Limits...
Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population

View Article: PubMed Central - PubMed

ABSTRACT

Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.

No MeSH data available.


Related in: MedlinePlus

Family pedigree and audiological phenotype of families with causative mutations in SLC26A4 or GJB2.(a) The family pedigree of a representative patient with sporadic congenital hearing loss (YUEVA67) from among twelve patients with bi-allelic mutations of SLC26A4 is shown. The estimated thresholds for auditory steady-state response (ASSR) are >90 dB HL at 500, 1000, 2000, and 4000 Hz (red color, right ear; blue color, left ear). Internal auditory canal magnetic resonance imaging and temporal bone computed tomography images reveal bilateral enlarged vestibular aqueduct and endolymphatic sac. (b) The family pedigree and ASSR findings of a representative patient with sporadic congenital hearing loss (YUHL19-21) from among three patients with bi-allelic mutations of GJB2 are depicted. YUHL, Yonsei University hearing loss; YUEVA, Yonsei University enlarged vestibular aqueduct.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5382691&req=5

f1: Family pedigree and audiological phenotype of families with causative mutations in SLC26A4 or GJB2.(a) The family pedigree of a representative patient with sporadic congenital hearing loss (YUEVA67) from among twelve patients with bi-allelic mutations of SLC26A4 is shown. The estimated thresholds for auditory steady-state response (ASSR) are >90 dB HL at 500, 1000, 2000, and 4000 Hz (red color, right ear; blue color, left ear). Internal auditory canal magnetic resonance imaging and temporal bone computed tomography images reveal bilateral enlarged vestibular aqueduct and endolymphatic sac. (b) The family pedigree and ASSR findings of a representative patient with sporadic congenital hearing loss (YUHL19-21) from among three patients with bi-allelic mutations of GJB2 are depicted. YUHL, Yonsei University hearing loss; YUEVA, Yonsei University enlarged vestibular aqueduct.

Mentions: This study included 28 unrelated children (male, 15; female, 13; mean age, 2.6 ± 1.8 years; age range, 8–70 months) with sporadic severe-to-profound NSHL and without syndromic features or familial history of hearing impairment. The average thresholds for ASSR in the right and left ears were 103.0 ± 24.5 dB and 97.4 ± 23.0 dB, respectively. Of the 28 children, 12 exhibited EVA and/or Mondini’s deformity (cochlear anomaly where the cochlea has only 1.5 turns), representing DFNB4 hearing impairment with bi-allelic mutations in SLC26A4 (Fig. 1a). Direct Sanger sequencing for all of the exons of SLC26A4 revealed bi-allelic mutations in SLC26A4 in all 12 of these subjects (Table 1); one of the subjects, Yonsei University enlarged vestibular aqueduct (YUEVA)-65, exhibited a novel variant—a nonsense mutation of p.Y27*. Apart from EVA and/or Mondini’s deformity, these subjects exhibited no other anatomical inner/middle ear anomalies. Direct Sanger sequencing for GJB2 in the 16 children without EVA revealed pathogenic bi-allelic mutations in GJB2 in 3 subjects (Fig. 1b and Table 1).


Genetic Predisposition to Sporadic Congenital Hearing Loss in a Pediatric Population
Family pedigree and audiological phenotype of families with causative mutations in SLC26A4 or GJB2.(a) The family pedigree of a representative patient with sporadic congenital hearing loss (YUEVA67) from among twelve patients with bi-allelic mutations of SLC26A4 is shown. The estimated thresholds for auditory steady-state response (ASSR) are >90 dB HL at 500, 1000, 2000, and 4000 Hz (red color, right ear; blue color, left ear). Internal auditory canal magnetic resonance imaging and temporal bone computed tomography images reveal bilateral enlarged vestibular aqueduct and endolymphatic sac. (b) The family pedigree and ASSR findings of a representative patient with sporadic congenital hearing loss (YUHL19-21) from among three patients with bi-allelic mutations of GJB2 are depicted. YUHL, Yonsei University hearing loss; YUEVA, Yonsei University enlarged vestibular aqueduct.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382691&req=5

f1: Family pedigree and audiological phenotype of families with causative mutations in SLC26A4 or GJB2.(a) The family pedigree of a representative patient with sporadic congenital hearing loss (YUEVA67) from among twelve patients with bi-allelic mutations of SLC26A4 is shown. The estimated thresholds for auditory steady-state response (ASSR) are >90 dB HL at 500, 1000, 2000, and 4000 Hz (red color, right ear; blue color, left ear). Internal auditory canal magnetic resonance imaging and temporal bone computed tomography images reveal bilateral enlarged vestibular aqueduct and endolymphatic sac. (b) The family pedigree and ASSR findings of a representative patient with sporadic congenital hearing loss (YUHL19-21) from among three patients with bi-allelic mutations of GJB2 are depicted. YUHL, Yonsei University hearing loss; YUEVA, Yonsei University enlarged vestibular aqueduct.
Mentions: This study included 28 unrelated children (male, 15; female, 13; mean age, 2.6 ± 1.8 years; age range, 8–70 months) with sporadic severe-to-profound NSHL and without syndromic features or familial history of hearing impairment. The average thresholds for ASSR in the right and left ears were 103.0 ± 24.5 dB and 97.4 ± 23.0 dB, respectively. Of the 28 children, 12 exhibited EVA and/or Mondini’s deformity (cochlear anomaly where the cochlea has only 1.5 turns), representing DFNB4 hearing impairment with bi-allelic mutations in SLC26A4 (Fig. 1a). Direct Sanger sequencing for all of the exons of SLC26A4 revealed bi-allelic mutations in SLC26A4 in all 12 of these subjects (Table 1); one of the subjects, Yonsei University enlarged vestibular aqueduct (YUEVA)-65, exhibited a novel variant—a nonsense mutation of p.Y27*. Apart from EVA and/or Mondini’s deformity, these subjects exhibited no other anatomical inner/middle ear anomalies. Direct Sanger sequencing for GJB2 in the 16 children without EVA revealed pathogenic bi-allelic mutations in GJB2 in 3 subjects (Fig. 1b and Table 1).

View Article: PubMed Central - PubMed

ABSTRACT

Discriminating between inherited and non-inherited sporadic hearing loss is challenging. Here, we attempted to delineate genetic inheritance in simplex cases of severe-to-profound congenital hearing loss in Korean children. Variations in SLC26A4 and GJB2 in 28 children with bilateral severe-to-profound non-syndromic hearing loss (NSHL) without familial history were analyzed using Sanger sequencing. Genetic analysis of individuals without mutations in SLC26A4 and GJB2 was performed by whole exome sequencing (WES). Bi-allelic mutations in SLC26A4 and GJB2 were identified in 12 and 3 subjects, respectively. Of the 13 individuals without mutations in SLC26A4 and GJB2, 2 and 1 carried compound heterozygous mutations in MYO15A and CDH23, respectively. Thus, 64.3% (18/28) of individuals with NSHL were determined to be genetically predisposed. Individuals with sporadic severe-to-profound NSHL were found to mostly exhibit an autosomal recessive inheritance pattern. Novel causative candidate genes for NSHL were identified by analysis of WES data of 10 families without mutations in known causative genes. Bi-allelic mutations predisposing to NSHL were identified in 64.3% of subjects with sporadic severe-to-profound NSHL. Given that several causative genes for NSHL are still unidentified, genetic inheritance of sporadic congenital hearing loss could be more common than that indicated by our results.

No MeSH data available.


Related in: MedlinePlus