Pathogenic REST variant causing Jones syndrome and a review of the literature

doi:10.21203/rs.3.rs-2007051/v1

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Pathogenic REST variant causing Jones syndrome and a review of the literature

https://doi.org/10.21203/rs.3.rs-2007051/v1

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published 13 Dec, 2022

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Jones syndrome is a rare dominantly inherited syndrome characterized by gingival fibromatosis and progressive sensorineural hearing loss becoming symptomatic in the second decade of life. Here, we report a father and his two daughters presenting with a typical Jones syndrome phenotype. Exome sequencing identified a repressor element 1-silencing transcription factor (REST) (NM_005612.5) c.2670_2673del p.(Glu891Profs*6) variant segregating with Jones syndrome in the family. We review the clinical data from all previously published patients with Jones syndrome and previously published patients with pathogenic REST variants associated with gingival fibromatosis or sensorineural hearing loss. This study suggests that pathogenic REST variants are the cause of Jones syndrome.

Jones syndrome

REST

gingival fibromatosis

hearing loss

In 1977, Jones et al. described five generations of a family with autosomal dominantly inherited gingival fibromatosis and progressive sensorineural hearing loss (SNHL) becoming symptomatic late in the second decade of life (1). The affected individuals had hypertrophied, pink, stippled, and nodular gingiva, predominantly in the anterior part of the mouth and predominant premaxillae. Clinical and audiometric examinations revealed progressive downward sloping SNHL. The syndrome was named Jones syndrome (OMIM 135550), and several families with Jones syndrome were later described in the medical literature (2–5). However, the underlying gene causing Jones syndrome remains elusive.

Pathogenic variants in the repressor element 1-silencing transcription factor (REST) gene (OMIM 600571) have previously been associated with either dominantly inherited deafness (6, 7) or gingival fibromatosis (8, 9). Here, we describe a Finnish family with a typical Jones syndrome phenotype. Exome sequencing identified a pathogenic REST variant segregating with the phenotype. To our knowledge, this is the first report of the association between a pathogenic REST variant and Jones syndrome.

Clinical data

Patient 1 is an 11-year-old female (Supplementary Figure 1A, II-5). After birth, transient evoked otoacoustic emissions were not obtained, but an automated auditory brainstem response was obtained bilaterally. Her growth and development were normal. At age 10, she was referred for further investigations due to gingival fibromatosis prolonging the retention of primary teeth and delaying permanent tooth eruption (Figure 1A). Dental panoramic tomography (DPT) showed that all the missing teeth were present and had normal root development (Figure 1C), and lateral cephalometric radiograph showed a convex profile with an open bite tendency (Figure 1D). Extractions of over-retained primary teeth and the removal of excessive gingiva covering non-erupted permanent teeth were performed to ensure the eruption of the teeth (Figure 1B). An audiogram revealed mild bilateral SNHL affecting the high frequencies (Figure 1E). She does not need hearing aids and has mild hypertrichosis and hypertelorism.

Patient 2, an older sister of Patient 1, is a 14-year-old female. Her growth and development were normal. At the age of five years, mild bilateral SNHL affecting the high frequencies was identified (Figure 1F). No remarkable progression has been noted, and she does not need hearing aids. She has gingival fibromatosis, which has delayed permanent tooth eruption. The DPTs showed normal root development, with delayed eruption because of primary retention. Cephalometric analysis showed sagittal jaw discrepancy with neutral facial growth. She also has mild hypertrichosis.

Patient 3, the father of Patients 1 and 2, is a 42-year-old male who is the seventh child of his primary family. His parents and siblings do not have SNHL or gingival fibromatosis. At the age of one year, bilateral inguinal hernias were corrected surgically. At age four, right-sided Legg-Perthes-Calve disease was treated with osteotomy. His bone age was delayed.

At age five, he was diagnosed with bilateral SNHL affecting predominantly high frequencies (Figure 1G), and his hearing loss has slowly progressed. His latest audiograms at age 40 revealed SNHL affecting the middle and high frequencies (Figure 1H). He is using hearing aids.

At age ten, he was referred to a dentist due to markedly delayed (2.5 years) permanent tooth eruption. At age 14, he was referred to an orthodontist due to a convex profile with a retrognathic mandible, and labially inclined upper incisors with an excessive overjet and open bite. There was also generalized gingival fibromatosis preventing the eruption of several permanent teeth. He was treated with orthodontics as a teenager, and a gingivectomy was performed at age 20. At follow-up, gingival fibromatosis had not reoccurred.

He has mild hypertrichosis, almond-shaped eyes, and hypoplastic antihelixes.

Whole-exome sequencing

Whole-exome sequencing (WES) of Patients 1–3 (Centogene, Rostock, Germany) identified a heterozygous REST (NM_005612.5) c.2670_2673del p.(Glu891Profs*6) (GRCh38 g.4:56931528_56931531del) variant. Sanger sequencing of the unaffected siblings confirmed the segregation (Fig. 1). The variant is not present in the Genome Aggregation Database (v.2.1.1). In silico, it is predicted to be disease causing (Mutation Taster), and it is classified as pathogenic (PVS1, PM2, PP1) according to the ACMG criteria (10).

Review of the literature

The clinical and genetic details of the REST-related phenotypes are summarized in Table 1 and pathogenic REST variants reported in the literature are shown in Supplementary Fig. 1B.

Table 1

Known pathogenic variants of the *REST* gene and the clinical findings of cases reported.
Study	REST variant (NM_005612.5)	Phenotype	Origin	Age (years)	Sex	Age of onset for GF (years)	Age of onset for HL (years)
This study	c.2670_2673del; p.(Glu891Profs*6)	Jones syndrome	Finland	11	F	10	NA
This study	c.2670_2673del; p.(Glu891Profs*6)	Jones syndrome	Finland	14	F	NA	4
This study	c.2670_2673del; p.(Glu891Profs*6)	Jones syndrome	Finland	42	M	10	5
Chen et al. 2021	c.2449C > T; p.(Arg817*)	GF	Taiwan	46	M	NA	No HL
Chen et al. 2021	c.2771_2793dup; p.(Glu932Lysfs*3)	GF	Taiwan	15	F	NA	No HL
Bayram et al. 2017	c.2865_2866delAA; p.(Asn958Serfs*9)	GF	Turkey	17	M	7–8	No HL
Bayram et al. 2017	c.2865_2866delAA; p.(Asn958Serfs*9)	GF	Turkey	48	M	NA	No HL
Bayram et al. 2017	c.2865_2866delAA; p.(Asn958Serfs*9)	GF	Turkey	13	M	7–8	No HL
Bayram et al. 2017	c.1310T > A; p.(Leu437*)	GF	Turkey	9	M	3–4	No HL
Bayram et al. 2017	c.1310T > A; p.(Leu437*)	GF	Turkey	38	F	3–4	No HL
Bayram et al. 2017	c.1310T > A; p.(Leu437*)	GF	Turkey	14	F	3–4	No HL
Bayram et al. 2017	c.1310T > A; p.(Leu437*)	GF	Turkey	16	M	3–4	No HL
Bayram et al. 2017	c.1310T > A; p.(Leu437*)	GF	Turkey	32	M	3–4	No HL
Bayram et al. 2017	c.2413delC; p.(Leu805Phefs*38)	GF	USA	9	F	3–4	No HL
Manyisa et al. 2021	c.1244G > C; p.(Cys415Ser)	BSNHL	South Africa	12	M	No GF	3
Manyisa et al. 2021	c.1244G > C; p.(Cys415Ser)	BSNHL	South Africa	37	F	No GF	27
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	NA	F	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	69	M	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	47	M	No GF	33
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	35	F	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	65	M	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	64	M	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	41	M	No GF	28
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	57	F	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	42	F	No GF	NA
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	41	F	No GF	32
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	39	F	No GF	27
Peters et al. 2008	c.983-2247C > T	BSNHL	USA	28	M	No GF	NA
BSNHL = bilateral sensorineural hearing loss, F = female, GF = gingival fibromatosis, HL = hearing loss, M = male, NA = not applicable.

Previously published patients with Jones syndrome

Twelve patients with Jones syndrome have been described previously (Supplementary Table 1) (1–5). All had gingival fibromatosis, which was often severe, and five required surgical treatment. Histology of the extracted gingiva showed thickened epithelium, elongated rete ridges, inflammation, and dense fibrous connective tissue stroma. Ten had hearing loss, and audiogram results often moderate to severe SNHL affecting mainly higher frequencies. The average age of onset for SNHL was 14 years (10–20 years), and for gingival fibromatosis, it was 9 years (4–20 years). Other findings included hirsutism, hypermobility of the distal phalanges, hypertrophic scar, undescended testis, and intellectual disability.

Pathogenic REST variants causing gingival fibromatosis

An original report described nine individuals from three families with gingival fibromatosis caused by three different pathogenic REST final-exon-truncating variants (8). Chen et al. reported two patients with gingival fibromatosis caused by two novel truncating pathogenic REST variants (9). In vitro, reported gene assays demonstrated that these truncated RESTs had a partial or complete loss of repressor activity and that truncated RESTs impaired the repressive ability of the wild-type REST, suggesting a dominant negative effect (9).

Pathogenic REST variants causing sensorineural hearing loss

Peters et al. mapped a dominantly inherited postlingual progressive SNHL to the REST-containing DFNA27 locus in the chromosome 4 (11). Sequencing of all annotated exons in the DFNA27 locus failed to identify potentially pathogenic variants, but sequencing of conserved intronic regions of REST revealed a heterozygous intronic variant segregating with a hearing loss phenotype in the family (7). This intronic REST variant (NM_005612.5) c.983-2247C > T resulted in the prevention of alternative splicing of the REST mRNA, which was essential for the regulation of REST in the inner ear (7). Manyisa et al. reported on a South African family presenting with progressive non-syndromic SNHL caused by the REST c.1244G > C, p.(Cys415Ser) missense variant (6). The affected individuals in these two families showed either a flat-type audiogram affecting all frequencies or a downward sloping audiogram affecting mostly the high frequencies.

This brief report describes a father and his two daughters presenting with gingival fibromatosis and progressive SNHL, also known as Jones syndrome. WES identified a predicted loss-of-function variant in REST, segregating with the phenotype. REST c.2670_2673del is located in the last exon, leading to protein truncation, and it is predicted to escape nonsense-mediated decay. The dominant negative mechanism has been suggested as a disease mechanism in patients with pathogenic REST variants (9).

REST encodes a ubiquitously expressed transcriptional regulator (12). It contains a DNA- binding domain that can bind to a specific 21 base pair consensus sequence (RE-1) in the promoter region of its target genes to repress the transcription of the target genes (13). REST acts as a master negative regulator of neurogenesis, a regulator of osteoblast differentiation, and a key repressor of gene expression in hypoxia (14).

Previously, pathogenic REST variants were associated with progressive dominantly inherited deafness in two families (6, 7). The affected individuals in these two families had either a flat-type audiogram affecting all the frequencies or downward-sloping audiograms, similar to Patients 1–3 described in this report. REST is also involved in the organization of the auditory receptor cell stereocilium (14). Deletion of REST in the cochlea resulted in hearing impairment in mice and induced apoptosis of spiral ganglion neurons and hair cells (13), suggesting a loss-of-function disease mechanism. REST expression was decreased in hair cells and spiral ganglion neurons in age-related hearing loss in mice. REST has a protective role in age-related hearing loss, and its deficiency upregulates p53 and induces cochlear cell apoptosis, which then leads to deafness (13).

The TGF-β/Smad signaling cascade and overproduction of the extracellular matrix (ECM), especially collagen type I, have been proposed to account for gingival fibromatosis (15, 16). REST is expressed in the epithelium and lamina propria of normal and fibrotic gingiva (17), and it controls gingival homeostasis by supressing profibrotic genes and activating proteolytic genes (9). It is speculated that loss-of-function REST variants cause increased production but reduced turnover of the ECM leading to gingival fibromatosis (17), and ChIP-seq data supports this hypothesis (18). However, the exact pathophysiological mechanisms of how REST dysfunction leads to gingival fibromatosis, are currently unknown (12).

While further studies are required to confirm the association between REST and Jones syndrome, based on our study, we recommend detailed oral and hearing examinations of patients with potentially pathogenic heterozygous REST variants. As SNHL in young patients can be relatively mild, predominantly affecting high frequencies and progressing slowly, it may be undiagnosed without proper audiological testing.

Jones syndrome is a rare, possibly underdiagnosed, slowly progressive disease. Early diagnosis and follow-up allow timely treatment of gingival fibromatosis and hearing loss, decreasing the severity of the disease and improving patients’ quality of life.

Acknowledgments

We thank the family who participated in this study.

Authors’ disclosure

The authors declare no conflicts of interest.

Ethics declaration

Written informed consent was obtained from all the patients and unaffected siblings participating in the study. The study was approved by the Ethics Committee of the Northern Ostrobothnia Hospital District (Eettmk § 186, 17/08/2020).

Data Availability

The reported variant was submitted to the LOVD database hosted at Leiden University Medical Center, the Netherlands.

Funding

This study was funded by Academy of Finland (grant number 338446), Uolevi Mäki Foundation, and the Competitive State Research Financing of the Expert Responsibility Area of Oulu University Hospital (grant number VTR K36733).

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Figure1Jonessyndrome.jpg
Supplementary Figure 1: A. Pedigree of the family demonstrating the segregation of the REST c.2670_2673del with Jones syndrome. B. Known pathogenic variants in the REST gene (NM_005612.5). The REST variant reported in the current study (in red), known REST variants associated with gingival fibromatosis (GF) (in blue), and REST variants associated with SNHL (in purple). Exons are to scale, whereas the introns and UTRs (in yellow) are not to scale. Pathogenic variants cluster in the last exon of REST.
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You are reading this latest preprint version

Pathogenic REST variant causing Jones syndrome and a review of the literature

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Journal Publication

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Abstract

Figures

Introduction

Subjects And Methods

Results

Whole-exome sequencing

Review of the literature

Previously published patients with Jones syndrome

Pathogenic REST variants causing gingival fibromatosis

Pathogenic REST variants causing sensorineural hearing loss

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

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