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Abstract

Importance

The genetic variation in patients with sensorineural hearing loss (SNHL) in the Nordic countries has not been previously reported.

Objectives

The aim was to describe the genetic variation in a Swedish population and identify factors in favor of a high diagnostic yield.

Design

This was a prospective cohort study. Children with bilateral SNHL and adults with bilateral SNHL and clinically suspected genetic SNHL underwent genetic testing. A gene panel with ~200 genes was applied on whole genome sequencing (WGS) data. Variants were classified according to American College of Medical Genetics and Genomics criteria. Personal health data were extracted from medical records.

Setting and Participants

Eighty-five patients (aged 0-73 years) from Lund and Örebro University Hospitals, 2 tertiary referral centers for audiology in Sweden, with mild to profound SNHL.

Results

In almost half (45%, n = 38) of the cases, a genetic cause was identified across 24 different genes. Eleven cases had syndromic hearing loss. A majority (n = 57) had prelingual onset (<2 years) of SNHL and most of them had moderate-to-profound hearing loss (n = 52). Prelingual onset was associated with higher yield than postlingual onset (OR 6.3, 95% CI 2.1-19.0). In patients with moderate—profound prelingual SNHL, the diagnostic yield was 60% (n = 31/52).

Conclusion

This is the first reported cohort of hearing loss patients undergoing genetic testing with WGS from a Nordic country. Early onset of hearing loss favored a higher diagnostic yield than postlingual, and a genetic cause was found in a majority of cases in patients with prelingual, moderate-to-profound SNHL.

Graphical Abstract

Keywords

genetic hearing loss whole genome sequencing pathological variants prelingual SNHL diagnostic yield

Key Message

The first Nordic study of genetic variation among patients with sensorineural hearing loss (SNHL).

A majority of cases with moderate-to-profound SNHL had a genetic cause.

Diagnostic yield was highest in patients with early onset of hearing loss.

Introduction

Genetic Investigation of Hearing Loss

Sensorineural hearing loss (SNHL) is the most common sensory deficit in newborns and the prevalence increases with age.¹ Genetic variation is the most prevalent cause of SNHL in children, both in isolated and syndromic cases.^2-10 The most frequent syndromes, with SNHL as part of the symptom combination, are Pendred syndrome, with inner ear malformations and goiter¹¹ and Usher syndrome, with visual loss due to retinitis pigmentosa (RP) and vestibular impairment.¹² Usher syndrome is related to variants in 9 confirmed causative genes, and in several genes (such as MYO7A, USH1C, CDH23, and PCDH15), either related to isolated SNHL or concomitant progressive visual loss with RP. RP in young children is investigated with electroretinography (ERG) under general anesthesia.^13-16

In recent years, massive parallel sequencing is increasingly used for investigating SNHL with unknown cause¹⁷ (exome or genome sequencing). A gene panel including genes relevant for hearing is then applied, to filter the vast amount of data and facilitate the analysis.

Hearing loss is defined by WHO, based on hearing threshold on a pure-tone audiogram, as >20 dB hearing loss (HL) based on four-frequency (0.5, 1, 2, and 4 kHz) pure-tone average (4fPTA) and varies from mild to profound.¹⁸ Hearing loss can be conductive or sensorineural. Age of onset of hearing loss is often defined in relation to normal age for development of spoken language and can broadly be classified as pre- or postlingual.

Consanguinity within the family is uncommon in contemporary Swedish society, but in some immigrant communities, partnership with a cousin or other relative is within the cultural norm. This is relevant for SNHL as the risk of autosomal recessive traits being biallelic is increased in families with a common genetic background. According to the official statistic governmental agency, Statistics Sweden,¹⁹ 30% of the inhabitants in the regions of Sweden from which the current cohort was recruited (Skåne and Örebro) are either born, or have both parents born in a foreign country. Country of origin is not defined in this register.

In a study from Belgium in 2023, the diagnostic yield was 39% in 238 probands with congenital or late onset bilateral SNHL.²⁰ Similar findings were reported from the Netherlands in 2017 with 33.5% diagnostic yield in 200 probands with hearing impairment.⁷ In a study from Germany in 2022, the diagnostic yield was 25%, but in this study, a large proportion of adults with hearing loss was included.⁹ To our knowledge, no similar studies have been presented from Sweden or the Nordic countries.

The aims of this study were to describe (i) the genetic variation related to SNHL in a Swedish population and (ii) to identify the patient groups who would most benefit from genetic testing, in terms of diagnostic yield, depending on SNHL severity and time of onset.

Materials and Methods

As part of a clinical visit, probands with bilateral mild-to-profound SNHL (hearing threshold >25 dB HL) with unknown cause, were enrolled between July 2020 to December 2022 at 2 tertiary audiological referral centers in Sweden (Örebro University Hospital and Skåne University Hospital in Lund). Of 111 consented subjects, 85 provided venous blood from which DNA was extracted and whole genome sequencing (WGS) performed. Only data from the participants who underwent WGS were analyzed. Fifty-one patients were recruited from Skåne University Hospital and 34 patients from Örebro University Hospital. The patients from Lund had prelingual SNHL in 73% (n = 37/51) and from Örebro 62% (n = 21/34) of the cases. Children with an obvious clinical appearance of a syndrome were referred to a pediatrician for assessment and investigation and were not included in the study.

The study was approved by the Swedish Ethical Review Authority (Dnr 2018/282). After verbal and written information, the legal caregivers for children, or the proband, if they were adults, provided written consent.

Audiological Testing

The audiological examination was performed according to age-appropriate clinical procedures. Otoacoustic emission, auditory brainstem response, auditory steady-state response, and electrocochleography as well as subjective methods, visual reinforcement audiometry, conditioned play audiometry, or conventional pure-tone audiometry, when possible (in older children and adults), were used. SNHL was graded as mild (21-40 dB HL), moderate (41-60 dB HL), severe (61-80 dB HL), or profound (>80 dB HL) based on 4fPTA according to the WHO definition from 1991.²¹ The updated definition recommended by the Global Burden of Disease Expert Group on Hearing Loss¹⁸ is not validated for children.²² SNHL diagnosed before 2 years of age was defined as prelingual hearing loss.

Demographic and Clinical Data

A clinical research form including sex, age at SNHL diagnosis, degree and type of hearing loss, number of siblings with and without SNHL, and parental hearing loss status was completed when referral was made for genetic testing. Complementary personal data included parents’ self-reported country or region of birth, consanguinity, comorbidity, and vestibular findings; clinical examination and video head impulse test as previously described in Elander et al²³ were extracted from the medical records.

WGS and Hearing Loss Panel

DNA was sequenced (NovaSeq 6000, Illumina, USA) with an average read depth of 30×. The resulting files were run using an in-house bioinformatic pipeline (https://github.com/Clinical-Genomics-Lund/nextflow_wgs). Analysis of the mitochondrial genome (mtDNA) was added to the pipeline in May 2021. Variants [single-nucleotide variants, indels, copy number variants (CNVs)] were scored and ranked, based on the attributed information and uploaded to the main interpretation tool Scout (https://clinical-genomics.github.io/scout). Variants within genes in the current gene panel (HearSeq) as well as in mtDNA were interpreted in Scout, with support from Alamut (https://www.sophiagenetics.com/platform/alamut-visual-plus), Integrative Genomics Viewer (https://software.broadinstitute.org/software/igv) and locally developed visualization tools (https://github.com/Clinical-Genomics-Lund/gens). A genomewide CNV-analysis was performed to detect any larger CNVs. Furthermore, pathogenic variants in the ClinVar database outside the gene panel were assessed and reported if relevant for the clinical indication. For protein prediction for missense variants Align GVGD, MutationTaster, Polyphen-2 and SIFT were used. The ranking model included scores from CADD (for missense variants and indels), Polyphen and SIFT (for missense variants), and MaxEntScan (for splicing variants). All variants were classified according to the American College of Medical Genetics and Genomics standards and guidelines for interpretation of sequence variants.^24-26 In this report, if not explicitly specified, likely pathogenic (class 4) and pathogenic (class 5) variants are collectively described as pathogenic variants (PVs). Variants of uncertain significance (VUS) were not regarded as sufficient for diagnosis, even in autosomal recessive compound heterozygous cases with 1 PV in trans. The classification of inheritance pattern, autosomal recessive or autosomal dominant, was based on genetic diagnosis.

The gene panel HearSeq, developed at Skåne University Hospital in Sweden, was used and updated twice during the study. The initial gene panel (version 4.0) included 179 genes, whereas the next version 6.0 (updated 05-07-2021), included 196 genes and version 7.0 (updated 20-09-2022) included 201 genes.²⁷ The HearSeq panel includes genes related to isolated hearing loss and genes related to syndromic SNHL, where SNHL can be the first presenting symptom (Supplemental Table 1).

Statistical Analyses

Descriptive analyses of the data were performed for sex, degree of SNHL, age of onset of SNHL, origin, and heredity. Chi-square test was used to identify associations between genetic diagnostic yield and subgroups, both regarding degree of hearing loss and time of onset. The analysis was complemented with multinominal logistic regression analysis with profound SNHL as reference, to create a model of relationship between the predictor variable and the subgroups, and to analyze if time of onset was a confounder. The SNHL subgroups were compared separately with Fisher’s exact test. All analyses and calculations were executed in IBM SPSS Statistics, USA (version 29.0.0.0).

Results

Demographic Data

Fifty-seven probands (67%) had a prelingual SNHL. Age of onset of SNHL diagnosis varied from neonatal to 30 years of age. There was a preponderance of females (n = 51) versus males (n = 34). Degree of SNHL varied from mild (14%) to moderate (28%), severe (11%), and profound (47%) among the patients who underwent genetic testing (Figure 1).

Figure 1.

Flowchart showing all patients in the study and the genetic result at the gene level grouped by severity of sensorineural hearing loss (SNHL).

Most of the patients were otherwise healthy (68%). The dominating comorbidity was vestibular dysfunction (11%). Intellectual disability was found in 6% of the cases (Table 1).

Table 1.

Demographic Variables.

Degree of hearing loss	Mild (n = 12)	Moderate (n = 24)	Severe (n = 9)	Profound (n = 40)	Total (n = 85)
Sex (female:male), n	8:4	19:5	5:4	19:21	51:34
Genetic diagnosis, total, n (%)	1 (8%)	10 (42%)	6 (67%)	21 (53%)	38 (45%)
Genetic diagnosis, prelingual, n (%)	0	8 (33%)	5 (55.5%)	18 (45%)	31 (36%)
Genetic diagnosis, postlingual, n (%)	1 (8%)	2 (8%)	1 (11%)	3 (7.5%)	7 (8%)
Age at onset of SNHL
Median years (min.-max.)	1.5 (0-16)	0 (0-15)	2.25 (0-5)	0 (0-30)	0 (0-30)
Prelingual, <2 years, n (%)	5 (42%)	15 (63%)	5 (56%)	32 (80%)	57 (67%)
Postlingual
Preschool age, 2-5 years, n (%)	2 (17%)	3 (13%)	4 (44%)	4 (10%)	13 (15%)
School age, 6-12 years, n (%)	0	2 (8%)	0	3 (7.5%)	5 (6%)
Teenager, 13-19 years, n (%)	2 (17%)	2 (8%)	0	0	4 (5%)
Young adult, 20-29 years n (%)	1 (8%)	0	0	0	1 (1%)
Adult, 30 years, n (%)	2 (17%)	2 (8%)	0	1 (2.5%)	5(6%)
Age when genetic test
Median years (min.-max.)	11 (1-44)	10.5 (0.6-73)	4.5 (0.5-44)	3 (0.2-47)	6.75 (0.2-73)
<2 years when tested, n (%)	5 (42%)	5 (21%)	3 (33%)	17 (43%)	30 (35%)
≥2 years when tested, n (%)	7 (58%)	19 (79%)	6 (67 %)	23 (57%)	55 (65%)
Origin, n (%)
Sweden	8 (67%)	18 (75%)	3 (33%)	20 (50%)	49 (58%)
Rest of Europe	1 (8%)	0	3¹ (33%)	6 (15%)	10¹ (12%)
Middle East	2 (17%)	5 (21%)	2 (22%)	14 (35%)	23 (27%)
Other parts of the world	1 (8%)	1 (4%)	1 (11%)	0	3 (3%)
Comorbidity, n (%)
Healthy	9 (75%)	13 (54%)	9 (100%)	26 (65%)	58 (68%)
Vestibular symptoms or findings	1 (8%)	3 (13%)	0	5 (12.5%)	9 (11%)
Intellectual disability	0	3 (13%)	0	2 (5%)	5 (6%)
Heart disease	0	1 (4%)	0	1 (2.5%)	2 (2%)
Visual impairment	0	0	0	2 (5%)	2 (2%)
Other symptoms and anomalies²	2 (17%)	4 (17%)	0	4 (10%)	10 (12%)

Abbreviation: SNHL, sensorineural hearing loss.

Including a child with one parent from Norway and one from Tunisia.

Renal dysfunction, asthma, migraine, growth hormone therapy, facial anomalies, Mondini malformation and large vestibular aqueduct syndrome (LVAS), Down syndrome, suspected Cogan’s syndrome.

The majority had parents born in Sweden (58%, n = 49), while 27% (n = 23) had parents born in the Middle East (Syria = 6, Iraq = 6, Lebanon = 2, Turkey = 2, Afghanistan = 1, Palestine = 1, Kurd = 1, Arabic spoken, but country not specified = 3). In 1 family, 1 parent originated from Jordan and the other parent from Lebanon. Twelve percent of probands (n = 10) had parents from Europe outside of Sweden, and in 3 cases, parents originated from elsewhere in the world (India, China, and Eritrea). One child had 1 parent originating in Scandinavia and the other parent from North Africa. Consanguinity was not systematically documented but reported when documented in the medical records. More than half of the parents from the Middle East (n = 12) were documented relatives and in 10 cases, cousins. Parents of 1 child from East Africa were cousins.

Genetic Diagnostic Yield in Relation to Degree and Time of Onset of Hearing Loss

The overall genetic diagnostic yield was 45% with PVs reported in 38 probands and found in 24 different genes (Figure 2).

Figure 2.

Genes with variants related to sensorineural hearing loss (SNHL).

Twenty-seven patients (32%) with identified PVs had isolated SNHL. Eleven (13%) had syndromic SNHL. A vast majority of the patients with PVs (n = 34) had an autosomal recessive inheritance pattern and 21 were homozygous. The diagnostic yield in mild, moderate, severe, and profound SNHL groups was 8%, 42%, 67%, and 53%, respectively (Figure 3A).

Figure 3.

(A) Genetic verified diagnosis related to degree of sensorineural hearing loss (SNHL). (B) Genetic verified diagnosis related to age of onset of SNHL.

Chi-square test (linear-by-linear association) showed a significant difference in genetic diagnostic yield between SNHL subgroups (P < .01) and time of onset (P < .001). Logistic regression analysis, with verified genetic diagnosis as a dependent variable and SNHL subgroups as an independent variable with profound SNHL as reference, revealed a significant low odds ratio, OR = 0.08 (95% CI 0.01-0.7) (Figure 3A) in the mild SNHL group compared to the profound SNHL group. For moderate (OR = 0.6, 95% CI 0.2-1.8) and severe (OR = 1.8, 95% CI 0.4-8.3) SNHL, the odds were not significantly different from the profound hearing loss group. The odds ratio for a prelingual onset were high (OR = 6.3, 95% CI 2.1-19.0). When SNHL subgroups were adjusted in the regression model for time of onset, the difference in genetic findings between mild SNHL and the reference group was no longer statistically significant (OR = 0.1, 95% CI 0.01-1.1). However, regarding prelingual onset, a significantly higher diagnostic yield (OR = 6.6, 95% CI 1.9-22.6) remained after adjustment (Table 2B). In addition, the different subgroups were compared separately using the Fisher’s exact test, revealing a significant difference between mild and severe SNHL (P = .02) and between mild and profound SNHL (P = .01), respectively (Table 2A).

Table 2.

Comparison of genetic yield in subgroups of sensorineural hearing loss.

(A) Comparison of Ratio of Patients Receiving a Genetic Diagnosis Between SNHL Severity Sub-Groups, Calculated with Fisher’s Exact Test: Exact Sig. (2-sided)
	Mild	Moderate	Severe	Profound
Mild		P = .6	P = .02	P = .01
Moderate			P = .3	P = .5
Severe				P = .5
(B) Logistic Regression Analyzes of Predictors Affecting Odds of Patients with SNHL Receiving a Genetic Diagnosis. There is an increased OR in receiving genetic diagnosis in prelingual SNHL in both the unadjusted and adjusted model
	Unadjusted, OR (95% CI)		Adjusted, OR (95% CI)
Severity of hearing loss
Mild	0.1 (0.01-0.7)		0.1 (0.01-1.1)
Moderate	0.6 (0.2-1.8)		0.8 (0.3-2.6)
Severe	1.8 (0.4-8.3)		3.4 (0.6-19.8)
Profound (ref)
Time of onset
Prelingual	6.3 (2.1-19.0)		6.6 (1.9-22.6)
Postlingual (ref)

Prelingual SNHL dominated with 67% versus 33% with a postlingual onset. A verified genetic diagnosis was found in 54% (n = 31/57) of the probands with prelingual, and in 25% (n = 7/28) of the probands with postlingual SNHL (Figure 3B). In patients with moderate-to-profound prelingual hearing loss the diagnostic yield was 60% (n = 31/52).

Mild-to-Profound SNHL

One child (nr 1) (8%) out of 12 patients with mild SNHL had compound heterozygous PVs in MYO7A, but no retinal changes could be identified at 7 years of age (Table 3A). This child had a younger sibling (not regarded as proband) with similar hearing loss, who had the same, previously described,^28,29 compound heterozygous variants in trans. The child is not yet tested with ERG.

Table 3.

Patients With Verified Genetic Diagnosis.

Patient number	Age at hearing loss diagnosis	ACMG criteria	Inheritance; variant type(s) and gene	Variants	4fPTA (right/left ear)	Isolated or syndromic SNHL	Comorbidity	Heredity, hearing loss in family and parents’ country of birth
(A) Mild hearing loss (21-40 dB HL)
1	4 y	4	AR; heterozygous in4-frame indel variant in MYO7A	NM_000260.4(MYO7A):c.4544_4551delinsCA;p.(Glu1515_Met1517delinsAla)	4fPTA38/34	Isolated SNHL	ERG without retinal changes	1(2) younger sibling has mild SNHL (ERG not preformed)Sweden
1	4 y	4	heterozygous missense variant in MYO7A	NM_000260.4(MYO7A):c.5494C>T;p.(Arg1832Trp)	4fPTA38/34	Isolated SNHL	ERG without retinal changes
(B) Moderate hearing loss (41-60 dB HL)
13	3 mo	5	AR; homozygous deletion including the STRC and CATSPER2 genes	seq[GRCh38] 15q15.3(43596411_43659185)x0	4fPTA41/46	Isolated SNHL		Sweden
14	<1 y	5	AR; homozygous deletion including exon 19–29 of STRC	seq[GRCh38] 15q15.3(43596411_43605610)x0	4fPTA43/43	Isolated SNHL	Migraine	Sweden
15	3 mo	5	AR; heterozygous deletion including STRC	seq[GRCh38] 15q15.3(43580201_43681200)x1	4fPTA43/45	Isolated SNHL	Autism, language disorder	Sweden
15	3 mo	5	heterozygous frameshift variant in STRC	NM_153700.2(STRC):c.2171_2174del;p.(Val724Glyfs*6)	4fPTA43/45	Isolated SNHL	Autism, language disorder	Sweden
16	2 mo	5	AR; homozygous splice variant in CABP2	NM_016366.3(CABP2):c.637+1G>T;p.?	ABR55/55	Isolated SNHL		Parents are cousins1(2) sibling has SNHLIraq
17	<1 y	5	AR; homozygous deletion including exon 19-29 of STRC	seq[GRCh38] 15q15.3(43596601_43605900)x0	4fPTA38/43	Isolated SNHL	Treated with growth hormone	1(1) sibling has SNHLSweden
18	3 mo	5	AR; heterozygous deletion including exon 22-32 of USH2A	seq[GRCh38] 1q41(216037606_216127696)x1	4fPTA53/58	Usher syndrome type 2A		Sweden
18	3 mo	5	heterozygous splice variant in USH2A	NM_206933.4(USH2A):c.9371+1G>C;p.?	4fPTA53/58	Usher syndrome type 2A		Sweden
19	1.5 y	4	AR; homozygous nonsense variant in COL11A2	NM_080680.3(COL11A2):c.4798C>T;p.(Arg1600*)	ABR55/55	Stickler syndrome type III		Parents are relativesSyria
20	<1 y	4	AR; heterozygous missense variant in SLC26A4	NM_000441.2(SLC26A4):c.1574C>T;p.(Pro525Leu)	ABR60/60	Pendred syndrome	Follow up by pediatrician regarding thyroid status	Lebanon
20	<1 y	4	heterozygous deletion encompassing exon 4-6 of SLC26A4	seq[GRCh38] 7q22.3(107668671_107682230)x1	ABR60/60	Pendred syndrome	Follow up by pediatrician regarding thyroid status	Lebanon
21	<1 y	5	AD; heterozygous frameshift variant in ANKRD11	NM_013275.6(ANKRD11):c.6031_6041del;p.(Ser2011Valfs*17)	4fPTA40/41(air)5/13 (bone)	KBG syndrome	Conductive hearing loss. Abnormal ossicular chain.Seizures at 8 y. Velopharyngeal insufficiency	Sweden
22	11 y	5	AD; heterozygous deletion including the FOXC1 gene	seq[GRCh38] 6p25.3p25.2(150701_3298100)x1	4fPTA39/49	Axenfeld-Rieger syndrome	Intellectual disability, glaucoma	Syria
(C) Severe hearing loss (61-80 dB HL)
37	1 y	4	AR; homozygous frameshift variant i TECTA	NM_005422.4(TECTA):c.4147_4150del;p.(Val1384Alafs*10)	4fPTA70/70	Isolated SNHL		Parents are cousins2(3) siblings have SNHLSyria
38	1 mo	4	AR; homozygous missense variant in MYO7A	NM_000260.4(MYO7A):c.287C>T;p.(Thr96Met)	ASSR65-70	Isolated SNHL	ERG without retinal changes	1(2) sibling has SNHLKosovo
39	4 y	4	AD; heterozygous frameshift variant in MYO6	NM_004999.4(MYO6):c.2751del;p.(Lys917Asnfs*10)	4fPTA64/73	Isolated SNHL		Father and 1(3) sibling has SNHLSweden
40	1 mo	4	AR; homozygous frameshift variant in LOXHD1	NM_001384474.1(LOXHD1):c.71del;p.(Leu24Argfs*74)	ABR70/70	Isolated SNHL		Parents are cousins1(4) sibling has SNHLAfganistan
41	2 mo	5	AR; homozygous nonsense variant in TRIOBP	NM_001039141.3(TRIOBP):c.1039C>T;p.(Arg347*)	ABR60/60	Isolated SNHL		Parents are cousins, one uncle deaf1(1) sibling has SNHLEritrea
Patient number	Age at hearing loss diagnosis	ACMG criteria	Inheritance; variant type(s) and gene	Variants	4fPTA (right/left ear)	Isolated or syndromic SNHL	Comorbidity	Heredity, hearing loss in family and parents’ country of birth
(D) Profound hearing loss (>80 dB HL)
42	1 mo	5	AR; heterozygous frameshift variant in GJB2	NM_004004.6(GJB2):c.35del;p.(Gly12Valfs*2)	4fPTA73/63	Isolated SNHL		Sweden
42	1 mo	5	heterozygous missense variant in GJB2	NM_004004.6(GJB2):c.94C>T;p.(Arg32Cys)	4fPTA73/63	Isolated SNHL		Sweden
46	2 mo	5	AR; homozygous nonsense variant in GJB2	NM_004004.6(GJB2):c.71G>A;p.(Trp24*)	ABR>90/>90	Isolated SNHL	Normal vestibular function (VHIT)	Albania
47	1.5 y	5	AR; homozygous frameshift variant in GJB2	NM_004004.6(GJB2):c.35del;p.(Gly12Valfs*2)	Deaf, diagnosed abroad	Isolated SNHL	—	Poland
48	3 mo	5	AR; homozygous nonsense variant in GJB2	NM_004004.6(GJB2):c.71G>A;p.(Trp24*)	ABR>90/80	Isolated SNHL	Congenital cholesteatoma left ear	Hearing loss within the family of the motherMacedonia
49	2 mo	5	AR; heterozygous frameshift variant in GJB2	NM_004004.6(GJB2):c.35del;p.(Gly12Valfs*2)	ABR>80/>80	Isolated SNHL	Down syndrome	3(6) siblings have SNHLSyria
49	2 mo	5	heterozygous in-frame deletion in GJB2	NM_004004.6(GJB2):c.358_360del;p.(Glu120del)	ABR>80/>80	Isolated SNHL	Down syndrome	3(6) siblings have SNHLSyria
50	4 mo	5	AR; homozygous frameshift variant in GJB2	NM_004004.6(GJB2):c.35del;p.(Gly12Valfs*2)	ABR>80/>80	Isolated SNHL	—	Serbia
51	1 mo	4	AR; heterozygous missense variant in TMPRSS3	NM_001256317.3(TMPRSS3):c.310G>A;p.(Glu104Lys)	ABR>80/>80	Isolated SNHL	—	Sweden
51	1 mo	5	heterozygous frameshift variant in TMPRSS3	NM_001256317.3(TMPRSS3):c.208del;p.(His70Thrfs*19)	ABR>80/>80	Isolated SNHL	—	Sweden
52	2 mo	5	AR; homozygous splice site variant in TMC1	NM_138691.3(TMC1):c.236+1G>A;p.?	ABR>95/>95	Isolated SNHL	Normal vestibular function (VHIT)	Parents are relativesKurd
53	2.5 y	5	AR; homozygous frameshift variant in TPRN	NM_001128228.3(TPRN):c.225_235del;p.(Gly76Alafs*150)	4fPTA94/89	Isolated SNHL		Middle east
54	<1 y	5	AR; homozygous nonsense variant i OTOF	NM_194248.3(OTOF):c.1422T>G;p.(Tyr474*)	4fPTA110/91	Isolated SNHL/auditory neuropathy-1	Visual impairment, obesity, diabetes type 2	Parents are cousins2(5) siblings have SNHLIraq
55	1 mo	4	AR; homozygous frameshift variant in MARVELD2	NM_001038603.3(MARVELD2):c.1203del;p.(Asp402Thrfs*13)	ABR>90/>90	Isolated SNHL		Parents are cousins1(3) sibling has SNHLSyria
56	2 mo	4	AR; heterozygous nonsense variant in MYO15A	NM_016239.4(MYO15A):c.4612A>T;p.(Lys1538*)	ABR>90/>90	Isolated SNHL		Sweden
56	2 mo	4	heterozygous frameshift variant in MYO15A	NM_016239.4(MYO15A):c.9642_9645del;p.(Leu3215Phefs*30)	ABR>90/>90	Isolated SNHL		Sweden
57	1 y	4	AR; heterozygous nonsense variant in TMPRSS3	NM_001256317.3(TMPRSS3):c.46C>T;p.(Arg16*)	4fPTA>109/>110	Isolated SNHL		1(3) sibling has SNHLSweden
57	1 y	5	heterozygous nonsense variant in TMPRSS3	NM_001256317.3(TMPRSS3):c.271C>T;p.(Arg91*)	4fPTA>109/>110	Isolated SNHL		1(3) sibling has SNHLSweden
58	1 mo	4	AR; heterozygous nonsense variant in PJVK	NM_001042702.5(PJVK):c.532C>T;p.(Arg178*)	ABR>90/75	Isolated SNHL	Normal vestibular function (VHIT)	Sweden
58	1 mo	4	heterozygous missense variant in PJVK	NM_001042702.5(PJVK):c.671T>G;p.(Leu224Arg)	ABR>90/75	Isolated SNHL	Normal vestibular function (VHIT)	Sweden
59	3 mo	4	AR; homozygous frameshift variant in MYO15A	NM_016239.4(MYO15A):c.10470del;p.(Leu3491Cysfs*63)	ABR>80/>80	Isolated SNHL	Normal vestibular function (VHIT, VNG, VEMP)	Turkey
60	2 mo	4	AR; homozygous deletion encompassing exon 2 of GRXCR1	seq[GRCh38] 4p13(42963662_42967656)x0	4fPTA88/93	Isolated SNHL		Parents are cousinsMiddle east
61	2 mo	5	AD; heterozygous synonymous variant affecting splicing in MITF	NM_001354604.2(MITF):c.1230G>A;p.(Thr410=)	ABR>80/>80	Waardenburg syndrome type 2A		Sweden
62	Childhood <13 y	4	AR; heterozygous in-frame indel variant in MYO7A	NM_000260.4(MYO7A):c.4544_4551delinsCA;p.(Glu1515_Met1517delinsAla)	4fPTA>116/>119	Usher syndrome type 1B	Retinitis pigmentosa	Father and 1(5) sibling have SNHLSweden
62	Childhood <13 y	5	heterozygous splice variant in MYO7A	NM_000260.4(MYO7A):c.2187+1G>A;p.?	4fPTA>116/>119	Usher syndrome type 1B	Retinitis pigmentosa	Father and 1(5) sibling have SNHLSweden
63	2 mo	5	AR; homozygous nonsense variant in USH2A	NM_206933.4(USH2A):c.2610C>A;p.(Cys870*)	ABR80/75	Usher syndrome type 2A	Normal vestibular function (VHIT)	Parents are cousinsTurkey
64	1 y	3	AR; homozygous missense VUS in MYO7A	NM_000260.4(MYO7A):c.1400G>C;p.(Arg467Pro)	ABR>90/>90	Usher syndrome type 1B	Retinitis pigmentosaBilateral vestibular dysfunction.	Palestine
Patient number	Age at hearing loss diagnosis	ACMG criteria	Inheritance; variant type(s) and gene	Variants	4fPTA (right/left ear)	Isolated or syndromic SNHL	Comorbidity	Heredity, hearing loss in family and parents’ country of birth
(D) Profound hearing loss (>80 dB HL)
65	2.5 mo	5	AR; heterozygous splice variant in USH1C	NM_153676.4(USH1C):c.104+1G>A;p.?	ABR>80/>80	Usher syndrome type 1C		Sweden
65	2.5 mo	5	heterozygous frameshift variant in USH1C	NM_153676.4(USH1C):c.238dup;p.(Arg80Profs*69)	ABR>80/>80	Usher syndrome type 1C		Sweden
66	<1 y	4	AR; homozygous frameshift variant in CDH23	NM_022124.6(CDH23):c.494dup;p.(Ser166GInfs*16)	4fPTA>115/>115	Usher syndrome type 1D		Iraq
67	3 mo	5	AR; homozygous missense variant in SLC26A4	NM_000441.2(SLC26A4):c.1588T>C;p.(Tyr530His)	ABR>90/>90	Pendred syndrome	Mondini malformation, LVAS and large endolymphatic sac	Sweden

Abbreviations: Autosomal Recessive (AR), Autosomal Dominant (AD), Electroretinography (ERG), the American College of Medical Genetics and Genomics (ACMG), Four-Frequency Pure-Tone Average(4fPTA), Auditory Brainstem Response (ABR), Video Head Impulse test (VHIT), Videonystagmography (VNG), Vestibular Evoked Myogenic Potentials (VEMP), Large vestibular aqueduct syndrome (LVAS).

Waardenburg syndrome: Varying degrees of hearing loss and abnormalities in pigmentation of hair, skin and eyes.

Usher syndrome: A combination of sensorineural hearing loss (SNHL), progressive visual loss due to retinitis pigmentosa and frequently vestibular dysfunction (subgroups defined in the text).

Stickler syndrome: Systemic connective tissue disorder often associated with SNHL.

Pendred syndrome: A syndrome associated with thyroid goiterand inner ear abnormalities: SNHL, vestibular aqueduct enlargement, cochlear hypoplasia.

KBG syndrome: A syndrome associated with short stature, facial and skeletal anomalies, intellectual disability and macrodontia.

Axenfeld-Rieger syndrome: SNHL combined with ocular, dental, facial, and abdominal abnormalities.

In patients with moderate SNHL a genetic diagnosis was identified in 42% (n = 10/24), whereas 5 had isolated SNHL with PVs in CABP2 (n = 1) and in STRC (n = 4), and 5 were syndromic-associated variants. One of the variants affecting STRC (nr 13) was a homozygous deletion covering both STRC and CATSPER2; in males, this would have caused a combination of deafness and infertility,³⁰ but this was a female patient, and the hearing loss was thus not syndromic. Syndromic-associated variants resulted in Usher syndrome type 2A, Stickler syndrome type 3, and Pendred syndrome (USH2A, COL11A2, and SLC26A4), a frameshift variant in ANKRD11 resulted in KBG syndrome (short stature, facial and skeletal anomalies, intellectual disability, and macrodontia syndrome) and a large deletion including FOXC1 resulted in Axenfeld–Rieger syndrome (Table 3B). In the 2 cases with PVs in CABP2 and COL11A2, the parents were relatives.

In patients with severe SNHL, PVs were identified in 6 out of 9 cases (67%) and were related to isolated SNHL (GJB2, TECTA, MYO7A, MYO6, LOXHD1, and TRIOBP). The child with a homozygous variant in MYO7A (nr 38) was examined with ERG, without retinal changes, before 2 years of age. Three of the probands (TECTA, LOXHD1, and TRIOBP) (nr 37, 40, 41) had parents who were cousins (Table 3C).

Among patients with profound SNHL, a genetic cause was identified in 21/40 cases (53%). Of the 32 probands with prelingual onset of hearing loss, 59% (n = 19) received a genetic diagnosis. Isolated SNHL was identified in 15 cases [GJB2 (n = 5), TMPRSS3 (n = 2), MYO15A (n = 2), TMC1, TPRN, OTOF, MARVELD2, PJVK, and GRXCR1] and a syndromic SNHL genetically detected in 6 cases. The dominating syndrome was Usher, found in 4 cases (MYO7A, USH1C, USH2A, and CDH23). The remaining patients with syndromic SNHL had Pendred (SLC26A4) and Waardenburg syndrome type 2A (MITF). Parents were documented to be relatives in 3 cases (Table 3D).

Usher Syndrome and Related Variants

The most common syndrome was Usher syndrome (n = 6). Genetic variants were found in USH1C, USH2A (n = 2), MYO7A, CDH23, and a VUS in MYO7A. The patient (nr 64) with the VUS was clinically diagnosed with Usher syndrome and despite the absence of a definite genetic diagnosis regarded as having Usher syndrome and reported here. In addition, 2 cases with variants in MYO7A (nr 1 and nr 38), and 1 case with VUS in an Usher-related gene (PCDH15) (nr 79, Supplemental Table 2) underwent ERG, and no retinal changes were detected. Nevertheless, ophthalmological re-examinations were planned as the children grow older to monitor whether RP develops over time. The 2 cases with variants in MYO7A were regarded as having mild and severe isolated hearing loss, respectively, reported in Table 3, and the VUS in the last case, with no additional clinical symptom, was regarded as not being clinically relevant and thus, not reported in Table 3.

Inheritance Pattern and Consanguinity

Autosomal recessive (AR) inheritance pattern was seen in 90% (n = 34/38) of the cases with PVs, and in all but 1 case (95%) with isolated SNHL. The AR PVs were homozygous in 20 cases. In the group with self-reported consanguinity (n = 13), homozygous variants were seen in 10 cases. Among the other 10 with homozygous variants, 4 had parents originating from Sweden, 1 from the Middle East and 1 each from Turkey, Macedonia, Serbia, Albania, and Poland. In the group with compound heterozygous variants, 11 had parents originating from Sweden, 2 from the Middle East (Syria, Lebanon), and 1 from Kosovo. Of the patients with a verified genetic diagnosis, 39% (n = 15/38) were multiplex families, with one (n = 9) or more (n = 6) first-degree relatives, siblings or parents, with hearing loss. Among patients where we did not find a genetic explanation, 21% (n = 10/47) had one (n = 5) or more (n = 5) first-degree relatives with hearing loss. Of the 4 with autosomal-dominant inheritance patterns, 1 had a parent and a sibling with hearing loss.

Discussion

Main Results

In our prospective cohort study, PVs were found in 24 genes, and the diagnostic yield in the entire cohort was 45%. Probands with prelingual moderate-to-profound SNHL were likely to receive a genetic diagnosis, with a diagnostic yield of 60% (n = 31/52).

In total, 8 PVs in this cohort were CNVs, showing the importance of including a copy number analysis in genetic diagnostics.

The Value of Genetic Testing, in Relation to Diagnostic Yield and Onset

In this cohort, patients with a prelingual SNHL were more likely to have an identifiable genetic cause than individuals with postlingual SNHL. The association between prelingual SNHL and a genetic diagnosis was significant and also an important confounder when comparing subgroups of children with SNHL of various degree. The preponderance of genetic findings among patients with prelingual hearing loss has been described previously, for example, in a Dutch population⁷ and in a recent German publication as previously discussed.⁹

The classification of pre- and postlingual hearing loss involves some uncertainty as neonatal screening with Transient Evoked Otoacustic Emissions does not detect mild SNHL, SNHL isolated to high or low frequencies and auditory neuropathies. Nevertheless, the main part of the probands in our study had prelingual hearing loss. There is a risk of ascertainment bias, where the genetic background of prelingual moderate-to-severe SNHL is more thoroughly investigated. In the postlingual population, there might be other genetic/polygenic or covariable factors involved.

There is currently no approved gene therapy available for clinical use for patients with SNHL. Nevertheless, the first results of a clinical trial for inherited hearing loss due to PVs in OTOF has been published (the study is still ongoing).³¹ The rapid development of such treatment is an exciting field, but it is yet unclear how efficient such therapies will be compared to treatment with hearing aids or CI. The value of genetic typing of people with SNHL is currently limited to the intrinsic value that the knowledge can offer to the family, as well as enabling specific patient-tailored follow-up. The genotype can facilitate the identification of symptoms and signs from other organ systems involved in a syndromic disease. While we recognize that mild hearing loss affects language development and may cause communication problems, we believe that there is a rationale to propose genetic testing in the first instance for patients with moderate-to-profound SNHL and in particular for cases with prelingual onset, based on the expected genetic diagnostic yield.

Usher Syndrome and Related Genetic Variants Pose New Challenges for the Clinician

Usher syndrome was the most common syndromic presentation in this cohort (n = 6). Early identification of a decreased peripheral vision can be detected with ERG. Genetic testing allows for detection of PVs in genes related to Usher before the vision impairment is symptomatic. Usher syndrome is divided into 4 subtypes based on symptomatology and onset. USH1 is the most severe form with profound SNHL, vestibular dysfunction, and progressive RP from birth, while USH2 is the most common subtype with usually normal vestibular function and progressive hearing loss and visual impairment during puberty. In USH3, SNHL and impaired vision occur somewhat later in life, and USH4 is an atypical form with even later onset. We found 4 cases with USH1 and 2 with USH2, and the variants were found in the expected genes.¹²

Variants in Usher-related genes where the phenotype could either be isolated SNHL or Usher syndrome, and VUS in Usher-related genes, pose a particular challenge for the clinician, as well as for the patients and their families. Usher syndrome is clinically defined as a combination of manifest SNHL and RP. However, for USH2, the natural phenotype is normal vision until adolescence and can include vestibular dysfunction. Thus, with genetic PVs in Usher-related genes the SNHL can be diagnosed as syndromic before vision deterioration. This, and PVs in genes with several possible phenotypes, will pose new challenges to otolaryngologists and audiologists, requiring understanding of the complexities of genetics. Instead of just informing patients and caregivers about a manifest disease, with a well-described expected clinical trajectory, information has to be given with a higher level of uncertainty which from our experience may be very stressful for the families.

Consanguinity Affects the Rate of Hearing Loss in Sweden

Compared to the general population in Skåne and Örebro regions, where 30% of residents had a foreign background, 42% had foreign background in our cohort. Recently, Boudewyns et al described a Belgian cohort of 238 patients with hearing loss and a diagnostic yield of 39.5%, where around 40% were non-Europeans, mostly from North Africa and the Middle East. They found that a confirmed genetic diagnosis was more frequent in probands from North Africa (67%) and the Middle East (55%). Among the patients with a genetic diagnosis and non-European origin, consanguinity was spontaneously self-reported in almost 70% of the cases.²⁰ In a study from Saudi Arabia,³² in a population with 56% consanguinity 83% of children with hereditary SNHL had related parents. Sanyelbha et al also conducted a study in Saudi Arabia and described a prevalence of SNHL of 1.4% to 1.7% in the population compared to 0.1% to 0.3% in western countries. There was an increased risk of 76% of having a child with SNHL in consanguineous marriages.³³ Also in this study, self-reported consanguinity was associated with SNHL with a homozygous AR inheritance.

The Genetics of Hearing Loss is Relatively Consistent Between Populations

In a cohort from Japan with 1120 cases of nonsyndromic hearing loss,² variants were seen in the same genes (except PJVK, MITF, and the 2 CNVs) as in our study. In an American cohort of nonsyndromic SNHL, genetic findings were made in 440/1119 patients (39%),⁶ using the gene panel OtoSCOPE^® v.5 (University of Iowa, USA). The genes, where PVs were more prevalent, were similar to this present study. Recent publications examining European populations in Germany⁹ and Belgium²⁰ showed similarity with our study, with multiple genetic findings in GJB2, MYO15A, TMPRSS3, and SLC26A4. PVs in the genes STRC, CDH23, TMPRSS3, SLC26A4, GJB2, MYO7A, MYO15A, MITF, and MARVELD2, are found in all 3 studies, while variants in PJVK, FOXC1, TRIOBP, GRXCR1, COL11A2, USH1C, and ANKRD11 are only present in the Swedish cohort. The prevalence of GJB2 in our cohort was 7% (n = 6/85) and regarded as less than expected,^34,35 but it is comparable to recent studies from Germany (8%, n = 19/305)⁹ and Belgium (8.4%, n = 20/239).²⁰

Although there is considerable heterogeneity among the genetic variants leading to hearing loss, the majority of the genes involved in SNHL seem to be consistent between population groups. In this study, there were 5 recurrent variants, 1 nonsense, and 1 frameshift variant in GJB2, 1 indel variant in MYO7A, 1 deletion of STRC and CATSPER, and 1 deletion of STRC. The most common GJB2 variant (n = 4) was identified in 1 patient with parents born in Sweden, Serbia, Syria, and Poland, respectively (Supplemental Table 2). Thus, the recurrent variants were relatively few, making it difficult to draw any major conclusions about how the variants segregate in different populations. There was still a substantial group of unsolved cases in this study and as a next step, a trio analysis, using parental samples as controls to enable analysis of all protein-coding genes, would likely be of value.

Conclusion

In this Swedish cohort, PVs were found across 24 different genes and the total diagnostic yield was 45%. A genetic cause was found in a majority of cases in patients with prelingual, moderate-to-profound SNHL. Early onset of SNHL favored a higher diagnostic yield. In children, the genetic diagnosis provided guidance for further investigation, especially when syndromic SNHL was suspected or identified.

Supplemental Material

sj-docx-1-ohn-10.1177_19160216251345471 – Supplemental material for Diagnostic Yield and Genetic Variation in 85 Swedish Patients with Mild to Profound Hearing Loss Analyzed by Whole Genome Sequencing

Supplemental material, sj-docx-1-ohn-10.1177_19160216251345471 for Diagnostic Yield and Genetic Variation in 85 Swedish Patients with Mild to Profound Hearing Loss Analyzed by Whole Genome Sequencing by Johanna Elander, Tove Ullmark, Karolina Löwgren, Karin Stenfeldt, Karolina Falkenius-Schmidt, Maria Löfgren, Alessandro Castiglione, Micol Busi, Tord Jonson, Sofie Ivarsson, Hans Ehrencrona, Johannes K Ehinger and Maria Värendh in Journal of Otolaryngology - Head & Neck Surgery

Supplemental Material

sj-docx-2-ohn-10.1177_19160216251345471 – Supplemental material for Diagnostic Yield and Genetic Variation in 85 Swedish Patients with Mild to Profound Hearing Loss Analyzed by Whole Genome Sequencing

Supplemental material, sj-docx-2-ohn-10.1177_19160216251345471 for Diagnostic Yield and Genetic Variation in 85 Swedish Patients with Mild to Profound Hearing Loss Analyzed by Whole Genome Sequencing by Johanna Elander, Tove Ullmark, Karolina Löwgren, Karin Stenfeldt, Karolina Falkenius-Schmidt, Maria Löfgren, Alessandro Castiglione, Micol Busi, Tord Jonson, Sofie Ivarsson, Hans Ehrencrona, Johannes K Ehinger and Maria Värendh in Journal of Otolaryngology - Head & Neck Surgery

Footnotes

Acknowledgements

We acknowledge colleagues at all ENT-centers that have included patients for taking time and effort informing parents. We also thank Anders Wirén for valuable statistical advice and Professor Robin L. Anderson for language review.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was funded by ENT-department, Skane University Hospital, Lund; Acta Oto-Laryngologica Foundation; Hörselforskningsfonden; Södra Sjukvardsregionen Regionmedel, the Swedish Royal Physiographic Society; The Magnus Bergvall Foundation; Fredrik and Ingrid Thuring’s Foundation; The Lars Hierta Memorial Foundation; The Crafoord Foundation; The Jeansson Foundations, and The Swedish Society of Medicine.

ORCID iDs

Johanna Elander

Karolina Löwgren

Karolina Falkenius-Schmidt

Sofie Ivarsson

Hans Ehrencrona

Johannes K Ehinger

Supplemental Material

Additional supporting information is available in the online version of the article.

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