in 4 known deafness-associated genes, Vona et al. (2016) performed targeted deafness-gene enrichment and next-generation sequencing, and identified compound heterozygosity for a nonsense mutation (Q550X; 612971.0008) and a 1-bp deletion (612971.0009) in the PDZD7 gene. Her unaffected parents and brother were each heterozygous for 1 of the mutations.

In 2 unrelated Chinese families segregating autosomal recessive nonsyndromic hearing loss (ARNSHL), Guan et al. (2018) performed targeted high-throughput sequencing using a 128-gene deafness panel and identified homozygosity for a missense mutation in the PDZD7 gene (R66L; 612971.0010) in affected individuals of 1 family (CN-1507352), and compound heterozygosity for frameshift mutations (612971.0001 and 612971.0011) in affected members of the other family (CN-0501754). The mutations segregated with disease in both families and were not found in 1,751 Chinese controls or in 122 unrelated Chinese families segregating apparent ARNSHL.