NLRP3 mutation and cochlear autoinflammation cause syndromic and nonsyndromic hearing loss DFNA34 responsive to anakinra therapy.

The NLRP3 inflammasome is an intracellular innate immune sensor that is expressed in immune cells, including monocytes and macrophages. Activation of the NLRP3 inflammasome leads to IL-1ß secretion. Gain-of-function mutations of NLRP3 result in abnormal activation of the NLRP3 inflammasome, and cause the autosomal dominant systemic autoinflammatory disease spectrum, termed cryopyrin-associated periodic syndromes (CAPS). Here, we show that a missense mutation, p.Arg918Gln (c.2753G > A), of NLRP3 causes autosomal-dominant sensorineural hearing loss in two unrelated families. In family LMG446, hearing loss is accompanied by autoinflammatory signs and symptoms without serologic evidence of inflammation as part of an atypical CAPS phenotype and was reversed or improved by IL-1ß blockade therapy. In family LMG113, hearing loss segregates without any other target-organ manifestations of CAPS. This observation led us to explore the possibility that resident macrophage/monocyte-like cells in the cochlea can mediate local autoinflammation via activation of the NLRP3 inflammasome. The NLRP3 inflammasome can indeed be activated in resident macrophage/monocyte-like cells in the mouse cochlea, resulting in secretion of IL-1ß. This pathway could underlie treatable sensorineural hearing loss in DFNA34, CAPS, and possibly in a wide variety of hearing-loss disorders, such as sudden sensorineural hearing loss and Meniere's disease that are elicited by pathogens and processes that stimulate innate immune responses within the cochlea.

A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct.

BACKGROUND: Enlargement of the vestibular aqueduct (EVA) is the most common radiological abnormality in children with sensorineural hearing loss. Mutations in coding regions and splice sites of the SLC26A4 gene are often detected in Caucasians with EVA. Approximately one-fourth of patients with EVA have two mutant alleles (M2), one-fourth have one mutant allele (M1) and one-half have no mutant alleles (M0). The M2 genotype is correlated with a more severe phenotype. METHODS: We performed genotype-haplotype analysis and massively parallel sequencing of the SLC26A4 region in patients with M1 EVA and their families. RESULTS: We identified a shared novel haplotype, termed CEVA (Caucasian EVA), composed of 12 uncommon variants upstream of SLC26A4. The presence of the CEVA haplotype on seven of ten 'mutation-negative' chromosomes in a National Institutes of Health M1 EVA discovery cohort and six of six mutation-negative chromosomes in a Danish M1 EVA replication cohort is higher than the observed prevalence of 28 of 1006 Caucasian control chromosomes (p<0.0001 for each EVA cohort). The corresponding heterozygous carrier rate is 28/503 (5.6%). The prevalence of CEVA (11 of 126) is also increased among M0 EVA chromosomes (p=0.0042). CONCLUSIONS: The CEVA haplotype causally contributes to most cases of Caucasian M1 EVA and, possibly, some cases of M0 EVA. The CEVA haplotype of SLC26A4 defines the most common allele associated with hereditary hearing loss in Caucasians. The diagnostic yield and prognostic utility of sequence analysis of SLC26A4 exons and splice sites will be markedly increased by addition of testing for the CEVA haplotype.

Asian oral-facial cleft birth prevalence.

OBJECTIVE: To determine the clefting birth prevalence among Asian populations, specifically Chinese and Japanese, using raw counts from nonoverlapping published studies of Asian populations, and to investigate whether Asian clefting rates have been interpreted accurately as being up to twice the Caucasian rate. DESIGN: A literature review of articles giving raw counts of clefting in Asian populations, primarily Japanese and Chinese. MAIN OUTCOME MEASURES: Where possible, clefts were identified by the patients' ethnicity, country of origin, cleft type, syndromic status, and birth status. RESULTS: Prevalence rates of cleft lip with or without cleft palate per 1000 live births are reported. Syndromic plus nonsyndromic cleft lip with or without cleft palate: Chinese, 1.30; Japanese, 1.34; Other Asian, 1.47; and total, 1.33. Nonsyndromic cleft lip with or without cleft palate: Chinese, 1.20; Japanese, 1.18; Other Asian, 1.22; and total, 1.19. CONCLUSIONS: Overall, Chinese and Japanese live birth prevalence rates for nonsyndromic cleft lip with or without cleft palate, based on the published reports of birth prevalence, are significantly lower than the oft-quoted rate of 2 per 1000 for Asians. The apparent reason for the discrepancy is that many published prevalence rates included all pregnancies (live births plus pregnancy losses) and do not distinguish between syndromic and nonsyndromic clefts or between cleft palate alone and cleft lip with or without cleft palate. These results demonstrate that it is extremely important for current population-based studies of clefts to include careful delineation of population groups, syndromes, cleft type, and birth status.