Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome

Abstract

Mutations in myosin XVA are responsible for the shaker 2 (sh2) phenotype in mice and nonsyndromic autosomal recessive profound hearing loss DFNB3 on chromosome 17p11.2. We have ascertained seven families with profound congenital hearing loss from Pakistan and India with evidence of linkage to DFNB3 at 17p11.2. We report three novel homozygous mutations in MYO15A segregating in three of these families. In addition, one hemizygous missense mutation of MYO15A was found in one of eight Smith-Magenis syndrome (del(17)p11.2) patients from North America who had moderately severe sensorineural hearing loss.

Unmasking of a hemizygous WFS1 gene mutation by a chromosome 4p deletion of 8.3 Mb in a patient with Wolf–Hirschhorn syndrome

“…26,27 In addition, unmasking a recessive deafness allele in the MYO15A is associated with sensorineural deafness in a patient with Smith -Magenis syndrome carrying the common 17p11.2 deletion. 28 Here, we demonstrate for the first time that a similar combination of a deletion and a recessive mutation may explain complex phenotypes of certain patients with WHS or WFS. We propose that phenotypic variability among patients with similar deletion syndromes may in part be due to hemizygous expression of a recessive mutation on the non-deleted homologue.…”

Analysis and functional evaluation of the hair-cell transcriptome

“…Of these, four genes are known to be expressed in the zebrafish: cacna1d (9), cadherin 4 (10), parvalbumin 3a (11), and ribeye b (12). The hair-cell set also contains seven confirmed or candidate genes that, when mutated, cause syndromic or nonsyndromic deafness in humans or other vertebrates; these include cacna1d (13) and the genes encoding proteins similar to Otof (14), Pmca2 (15), SALL4 (16), Ush1c (17), USH1G (18), and MYO15A (19). By contrast, the supporting-cell markers claudin b (20), hes5 (21), and p27 kip1 (22) are not included in the hair-cell transcriptome.…”

Discovery of variants unmasked by hemizygous deletions

“…16,17,36 The latter may further increase the phenotypic variability among patients with disorders resulting from structural genome variations. 36 Of note is that in contrast to the patients selected for this study, most reports of unmasking hemizygosity in the literature describe patients who combine two distinct, recognizable syndromes or diseases, such as Prader Willi Syndrome + albinism, 45 Angelman Syndrome + albinism, 46 Smith Magenis Syndrome + sensorineural hearing loss, 47 or Wolf-Hirschhorn syndrome + Wolfram syndrome 48 (see also Supplementary Tables 1 and 2), which may relate to the frequency of the mechanism under study here.…”