Laboratory Issues

Over 70 coding allele variants of WFS1 have been reported, including synonymous and nonsynonymous changes.61 Many of these changes have been found in persons with DIDMOAD and DFNA6/14, and cosegregate with known disease-causing mutations. Those that have been detected in controls are likely to be benign polymorphisms, but the effect of other mutations (K193Q, L432V, L499F, G576S, A559T, A671V, A684V, R708C, R818C, D866N, V871M) on disease phenotype is more difficult to judge, as they have been described both as disease-causing mutations and as polymorphisms.59

BRANCHIO-OTO-RENAL-SYNDROME (EYA1) Molecular Basis of Disease

Mutations in EYA1 cause branchio-oto-renal (BOR) syndrome (OMIM #113650).65-69 Disease prevalence is estimated at 1 in 40,000 in the general population, and the syndrome is reported to occur in about 2% of profoundly deaf children.70 Clinical expression is highly variable within and among families, but typical manifestations include branchial arch anomalies (preauricular pits, branchial fistulae, and pinnae abnormalities), hearing loss (conductive, sensorineural, or mixed), and renal hypoplasia.71

Phenotypic features that occur in more than 20% of affected persons are classified as major. Hearing loss and preauricular pits are most prevalent, affecting approximately 90% and 80% of individuals, respectively. Branchial cleft fistulae (~50%), lop-ear deformity (~35%), and stenotic external auditory canals (~30%) also are common. Temporal bone abnormalities can be identified in most individuals with hearing impairment examined by computed tomography, and renal anomalies are identified in approximately 65% of individuals examined by ultrasound or excretory urography.71

Hearing loss is mixed (~50%), conductive (~25%), or sensorineural (~25%), and ranges from mild to profound, but is most commonly severe (~35%), and is progressive in approximately 25% of affected persons. Temporal bone abnormalities include stenosis and atresia of the external auditory canal, malformation, malposition, dislocation or fixation of the ossicles, and reduction in size or malformation of the middle ear cavity. In the inner ear, the most common anomaly is cochlear hypoplasia. Enlargement of the cochlear and vestibular aqueducts and hypoplasia of the lateral semicircular canal also are found. Major renal anomalies include agenesis (most common), hypoplasia, and dysplasia. Calyceal diverticula, ureteral pelvic junction obstruction, hydronephrosis, pelviectasis, calyectasis, and vesico-ureteral reflux also are seen.71

In some families, anticipation may appear to be present; however, a study of seven three-generational families assessed for anticipation yielded conflicting results. In four of these families, the degree of hearing loss showed anticipation, but in the remaining three, a generational loss did not occur.71 With respect to renal disease, generational progression was present in three families, but in one family, the reverse trend was found.71 There is also no evidence for a parent-of-origin effect. Marked renal defects have been reported in six live-born offspring (including bilateral renal agenesis in three individuals) who had affected fathers and in 4 live-born offspring of affected mothers.72-77 An excess of unexplained fetal deaths, presumably a consequence of bilateral renal agenesis, occurred in all of these families.

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