Causal Variants of the GJB6 Gene are Associated with Hearing Loss and Skin Manifestations: A Case Report from Turkey : International Journal of Dermatology and Venereology

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Causal Variants of the GJB6 Gene are Associated with Hearing Loss and Skin Manifestations: A Case Report from Turkey

Duzkale, Neslihan1,*; Aygar, Gamze Tas2; Keseroglu, Kemal3; Mutlu, Murad3; Ugur, Mehmet Birol4

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International Journal of Dermatology and Venereology: September 2022 - Volume 5 - Issue 3 - p 166-168
doi: 10.1097/JD9.0000000000000231
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Abstract

Introduction

Hearing loss (HL) is the most common sensory deficit in humans, affecting 10% of the entire world population, and environmental and genetic factors play a role in the formation of this heterogeneous disease.1 About 50% of cases of HL have a genetic basis, and about 70% of cases are nonsyndromic HL.2 Approximately 75% to 80% of cases of nonsyndromic HL are inherited as autosomal recessive disorders, and 20% to 25% are autosomal dominant. X-linked inheritance (about 1%) and mitochondrial inheritance (<1%) are rare.3 Gap junction beta 6 (OMIM *604418), also known as GJB6, is a gene that causes both autosomal recessive and autosomal dominant hereditary HL and is responsible for the synthesis of connexin 30 (Cx30). Cx30, an important member of the connexin protein family, plays a role in the maintenance of the condition of the epidermis and inner ear and accomplishes this through gap junctions. Gap junctions, also known as hemiconnexon structures, allow for intercellular communication via protein channels that regulate the transfer of neurotransmitters, ions, and hormones from one cell to another. These important associations form the basis of the cellular and physiological regulation processes of the organism. The cochlear hemostasis of the inner ear and proper continuation of the epidermal differentiation of the skin are directly related to Cx30.4

Causal variants of GJB6, which encodes Cx30, have been associated with the occurrence of various hereditary diseases, particularly those affecting the epidermis, hair, nails, and/or inner ear. Many variants of GJB6 have been reported in various diseases, particularly those involving the ear and skin.4

In this report, we describe a Turkish girl with prelingual deep nonsyndromic HL with p. Gly59Arg heterozygous missense mutation in the GJB6 gene, which was detected for the first time in Turkey and for the second time in the literature.

Case report

The proband was a 1-year-old girl with nonconsanguineous parents. Her prenatal and perinatal periods had been normal, but bilateral HL was found on an audiogram at the age of 1 month. Her physical examination findings and growth charts were normal, and no clinical abnormalities other than deafness were found. A pedigree analysis of the patient showed that both her mother and grandfather had been previously diagnosed with prelin-guistic HL and could only speak sign language (Fig. 1). Their resumes were given to us by the grandmother, who had normal hearing, during genetic counseling. Her mother and grandfather had mild diffuse palmar and plantar hyperkeratosis without a honeycomb appearance and knuckle pads on the dorsal aspect of the fingers. These lesions had begun to appear in her mother around the age of 6 years, but no clear information regarding the age at onset in her grandfather could be obtained. A hyperkeratotic plaque was observed on her mother’s left ankle. We believe that this lesion had developed because of frequent exposure of this area to mechanical stress induced by frequent repetition of the Muslim prayer ritual and the kneeling prayer position. Linear areas of hyperpigmentation were observed on her grandfather’s ankles. Her mother had had dry, brittle, pale hair and partial hair loss since 16 years of age, and she still had thin hair in the frontoparietal area and dryness of the entire scalp. Both the mother’s and grandfather’s teeth were normal. Neither of them described any other medical problems, including sweating (Fig. 2).

F1
Figure 1.:
Pedigree analysis of a Turkish family with autosomal dominant hearing loss and mild palmoplantar keratoderma phenotype. The proband is indicated by an arrow. Filled symbols indicate affected family members. Individuals who underwent genetic analysis are indicated by the star symbol. Ages and genotypes of family members are listed below the symbols. GJB6 M/W defines the heterozygous genotype. The clinical findings of the cases were I.3, deafness and palmoplantar keratoderma; II.4, deafness, palmoplantar keratoderma, and partial hair loss; and III. 1, deafness.
F2
Figure 2.:
Clinical picture of the patient’s family and their skin lesions. Benign subcutaneous fibrotic plaques (knuckle pads) on the extensor side of the metacarpophalangeal joints of the mother (A) and grandfather (B). C: Hyperkeratotic plaque on the left ankle joint of the mother. Mild palmoplantar keratoderma of the palms of the mother (D) and grandfather (E). (F) Hyperkeratotic hyperpigmented plaques (bilateral dorsal fourth metatarsal part) on the grandfather’s toes. G: Dry, brittle, and scrawny hair and partial hair loss, especially in the frontoparietal area, of the patient’s mother.

The QIAamp DNA Blood Kits (Qiagen, Hilden, Germany) were used to isolate genomic DNA from peripheral venous blood of the proband, and this process was performed on the QIAcube Connect (Qiagen) automated isolation device. The study was carried out on the NextSeq platform (Illumina, San Diego, CA, USA) and with the next-generation sequencing method using the Hereditary Disease Solution kit V3 (Sophia Genetics, Boston, MA, USA). The Integrative Genomic Viewer tool was used to examine, validate and interpret gene variants detected in aligned reads obtained by next-generation sequencing.5 Bioinformatic analyses were performed using the Sophia DDM software and a web-based bioinformatics program (https://www.sophiagenetics.com/home.html), and 75 genes known to be associated with deafness phenotype were evaluated. The guidelines in the Genomics England PanelApp, a public database, were used to select these genes (https://panelapp.genomicsengland.co.uk/). The examined genes were ADGRV1, ARSB, BCS1L, BSND, BBS1, BBS4, BTD, CDH23, CLDN14, CLRN1, COL4A3, COL4A4, CDC14A, COL11A1, COL9A1, COL9A2, DMD, EDN3, EDNRB, ESPN, ESRRB, ERCC4, FOXG1, GJB2, GJB3, GJB6, GRXCR1, GUSB, HAL, HSD17B4, HGF, IGF1, LAMA2, LARGE1, LHX3, LHFPL5, LOXHD1, LRTOMT, MARVELD2, MYO15A, MYO3A, MYO6, MYO7A, MKKS, OTOA, OTOF, PAX3, PCDH15, PDZD7, POU3F4, PRPS1, PDSS1, PLS1, POU1F1, PROP1, RDX, RPGR, SLC26A4, SLC26A5, SLC4A11 , SNAI2, STRC, TBC1D24, TECTA, TMC1, TMIE, TMPRSS3, TPRN, TRIOBP, TSHR, TYRP1, USH1C, USH2A, WFS1, and WHRN. Raw data obtained by next-generation sequencing were analyzed according to the reference genome [GRCh37 (h19)]. Variations detected according to a 30 × reading depth per allele (reference allele/alternative allele) were evaluated. Single-base mutations and small deletions/ duplications in the coding regions (exon) and exon-intron boundaries (20 base pairs) were examined. The variants were examined according to the American College of Medical Genetics and Genomics criteria, taking into account the information available from the relevant databases.6

The target region coverage rate in this study was 99.97% at a 50× reading depth. As a result of the genetic analysis, an NM_001110221.2(GJB6):c.175G>A(p.Gly59Arg) genomic change in the proband was determined as heterozygous and classified as likely pathogenic (Fig. 3). The read depth of the causal variant detected was greater than 500×. This variant, which was previously reported in the literature, was also detected heterozygously in the proband’s mother and grandfather.

F3
Figure 3.:
Next-generation sequencing image of heterozygous variant of GJB6 c.175G>A (p.Gly59Arg) obtained by IGV software (https:/software.broadinstitute.org/software/igv/). IGV: Integrative Genomic Viewer.

Before the study, written informed consent was obtained from the patient and her relatives who underwent genetic analysis for the publication of this case report and accompanying images. The present study was conducted according to the ethical guidelines of the World Medical Association and Declaration of Helsinki.

Discussion

In this study, we evaluated the genotype-phenotype relationship between a case in which a GJB6 gene p. Gly59Arg mutation was detected for the first time in Turkey and the affected family members. Cellular studies have demonstrated that Cx30 p.Gly59Arg is a loss-of-function mutation leading to defective connexin oligomerization, particularly in the Golgi apparatus and endoplasmic reticulum.7

The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL. Signs of pseudoainhum were also observed in the toes of this patient. These findings are similar to Bart–Pumphrey syndrome and Vohwinkel syndrome, which are observed in patients with mutations of GJB2 encoding the Cx26 protein.8

Clouston syndrome (hidrotic ectodermal dysplasia type 2), which is an autosomal dominantly inherited disease that results from heterozygous causal variants of GJB6. The main clinical signs are partial to complete hair loss, severe nail dystrophy, and mild to severe palmoplantar keratoderma.9 While the function of the tooth and eccrine glands is normal. Sensorineural deafness, mental retardation, pebbled/grid-like acral papules, and hyperpigmentation of the skin over large joints have also been described in affected patients.10

Diffuse hyperkeratosis, sensorineural deafness, hyperpigmentation, and knuckle pads in family members carrying the mutation are features similar to those of our patient with Clouston syndrome. In addition, normal tooth development and the absence of sweating problems are similar to those in patients with this syndrome. In Clouston syndrome, we would expect to see more severe nail dystrophy instead of leukonychia. In another patient in whom the p.Gly59Arg mutation was reported, deafness, knuckle pads, and diffuse keratoderma were observed, similar to our patient; however, pseudoainhum was also reported, unlike our patient.8 The skin abnormalities and HL observed in our patient’s mother and grandfather are consistent with the findings in previously reported cases.

Our patient was only 1 year of age, and palmoplantar keratoderma was not observed; however, we predicted that such skin abnormalities could occur in subsequent years. Genetic analysis allows the disease to be diagnosed early and the prognosis to be improved. Identification of an inherited syndrome is important in including individuals at risk and their relatives in an intensive screening, monitoring, and prevention program. In such cases, patients and their relatives will be advised to seek genetic counseling, undergo additional diagnostic procedures and analyses, and seek individual recommendations for early detection/screening tests.

References

[1]. Morton NE. Genetic epidemiology of hearing impairment. Ann NY Acad Sci. 1991;630:16–31. doi: 10.1111/j.1749-6632.1991.tb19572.x.
[2]. Yang T, Guo L, Wang L, et al. Diagnosis, intervention, and prevention of genetic hearing loss. Adv Exp Med Biol. 2019;1130:73–92. doi: 10.1007/978-981-13-6123-4_5.
[3]. Morgan A, Lenarduzzi S, Spedicati B, et al. Lights and shadows in the genetics of syndromic and non-syndromic hearing loss in the Italian population. Genes(Basel). 2020;11(11):1237. doi: 10.3390/genes11111237.
[4]. Falah M, Houshmand M, Balali M, et al. Role of GJB2 and GJB6 in Iranian nonsyndromic hearing impairment: from molecular analysis to literature reviews. Fetal Pediatr Pathol. 2020;39(1):1–12. doi: 10.1080/15513815.2019.1627625.
[5]. Robinson JT, Thorvaldsdöttir H, Wenger AM, et al. Variant review with the integrative genomics viewer. Cancer Res. 2017;77(21):e31–e34. doi: 10.1158/0008-5472.CAN-17-0337.
[6]. Maxwell KN, Hart SN, Vijai J, et al. Evaluation of ACMG-guideline-based variant classification of cancer susceptibility and non-cancer-associated genes in families affected by breast cancer. Am J Hum Genet. 2016;98(5):801–815. doi: 10.1016/j.ajhg.2016.02.024.
[7]. Berger AC, Kelly JJ, Lajoie P, et al. Mutations in Cx30 that are linked to skin disease and non-syndromic hearing loss exhibit several distinct cellular pathologies. J Cell Sci. 2014;127(8):1751–1764. doi: 10.1242/jcs.138230.
[8]. Nemoto-Hasebe I, Akiyama M, Kudo S, et al. Novel mutation p.Gly59Arg in GJB6 encoding connexin 30 underlies palmoplantar keratoderma with pseudoainhum, knuckle pads and hearing loss. Br J Dermatol. 2009;161(2):452–455. doi: 10.1111/j.1365-2133.2009.09137.x.
[9]. Cammarata-Scalisi F, Rinelli M, Pisaneschi E, et al. Novel clinical features associated with Clouston syndrome. Int J Dermatol. 2019;58(8): e143–e146. doi: 10.1111/ijd.14507.
[10]. Sanches S, Rebellato PRO, Fabre AB, et al. Do you know this syndrome? Clouston syndrome. An Bras Dermatol. 2017;92(3):417–418. doi: 10.1590/abd1806-4841.20175716.
Keywords:

hearing loss; GJB6; palmoplantar keratoderma; Clouston syndrome

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