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The article summarizes research published within the issue, titled "The Impact of Whole-Genome Sequencing on the Primary Care and Outcomes of Healthy Adult Patients," by J. L. Vassy, K. D. Christensen, E. F. Schonman and colleagues. Topics discussed include whole-genome sequencing (WGS) in primary care, research methodology, and limitations of the study.

Objective: To determine the spectrum of connexin 26 (Cx26) mutations and their phenotypes in children with sensorineural hearing loss (SNHL) or mixed hearing loss (MHL)., Design: Children with SNHL or MHL were prospectively tested for mutations in the entire coding region of the Cx26 gene., Patients: Children with SNHL or MHL with no obvious etiology for the hearing loss., Results: Between December 1, 1998, and July 1, 2000, 107 patients with SNHL or MHL from 99 families underwent Cx26 testing. Most patients were aged 1 week to 16 years (61 boys and 46 girls). Thirty (30%) of 99 probands had Cx26 mutations: biallelic mutations were detected in 18 (9 homozygous and 9 compound heterozygous) and single mutations were detected in 12. Twelve previously reported mutations (35delG, 167delT, E47X, L90P, M34T, G12V, V37I, R143W, V84L, V153I, V27I, and 310del14) and 3 novel mutations (E129K, T8M, and N206S) were found. Hearing loss in patients with biallelic Cx26 mutations ranged from unilateral high frequency to bilateral profound. Four children, 2 with biallelic mutations, had temporal bone abnormalities., Conclusions: Connexin 26 mutations are common in children with SNHL, and it is likely that the homozygous and compound heterozygous mutations cause the SNHL. However, pathogenicity is less certain when only a single Cx26 mutation is present. Patients with biallelic Cx26 mutations had a slightly higher incidence of milder hearing loss than in previous studies. Children with SNHL or MHL should be tested for Cx26 mutations early in their evaluation.

Recent advancements have been made in understanding, diagnosing, and treating deafness. In particular, much has been learned from the discovery of a small fraction of the genes responsible for deafness. This understanding will doubtless increase as additional genes are cloned and their functions elucidated. Trailing close behind these achievements will be more clinical advancements facilitating diagnosis of the etiologies of deafness. Integrating these genetic and clinical perspectives is critical to the development of better treatments and interventional strategies for deafness and its associated difficulties. Although opinions toward these advancements are likely to vary between the hearing population and the Deaf community, a growing understanding of the hearing process and how genetic variations result in deafness is ultimately likely to offer benefits to both groups.

Usher syndrome type IIa (OMIM 276901), an autosomal recessive disorder characterized by moderate to severe sensorineural hearing loss and progressive retinitis pigmentosa, maps to the long arm of human chromosome 1q41 between markers AFM268ZD1 and AFM144XF2. Three biologically important mutations in Usher syndrome type IIa patients were identified in a gene (USH2A) isolated from this critical region. The USH2A gene encodes a protein with a predicted size of 171.5 kilodaltons that has laminin epidermal growth factor and fibronectin type III motifs; these motifs are most commonly observed in proteins comprising components of the basal lamina and extracellular matrixes and in cell adhesion molecules.

A large Costa Rican kindred has been identified with 15 males affected with congenital blindness, progressive bearing loss, and venous insufficiency. Due to ophthalmological and audio-otological findings, including bilateral retinal dysplasia and detachment, progressive bilateral sensorineural hearing loss, and an X-linked pattern of inheritance, a tentative diagnosis of Norrie disease was considered. However, venous insufficiency is a clinical finding not reportedly associated with Norrie disease. Genetic linkage analysis using microsatellite repeat markers demonstrated linkage to Xp11.23-11.4 (z = 2.723 at theta = 0.0). A candidate gene approach using the Norrie disease gene (NDP), which maps to Xp11.3, revealed a point mutation in the third exon resulting in substitution of phenylalanine for leucine at position 61. The precise function of the gene product, norrin, has yet to be elucidated; however, it has been postulated to be involved in the regulation of neural cell differentiation and proliferation, although hypotheses have been considered for its role in vascular development in the eye. The finding of a mutation in NDP in association with peripheral vascular disease may provide valuable insight into the potential role of this gene in cellular processes.