Mutation analysis of theSLC26A4,FOXI1andKCNJ10genes in individuals with congenital hearing loss

Abstract

Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of sensorineural hearing loss disorders that typically result from biallelic mutations of the SLC26A4 gene. Although PDS and DFNB4 are recessively inherited, sequencing of the coding regions and splice sites of SLC26A4 in individuals suspected to be affected with these conditions often fails to identify two mutations. We investigated the potential contribution of large SLC26A4 deletions and duplications to sensorineural hearing loss (SNHL) by screening 107 probands with one known SLC26A4 mutation by Multiplex Ligation-dependent Probe Amplification (MLPA). A heterozygous deletion, spanning exons 4–6, was detected in only one individual, accounting for approximately 1% of the missing mutations in our cohort. This low frequency is consistent with previously published MLPA results. We also examined the potential involvement of digenic inheritance in PDS/DFNB4 by sequencing the coding regions of FOXI1 and KCNJ10. Of the 29 probands who were sequenced, three carried nonsynonymous variants including one novel sequence change in FOXI1 and two polymorphisms in KCNJ10. We performed a review of prior studies and, in conjunction with our current data, conclude that the frequency of FOXI1 (1.4%) and KCNJ10 (3.6%) variants in PDS/DFNB4 individuals is low. Our results, in combination with previously published reports, indicate that large SLC26A4 deletions and duplications as well as mutations of FOXI1 and KCNJ10 play limited roles in the pathogenesis of SNHL and suggest that other genetic factors likely contribute to the phenotype.

Functional Testing of SLC26A4 Variants—Clinical and Molecular Analysis of a Cohort with Enlarged Vestibular Aqueduct from Austria

“…FOXI1 (OMIM #601093) is a transcription factor for SLC26A4 [ 52 , 53 ], and KCNJ10 (OMIM #602208) is an inwardly rectifying K + channel essential for the maintenance of the endocochlear potential [ 54 ]. Although later studies showed that sequence alterations in FOXI1 or KCNJ10 are rare in the context of PS/non-syndromic EVA [ 55 , 56 , 57 , 58 ], analysis of these genes may be of value in individuals with monoallelic pathogenic SLC26A4 sequence alterations.…”

Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family

“…PDS is a complex genetic disease which may be inherited monogenically or digenically [ 4 , 9 – 11 ]. It has been well documented that biallelic mutations in SLC26A4 (MIM #605646) is the hallmark of PDS, with a frequency of 25% [ 4 , 9 ].…”

“…PDS is a complex genetic disease which may be inherited monogenically or digenically [ 4 , 9 – 11 ]. It has been well documented that biallelic mutations in SLC26A4 (MIM #605646) is the hallmark of PDS, with a frequency of 25% [ 4 , 9 ]. Clinically, SLC26A4 mutation has been used as genetic test to differentiate between PDS and non-syndromic familial EVA, which otherwise would not be possible to clinically distinguish, even with perchlorate discharge test [ 6 , 12 ].…”

“…However, nearly 50% probands harboured only monoallelic mutation in SLC26A4 , and for some patients, PDS is not due to S LC26A4 gene mutations [ 4 ]. The discovery of the involvement of other deafness genes, including FOXI1 (MIM #601093), KCNJ10 (MIM # 602208) and GJB2 (MIM #121011) [ 9 – 11 ] in combination with SLC26A4 monoallelic mutation has proposed the existence of digenic inheritance pattern in PDS and EVA. The complexity of the genetic defects attributed to PDS suggests that a comprehensive mutational screening is warranted to identify the disease causal genes.…”

Caratterizzazione della mutazione SLC26A4 c.918+2T>C e report di una nuova variante potenzialmente a rischio

“…The clinical features observed in PS typically result from biallelic (homozygote/compound heterozygote) mutations in the SLC26A4 gene. According to the Human Gene Mutation Database more than 260 mutations in the SLC26A4 gene have been identified to date 5 , including splice site aberrations, frame shift and nonsense mutations, as well as large deletions (rare cases) and a relatively common mutation, c.-103 T > C, in a regulatory element of the promoter region of the SLC26A4 gene 6 7 . The mutation spectrum of SLC26A4 varies widely among ethnic groups, with certain mutations demonstrating a higher prevalence in specific populations 8-11 .…”