Pendred Syndrome, or Not Pendred Syndrome? That Is the Question

Tesolin, Paola; Fiorino, Sofia; Lenarduzzi, Stefania; Rubinato, Elisa; Cattaruzzi, Elisabetta; Ammar, Lydie; Castro, Veronica; Orzan, Eva; Granata, Claudio; Dell’Orco, Daniele; Morgan, Anna; Girotto, Giorgia

doi:10.3390/genes12101569

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…The most common related gene is SLC26A4 (OMIM 605646) which is also the second most common cause of ARNSHL (DFNB4). This gene encodes for pendrin which is a transmembrane anion transporter highly expressed in the inner ear, thyroid, and kidney ( Gettelfinger and Dahl, 2018 ; Tesolin et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health

Mkaouar,

Riahi,

Marrakchi

et al. 2024

Front. Genet.

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Hearing impairment (HI) is a prevalent neurosensory condition globally, impacting 5% of the population, with over 50% of congenital cases attributed to genetic etiologies. In Tunisia, HI underdiagnosis prevails, primarily due to limited access to comprehensive clinical tools, particularly for syndromic deafness (SD), characterized by clinical and genetic heterogeneity. This study aimed to uncover the SD spectrum through a 14-year investigation of a Tunisian cohort encompassing over 700 patients from four referral centers (2007–2021). Employing Sanger sequencing, Targeted Panel Gene Sequencing, and Whole Exome Sequencing, genetic analysis in 30 SD patients identified diagnoses such as Usher syndrome, Waardenburg syndrome, cranio-facial-hand-deafness syndrome, and H syndrome. This latter is a rare genodermatosis characterized by HI, hyperpigmentation, hypertrichosis, and systemic manifestations. A meta-analysis integrating our findings with existing data revealed that nearly 50% of Tunisian SD cases corresponded to rare inherited metabolic disorders. Distinguishing between non-syndromic and syndromic HI poses a challenge, where the age of onset and progression of features significantly impact accurate diagnoses. Despite advancements in local genetic characterization capabilities, certain ultra-rare forms of SD remain underdiagnosed. This research contributes critical insights to inform molecular diagnosis approaches for SD in Tunisia and the broader North-African region, thereby facilitating informed decision-making in clinical practice.

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Section: Introductionmentioning

confidence: 99%

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health

Mkaouar,

Riahi,

Marrakchi

et al. 2024

Front. Genet.

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“…These contradiction between observational studies could be due to confounding bias or reverse causality. For instance, some genetic or chromosomal disorders can also present with hypothyroidism and hearing loss at the same time, including Pendred syndrome variants in the SLC26A4 gene (37)(38)(39), Woodhouse-Sakati Syndrome variants in the DCAF17 gene (40), Down syndrome (41), and TBL1X mutations (42). In animal experiments, Oliveira et al (43) observed that perinatal hypothyroidism leads to irreversible damage to cochlear function in offspring rats.…”

Section: Discussionmentioning

confidence: 99%

Causal relationship between hypothyroidism and the risk of hearing loss: A bidirectional two-sample Mendelian randomization study

Zhu

Liu

2023

Preprint

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Background Hypothyroidism's causal direction and the magnitude of its association with hearing loss is uncertain due to the limitations of observational studies. This study aims to investigate the relationship between hypothyroidism and hearing loss using bidirectional two-sample mendelian randomization (MR).Materials and Methods The genetic variants of 462,933 participants in the hypothyroidism study and 323,978 participants in the hearing loss study were used for bidirectional two-sample MR. Independent genetic variants that were significantly (P < 5×10− 8) associated with each exposure were considered as instruments. To test for sensitivity, Cochran's Q test, the MR-Egger intercept test, and leave-one-out analysis were applied apart from the multiplicative random effects-inverse variance weighted (MRE-IVW) approach used as the main MR analysis.Results The forward MR revealed a significant causal estimate for the genetically predicted hypothyroidism with the high risk of hearing loss [MRE-IVW: odds ratio (OR) = 1.092, P = 0.003]. However, the reverse MR analysis found no significant correlation between genetically predicted hearing loss and hypothyroidism (MRE-IVW: OR = 1.04, P = 0.113). Sensitivity analyses showed that the causal association estimations were stable and reliable.Conclusion In this MR study, we demonstrated hypothyroidism was causally associated with a high risk of hearing loss. However, there was no evidence to support the causality of hearing loss on hypothyroidism.

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“…Members with HL from F1 and F3 were homozygous for the same splice-site variant (c.165−1G>C), while those in F2 had compound heterozygous variants (p.Trp482* and p.Gly102Arg; Figure 1 and Figure 3 ). However, variants in SLC26A4 causing DFNB4 or PDS can also be di-genic with other genes such as FOX1, EPHA2, and KCNJ10 [ 30 , 31 , 32 , 33 , 34 ]. These genes did not harbor any candidate DCVs in our cases.…”

Section: Discussionmentioning

confidence: 99%

SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management

Tawalbeh

Aburizeg

Alragheb

et al. 2022

Genes

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SLC26A4 is one of the most common genes causing autosomal recessive non-syndromic sensorineural hearing loss (SNHL). It has been reported to cause Pendred Syndrome (PDS) and DFNB4 which is deafness with enlarged vestibular aqueduct (EVA). However, mutated SLC26A4 is not conclusive for having either DFNB4 or PDS. Three unrelated Jordanian families consisting of eight affected individuals with congenital bilateral hearing loss (HL) participated in this study. Whole-exome and Sanger sequencing were performed to investigate the underlying molecular etiology of HL. Further clinical investigations, including laboratory blood workup for the thyroid gland, CT scan for the temporal bone, and thyroid ultrasound were performed. Three disease-causing variants were identified in SLC26A4 in the three families, two of which were novel. Two families had a novel pathogenic homozygous splice-site accepter variant (c.165-1G>C), while the third family had compound heterozygous pathogenic variants (c.1446G>A; p.Trp482* and c.304G>A; p.Gly102Arg). Our approach helped in redirecting the diagnosis of several affected members of three different families from non-syndromic HL to syndromic HL. Two of the affected individuals had typical PDS, one had DFNB4, while the rest had atypical PDS. Our work emphasized the intra- and inter-familial variability of SLC26A4-related phenotypes. In addition, we highlighted the variable phenotypic impact of SLC26A4 on tailoring a personalized healthcare management.

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Pendred Syndrome, or Not Pendred Syndrome? That Is the Question

Cited by 9 publications

References 44 publications

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health

Current phenotypic and genetic spectrum of syndromic deafness in Tunisia: paving the way for precision auditory health

Causal relationship between hypothyroidism and the risk of hearing loss: A bidirectional two-sample Mendelian randomization study

SLC26A4 Phenotypic Variability Influences Intra- and Inter-Familial Diagnosis and Management

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