Molecular heterogeneity in two families with auditory pigmentary syndromes: the role of neuroimaging and genetic analysis in deafness

Abstract

We report two cases in which the probands presented with deafness and a family history of a dominantly inherited auditory pigmentary syndrome, yet the cause of deafness in each proband was not associated with the pigmentary abnormalities but was a result of mutations in SLC26A4, the gene mutated in Pendred's syndrome. The first case is a young woman with congenital sensorineural hearing loss and a family history of piebaldism. Despite showing no pigmentary abnormalities, the proband was found to harbor the same KIT mutation as her relatives affected by piebaldism, as well as two mutations in the SLC26A4 gene. In the second case, 2-year-old identical twin boys born to deaf parents presented with congenital sensorineural deafness and an extensive maternal family history of Waardenburg's syndrome type I (WSI). Their father had recessively inherited deafness associated with dilated vestibular aqueducts and a clinical diagnosis of Pendred's syndrome was made in him, which was confirmed molecularly. As the twin boys did not have features of WSI, both the mother and children were tested for mutations in SLC26A4 which showed the mother to be a carrier of a single mutation and both boys to be compound heterozygotes, illustrating pseudodominant inheritance of the condition.

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

“…Both mutated residues are conserved in all the mammalian orthologues, although the Glu at position 29 is not conserved in Danio rerio. The p.E29Q allele has been reported in two French patients 9,13 and in other three cases of unknown ethnic origin 11,20,24 and except in one patient, it is accompanied by a second mutation. The p.D724G mutation has only been described in one patient of unknown ethnic origin who also carried a second mutation, 20 as well as in our previously published Spanish family.…”

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

“…The two criteria used so far for assuming pathogenicity of mutations in the SLC26A4 gene are low incidence of the mutation in the control population and substitution of evolu- (5), (17), (22), (36), (37) (5), (17), † (22), (34), (35) …”

New KIT mutations in patients with piebaldism

“…Twenty-one missense mutations [3,[6][7][8][9][10][11][12][13][14][15] two nonsense mutations [9,14], five frameshift mutations [6,9,[16][17][18], four splice site mutations [9,14,16], one in-frame mutation [19], and various complete and partial large deletions [2,9,20] of the KIT gene have been reported in human piebaldism (Fig. 1).…”