ir253c-T1

Table 1: Demographic and molecular characterization of the study cohort.

Patient

1

2

3

4

5

6

7

8

9

10

11

Gender and age

Female, 48 years

Female, 45 years

Female, 36 years

Female, 15 years

Male, 6 years

Female, 10 years

Male, 8 years

Female, 37 years

Female, 30 years

Male, 12 years

Female, 21 years

Gene/Locus

USH2A / 1q41

GJB2 / 13q12.11

MITF / 3p13

MYO7A / 11q13.5

ADGRV1 / 5q14.3

GJB2 / 13q12.11

PEX5 / 12p13.31

BSND / 1p32.3

CEACAM16 / 19q13.31

USH2A / 1q41

SLC26A4 / 7q22.3

Negative

ClinVar/ACMG criteria

Deletion

(Exons 22-50)

c.5278del (p.Asp1760Metfs*10)

Frameshift; Stop codon

c.109G>A (p.Val37Ile)

Missense

c.101T>C (p.Met34Thr)

SNV; Missense

c.34G>T (p.Gly12Cys)

SNV;

Missense

Deletion (complete coding sequence)

c.4117C>T (p.Arg1373*)

SNV; Nonsense

Stop codon

Deletion

(Exons 53-54)

c.15736C>T (p.Arg5246*)

c.516G>A (p.Trp172*)

nonsense

Stop codon

c.34G>T (p.Gly12Cys)

SNV; Missense

c.317-2A>G (Splice acceptor)

c.859G>T (p.Glu287*)

SNV; Nonsense

Stop codon

c.631C>T (p.Arg211Cys)

SNV; Missense

c.10993G>A (p.Gly3665Arg)

SNV; Missense

c.1061T>C (p.Phe354Ser)

Missense

Negative

Classification

PV

PV (Low penetrance)

PV

LP

VUS

Negative

Zygosity (Patient)

Compound Heterozygous

Heterozygous

Compound Heterozygous

Heterozygous

Probably

Trigenic

inheritance

Heterozygous

Negative

Associated Inheritance Pattern

AR pattern

• AR pattern

• AD pattern

• AR pattern

• AD pattern

AD pattern

AR pattern

AD pattern

AR pattern

AD pattern

AR pattern

Negative

Findings in Present Cohort

Bilateral

RE Moderate (47.5 dB)

LE moderately severe (61.25 dB)

No imaging studies

Ophthalmologic evaluation:

Pigmentary retinosis, severe myopia and astigmatism (R 20/80; L 20/100)

Bilateral sensorineural

RE complete loss (120 dB)

LE moderately severe (51.25 dB)

CT: The absence of the cisternal and intracanalicular portions of the right VIII cranial nerve + hypodevelopment of the internal auditory canal

Bilateral sensorineural

RE Moderate (47.5 dB)

LE moderate (41.25 dB)

No imaging studies

Bilateral

RE Deep (82.5 dB)

LE severe (76.25 dB)

CT scan without evidence of structural ear pathology

Bilateral sensorineural

RE complete loss (111.25 dB)

LE complete loss (106.25 dB)

CT scan without evidence of structural ear pathology

Bilateral sensorineural

RE complete loss (120 dB)

LE complete loss (120 dB)

CT: Hypoplasia and/or agenesis of the cochlear nerve, left cochlear implant.

MRI: In the right ear, no presence of the cochlear nerve is shown, but the inferior vestibular nerve is present. In the left ear, the cochlear nerve is not identified

Bilateral sensorineural

RE Severe (67.5 dB)

LE moderately severe (58.75 dB)

CT scan without evidence of structural ear pathology

Bilateral

RE moderately severe (56.25 dB)

LE severe (75 dB)

CT: Subluxation of left hammer-anvil joint

RE Severe (66 dB)

LE Normal (7.5 dB)

CT: Left labyrinthitis, vascular finding

Ophthalmologic evaluation:

No alterations

Bilateral

RE Deep (86.25 dB)

LE deep (81.25 dB)

CT scan without evidence of structural ear pathology

Bilateral

RE complete loss (120 dB)

LE complete loss (120 dB)

CT: Right tympanic glomus, probable adenoma at the pituitary level

Reported Phenotypes in literature

Exons 22-50 usually result in more severe phenotypes, with earlier visual impairment and more pronounced hearing impairment. (Varsome)

Exon 26, Truncating mutation. Reported as pathogenic in Usher syndrome cohorts. Causes loss of protein function17

Biallelic: Associated with progressive NSHL.

Monoallelic: Associated with DFNA3A or syndromic forms (skin disorders)5

Mild, progressive HL; low penetrance. Highly controversial variant. May act as a hypomorphic allele in compound heterozygosity. Normal hearing was also reported18

NSHL, characterized by moderate to profound hearing loss. With a high frequency in the heterozygous state among Hispanic/Mexican patients19

Congenital sensorineural deafness, usually bilateral, extensive depigmentation, similar to Waardenburg type 2A and Tietz syndrome.

Susceptibility to malignant melanoma.20

(OMIM)

Pathogenic variants in the MYO7A gene, responsible for Usher syndrome type 1B, may also manifest as NSHL with both AD and AR inheritance patterns15

The ADGRV1 gene is associated with autosomal recessive Usher syndrome type 2C, retinitis pigmentosa and nonsyndromic deafness. No specific clinical manifestations have been described in the literature about this variant (Varsome)

The c.15736C>T variant causes a loss of function by introducing a premature stop codon. In the homozygous state, this mutation is known to suggest Usher syndrome type 2C, which includes sensorineural hearing loss (Varsome)

Severe-to-profound congenital hearing loss21

NSHL, characterized by moderate to profound hearing loss. With a high frequency in the heterozygous state among Hispanic/Mexican patients19

The PEX5 gene causes autosomal recessive ZSD, a syndromic disorder that involves deafness22

BSND is the causative gene for DFNB73 (NSHL), but mutations are also known to cause Bartter syndrome type IV. The HL phenotype may be accompanied by subclinical renal metabolic changes23

Bilateral NSHL with early onset and progressive course24

The available evidence is currently insufficient to determine the role of this variant in disease (Varsome)

Associated with NSHL and Pendred’s syndrome, also reported in autoimmune thyroid diseases25

Negative

ACMG = American College of Medical Genetics and Genomics.

AD = autosomal dominant.

AR = autosomal recessive.

Cx26 = Connexin 26.

HL = hearing loss.

LE = left ear.

LP = like pathogenic.

NSHL = non-syndromic hearing loss.

PV = pathogenic variant.

RE = right ear.

SNV = Single Nucleotide Variant.

VUS = Variant of Uncertain Significance.

ZSD = Zellweger spectrum disorder.

Demographic characteristics and study findings of the patient cohort.

* Stop codon.