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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2023, Vol. 17 Issue (2) : 330-338    https://doi.org/10.1007/s11684-022-0933-2
RESEARCH ARTICLE
A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome
Hequn Huang1,2,3, Mengyun Chen1,2,3, Xia Liu4, Xixi Xiong5, Lanbo Zhou5, Zhonglan Su5, Yan Lu5(), Bo Liang1,2,3,6()
1. Institute of Dermatology and Department of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei 230000, China
2. Key Laboratory of Dermatology (Anhui Medical University), Ministry of Education, Hefei 230000, China
3. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei 230000, China
4. Huai’an District Skin Disease Prevention and Treatment Hospital, Huai’an 223000, China
5. Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
6. Department of Clinical Laboratory, The First Affiliated Hospital, Anhui Medical University, Hefei 230000, China
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Abstract

Clouston syndrome (OMIM #129500), also known as hidrotic ectodermal dysplasia type 2, is a rare autosomal dominant skin disorder. To date, four mutations in the GJB6 gene, G11R, V37E, A88V, and D50N, have been confirmed to cause this condition. In previous studies, the focus has been mainly on gene sequencing, and there has been a lack of research on clinical manifestations and pathogenesis. To confirm the diagnosis of this pedigree at the molecular level and summarize and analyse the clinical phenotype of patients and to provide a basis for further study of the pathogenesis of the disease, we performed whole-exome and Sanger sequencing on a large Chinese Clouston syndrome pedigree. Detailed clinical examination included histopathology, hair microscopy, and scanning electron microscopy. We found a novel heterozygous missense variant (c.134G>C:p.G45A) for Clouston syndrome. We identified a new clinical phenotype involving all nail needling pain in all patients and found a special honeycomb hole structure in the patients’ hair under scanning electron microscopy. Our data reveal that a novel variant (c.134G>C:p.G45A) plays a likely pathogenic role in this pedigree and highlight that genetic testing is necessary for the diagnosis of Clouston syndrome.
Keywords Clouston syndrome      whole exome sequencing      GJB6 gene      novel variant      unique phenotype     
Corresponding Author(s): Yan Lu,Bo Liang   
Just Accepted Date: 20 October 2022   Online First Date: 13 January 2023    Issue Date: 26 May 2023
 Cite this article:   
Hequn Huang,Mengyun Chen,Xia Liu, et al. A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome[J]. Front. Med., 2023, 17(2): 330-338.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0933-2
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I2/330
Fig.1  Pedigree analysis of a Chinese family with hidrotic ectodermal dysplasia. The red cross indicates members who underwent WES, and the blue five-pointed star indicates those who underwent Sanger sequencing. The arrow indicates the proband.
Numbera Age (year) Sex Alopecia Eyebrows/eyelashes/body hair Nails Palmoplantar keratosis Nail pain
II:2 90–95 M – – + – +
II:4 90–95 F – – + – +
III:3 70–75 F +– – + – +
III:6 60–65 M +– – + – +
III:8 60–65 F +– – + – +
III:11 50–55 M +– + + + +
III:15 50–55 F – – + – +
IV:5 50–55 M + + + + +
IV:7 40–45 F – – + – +
IV:11 30–35 F +– + + – +
IV:13 30–35 F +– – + – +
IV:15 30–35 M +– – + – +
IV:17 40–45 F – – + – +
IV:19 30–35 M + + + + +
V:1 20–25 M + + + + +
V:2 15–20 M – – + – +
V:3 10–15 F – – + – +
V:6 10–15 M + + + – +
V:8 5–10 F + + + – +
V:10 10–15 F + + + – +
V:11 0–5 F + + + – +
Tab.1  Clinical information in affected individuals from the family with hidrotic ectodermal dysplasia
Fig.2  Clinical manifestations of the proband of this family. (A) The scalp hair, eyebrows, and eyelashes of the proband are totally absent. (B) The fingernails and toenails are short and thick, and grow slowly. (C) Slight hyperkeratosis of the palms of the hands and obvious hyperkeratosis of the plantar surface of the foot. (D) The scalp shows sparse, soft and curly hair, and the tip of some of the hair is thin (magnification 20×). (E) Biopsy of the proband’s scalp skin revealed a normal epidermis and typical distribution of eccrine and sebaceous glands. Hair follicles were almost absent with a small remnant (hematoxylin and eosin stain; original magnification 40×). (F) Biopsy of the proband’s nail bed revealed an increased number of small vessels in the superficial dermis that were dilated and congested (hematoxylin and eosin; original magnification 100×).
Fig.3  Clinical phenotype histogram of patients in pedigree.
Fig.4  Map of the mutation site peak and its location, and GJB6 gene mutation analysis. (A) Sequence analysis of the GJB6 gene from a normal individual. (B) The same region of the GJB6 gene derived from the proband showing a heterozygous missense variant NM_001110221: c.134g>C, NP_001103689: p.(Gly45Ala) (arrow) in the GJB6 gene. (C) The location of five gene mutations in Cx30. CL, cytoplasmic loop; E1 and E2, extracellular domains 1 and 2; M1–M4, plasma membrane domains 1–4. The red ☆ indicates the present.
Fig.5  Electron microscopic scanning of hair of the proband and control. Sample 1 (patient hair sample): (A) The hair diameter is 27.24 µm. The hair scales are sparse, disorderly distributed and rough on the surface. Magnification: 500×. (D) The scales are thin, with disordered edges and an uneven surface. Some scales have sieve holes, resembling a honeycomb. Magnification: 5000×. Sample 2 (patient hair sample): (B) The hair diameter is 68.78 µm. The scales are dense, distributed slightly disorderly, and the surface is slightly rough. Magnification: 500×. (E) The scales are thin, the edge is disordered, the surface is rough, and some scales present with a few pores. Magnification: 5000×. Sample 3 (control sample): (C) The hair diameter is 101.6 µm. The scales are dense, regular, and smooth. Magnification: 500×. (F) The scale edge is regular, and the surface is smooth. Magnification: 5000×.
Fig.6  Scanning electron microscope of hair section of proband. (A) Hair cross section: there are a large number of sieve structures in each layer of the hair. Magnification: 2500×. (B) Hair longitudinal section: the sieve pore structure is discontinuous. Magnification: 5000×.
No. Nucleotide and amino acid change of GJB6 gene Mutation type Protein domain Ethnic group MAF gnomAD-total population MAF gnomAD-patient’s ethnicity population Eyes phenotype Clubbed digits Reference
1 c.31G > A.(G11R) Missense N-terminal in cytoplasm French 3.99E–06 8.85E–06 / / Lamartine et al., 2000 [7]
2 Missense Dutch 8.85E–06 / / Maurice et al., 2003 [24]
3 Missense Chinese 0 / / Zhang et al., 2003 [2]
4 Missense Chinese 0 / / Chen et al., 2010 [18]
5 Missense German 8.85E–06 / / Fujimoto et al., 2013 [12]
6 Missense Chinese 0 / / Mousumi et al., 2013 [25]
7 Missense Chinese 0 / / Qiao et al., 2016 [26]
8 Missense / / / Odell et al., 2016 [27]
9 Missense Indian 0 / / Agarwal et al., 2016 [28]
10 Missense Chinese 0 / / Hu et al., 2015 [29]
11 c.263C > T.(A88V) Missense M2 domain in plasma membrane India, Malaysia, and Wales / / / / Lamartine et al., 2000 [7]
13 Missense Chinese / / / / Yang et al., 2016 [17]
14 Missense Venezuelan / / / / Cammarata-Scalisi et al., 2019 [30]
15 Missense Russian / / / / Marakhonov et al., 2012 [31]
16 c.148G > A.(D50N) Missense E1 domain in extracellular loops Ashkenazi Jews / / / / BARIS et al., 2008 [9]
17 c.110T > A.(V37E) Missense M1 domain in plasma membrane Scottish 3.98E–06 0 / / Frances et al., 2002 [8]
Tab.2  Four known GJB6 gene mutation sites information
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