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Comprehensive Catalog of Variants Potentially Associated with Hidradenitis Suppurativa, Including Newly Identified Variants from a Cohort of 100 Patients

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Abstract
Hidradenitis suppurativa (HS) is a chronic skin disease characterized by painful, recurrent abscesses, nodules, and scarring, primarily in skin folds. The exact causes of HS are multifactorial, involving genetic, hormonal, and environmental factors. It is associated with systemic diseases like metabolic syndrome and inflammatory bowel disease. Genetic studies have identified mutations in the γ-secretase complex, which affects Notch signaling pathways critical for skin cell regulation. Despite its high heritability, most HS reported cases do not follow a simple genetic pattern. In this article, we performed a whole-exome sequencing (WES) on a cohort of 100 individuals with HS and we provide a comprehensive review of the variants known to be described or associated with HS, referencing 91 of them in the γ-secretase and 78 in other genes involved in the Notch pathway, keratinization, or immune response. From this new genetic analysis, we add ten new variants to these catalogs.
Keywords: 
Subject: Medicine and Pharmacology  -   Dermatology

1. Introduction

Hidradenitis suppurativa (HS) is a debilitating dermatological disorder that affects approximately 1% of the global population. It is characterized by the formation of large suppurative abscesses, sinuses, nodules, and scars in intertriginous areas, including the axillae, groin, and/or anogenital regions [1]. Although the pathogenesis of HS is multifactorial and poorly understood, its pathomechanism is very likely linked to aberrant keratinization and autoinflammation. Consequently, HS is recognized as an autoinflammatory keratinization disease [2]. It remains uncertain whether autoinflammatory events precede or follow the hyperkeratotic changes in the hair follicle epithelia, although follicular occlusion is typically considered the primary event [3]. Several factors, including genetics, microbiota, and environmental factors such as obesity and smoking, may act as triggers or risk factors for HS. Many patients also suffer from syndromic forms of HS or have comorbidities [4,5,6,7,8], such as inflammatory bowel disease (IBD) like ulcerative colitis or Crohn’s disease (Supp. Figure S1).
Only a small proportion of patients with familial or syndromic HS reveal a monogenic etiology (5%), despite the estimated high heritability of HS (77-80%) [9]. Mutations in genes encoding γ-secretase, an intramembrane multisubunit protease complex, have been identified in several members of Chinese families with severe HS [10]. The γ-secretase complex comprises four protein subunits: the anterior pharynx-defective protein APH-1A or APH-1B (APH1A/B genes), the nicastrin protein NCSTN (NCSTN gene), the presenilin protein PS-1 or PS-2 (PSEN1/2 genes), and the presenilin enhancer PEN-2 (PSENEN gene). It has been established that γ-secretase proteolyzes the transmembrane domain of more than 100 substrates, including those derived from the amyloid precursor protein (APP) and the Notch family of cell surface receptors [11]. To date, 91 mutations have been described in the γ-secretase complex, with more than half located in the nicastrin subunit. Despite several articles implicating γ-secretase variants in HS, evidence for direct causal mechanisms is lacking [12]. Given the pivotal functions of Notch in maintaining epidermal and follicular homeostasis as well as regulating inflammatory processes, Notch deregulation has been proposed to underlie the molecular basis of HS observed in patients with pathogenic variants in γ-secretase protein-coding genes [13].
Furthermore, many other genes have been identified as potentially implicated in HS: AIM2 [14], DCD [15], DEFB126 [16], FGFR2 [17,18], GJB2 [19,20,21,22,23,24], IL1RN [25], IRF2BP2 [26], KDF1 [27,28], KRT6A [29], KRT17 [30,31], MEFV [17,24,25,32,33,34], NBPF12 [16], NF1P6 [16], NLRC4 [24], NLRP3 [25], NOD2 [17,24,25,33], NOTCH1 [35], NOTCH3 [16,36], NOTCH2NLA [16], OCRL [37], OTULIN [24], POFUT1 [38,39], POGLUT1 [40], PSTPIP1 [17,24,25,32,36,41,42,43,44,45,46,47,48], PSMB8 [25], RORC [16], SLC46A2 [16], TCIRG1 [16], and WDR1 [24]. Variants in these genes are often found in individuals with syndromic forms of HS. However, the precise contribution of each gene in HS development is difficult to determine.
Although no fully penetrant variants causing multigenerational disease have been identified, the high heritability rates suggest that sporadic forms of HS have a significant genetic component contributing to their causation [49]. However, the precise nature of the genetic variants causing common non-syndromic forms of HS is still unclear. Here, we performed a whole-exome sequencing (WES) on a cohort of 100 individuals with HS; as controls, we used a cohort of 100 individuals without HS from the French Exome consortium [50,51], examining genetic variants in genes described in the literature as being associated with the disease. We identified seven variants in the NCSTN gene, three of which were not described in dbSNP but were found only in articles. We pinpointed eight other variants (including two new ones) in the other γ-secretase complex genes. Finally, we found 21 variants in our HS individuals, described in the literature affecting other genes than γ-secretase genes, of which only three are of real interest (absent in our controls and with a high deleteriousness score), to which we added two noteworthy new variants in the SLC46A2 and NOTCH3 genes.

2. Results

2.1. Description of the Cohort

We collect data from 100 patients with HS and gathered detailed clinical characteristics (Table 1). Age at enrollment was 34.0 ± 11.5 years; 64 were female (sex ratio 2:1). Twenty-four were obese (BMI ≥ 30), and more than 50% were smokers. Four families were included, and 28 patients reported having an affected first-degree relative. Hurley phenotypes, as described by van der Zee and Jemec [52], were categorized at enrollment, with the majority exhibiting the regular phenotype.

2.2. Variants Identified in Nicastrin (NCSTN) Gene

As most known variants identified in HS patients are located in NCSTN (~37%), we start analyzing SNVs in the NCSTN gene. We identified seven variants, three of which have not been described in dbSNP or gnomAD, and whose bioinformatic predictions indicate that they might have a major impact on the protein structure.
The first variant, p.Leu17SerfsTer30 (c.47dupG; GRCh38:1: 160343443), is a frameshift variant that truncates the protein very prematurely (Supp. Figure S2), and is expected to induce a nonsense-mediated decay (NMD) reaction to eliminate the aberrant transcript. This heterozygous variant is present in a 43-year-old woman with a family history of HS.
The second variant, p.Ala300TrpfsTer20 (c.896_897dupTG; GRCh38:1:160352104), is another frameshift variant that truncates the protein at position 320 (Figure 1b), simply called W300. This would result in a protein without its active site (in orange) and its transmembrane domain (in red), which prevents it from integrating into the cell membrane. It would therefore produce a non-functional protein or a γ-secretase haploinsufficiency, even though the mutation is heterozygous. Although PhyloP shows a score of -7.97, demonstrating rapid evolution of this site in mammals, this specific variant has a CADD Phred-like score of 34 (i.e., in the 0.04% most deleterious variants). It affects three HS individuals in the same family: a father (I:1) and his two daughters (II:1 & II:2).
The third and fourth variants are nonsense variants p.Arg429* (Figure 1c) (rs771414318 already described in a Japanese individual [53]) and p.Trp648* (Figure 1d) (not known in dbSNP or gnomAD), truncating the protein beyond the small lobe of the nicastrin. The transmembrane domain, like the previous two variants, would be lost. These variants are found in sporadic cases of HS affecting a 50-year-old man and a 39-year-old woman, respectively. As expected, their CADD Phred-like scores are very high (39 and 51, respectively), and these variants are in fairly conserved regions (PhyloP=7.04 & 4.42). It is important to note that the p.Trp648* variant has a SpliceAI score that is very close to 0.5, suggesting a potential gain of a splice acceptor site.
With a lower impact, two missense variants p.Glu77Asp (c.231G>C) and p.Asn417Tyr (c.1249A>T), and an intronic variant c.1180-5C>G, as already described in the literature, were also found [17,36,54]. The p.Glu77Asp variant (rs35603924) (Supp. Figure S2) is found in a 17-year-old woman with a Hurley stage III HS. Although very rare in the European population, this variant is not so rare in the African population (AF~6%) and does not seem, according to prediction tools, to have a strong impact on the protein. Unfortunately, we do not have information about the phototype of this young woman. The second missense variant p.Asn417Tyr (rs143039637), affects a 33-year-old woman who also has a Hurley stage III HS. This is a non-familial case. This variant is very rare and, according to SIFT and PolyPhen-2, appears to be “deleterious” and “possibly damaging”. Finally, the intronic variant c.1180-5C>G (rs7528638), although described in the literature [54], is common in the population at over 5%. Similarly, in our cohort, 7.07% of patients and 12% of controls carry this variant. The SpliceAI and Pangolin prediction tools have scores below 0.5, which does not indicate a high probability of alternative splicing induced by this variant.

2.3. Variants Identified in Others Genes Involved in γ-Secretase Complex

Approximately 20% of variants associated with HS and described in the literature affect other γ-secretase genes than the nicastrin one. Yet, we report four variants for PS-1, one for PS-2, and three for APH-1B (Supp. Figure S2), of which three, one and two variants respectively are known from dbSNP and gnomAD.
The most interesting variant is a c.554del(A) frameshift deletion (p.Lys185SerfsTer10, rs745918508) which causes a truncation of the last third of the APH-1B protein. It is observed in a 36-year-old woman with no family history. Although it remains very rare in the population (0.007%), it was also found in one of our control individuals. The CADD Phred-like score of 27.8 is very close to the Ensembl deleteriousness threshold of 30.
The two other variants in the APH1B gene are missense SNVs. The p.Thr27Ala (rs77834210) variant affects two unrelated individuals, one of whom is a phototype 6 male, which is consistent with the greater presence of this variant in the African population (1.05% vs. 0.33% in non-Finnish Europeans). The other p.Leu71Val variant affects only one woman. This second variant has a very high probability of being deleterious (SIFT=0.01; PolyPhen-2=0.998).
Of the four variants detected in the PSEN1 gene, we report a new one: p.Gln325Glu in a single individual, which probably has no particular effect (only the REVEL score exceeds its threshold of 0.5). The other three variants have already been described in the literature [36,54,55] but do not have a strong impact on the protein. These are the variants c.868+16G>T (rs165932), p.Glu318Gly (rs17125721) and c.1248+8T>C (rs362382). The first two are shared by more controls than patients in our cohort (82 vs. 80% and 5 vs. 4%), which is perfectly consistent with what is known from gnomAD: 58% and 1% of the world population. The last variant showed scores of 0 for SpliceAI and Pangolin, demonstrating a null probability of splice site alteration.
Finally, we detected a new variant in PSEN2:p.Gly34Ser which is not listed in the literature or databases and is only carried by an individual with no family history. According to the prediction tools, this variant would not be considered deleterious.

2.4. Comprehensive Catalog of γ-Secretase Variants

To provide a useful resource for the medical and scientific communities, we have listed all the variants affecting γ-secretase described in the literature in patients with HS with or without comorbidities. They are listed in Table 2 and Supplementary Table S1. To ensure the resource is of high quality and value, we have provided the positions of the variants on different reference genomes in relation to the reference transcript defined by the MANE project, the aim of which is to harmonize the annotations of genes and transcripts. We have identified numerous errors in recent reviews (e.g., Supp. Table S2) and have corrected them in this article. The systematic verification of all variants requires a certain level of expertise and is very time-consuming when the variants are poorly annotated in articles. To avoid future issues, we also provide the left-normalized .vcf file of all variants discussed in this article as supplementary data to aid future studies and reviews.

2.5. Variants Identified in Others Genes Described as Being Associated with HS

To present an exhaustive review of all known variants described in the literature with a potential impact or link to HS, we also analyzed the 78 known SNVs that are not related to γ-secretase. These genes include AIM2 [14], DCD [15], DEFB126 [16], FGFR2 [17,18], GJB2 [19,20,21,22,23,24], IL1RN [25], IRF2BP2 [26], KDF1 [27,28], KRT6A [29], KRT17 [30,31], MEFV [17,24,25,32,33,34], NBPF12 [16], NF1P6 [16], NLRC4 [24], NLRP3 [25], NOD2 [17,24,25,33], NOTCH1 [35], NOTCH3 [16,36], NOTCH2NLA [16], OCRL [37], OTULIN [24], POFUT1 [38,39], POGLUT1 [40], PSTPIP1 [17,24,25,32,36,41,42,43,44,45,46,47,48], PSMB8 [25], RORC [16], SLC46A2 [16], TCIRG1 [16], and WDR1 [24]. They are primarily involved in the Notch signaling pathway, immune response pathway (principally the inflammasome) and keratinization, as described by Jfri et al. (Supp. Figure S3). Note that we cannot compare the proportions of variants between those in the γ-secretase and those in other genes since many studies have only performed targeted exome sequencing and have not examined all of these genes.
We found 21 variants in our cohort in common with published studies (Supp. Table S1). Of these, eight variants had an allelic frequency > 2% and five variants had a frequency between 1 and 2%. Among the remaining eight variants, five missense variants had no scores indicating deleteriousness, while the last three variants were of particular interest: RORC:p.Arg10* (rs17582155) [16], GJB2:p.Glu114Gly (rs2274083) [19] and NOD2:p.Ala891Asp (rs104895452) [17]. Their allelic frequencies are 0.279, 0.044, and 0.545% in the general population, respectively.
The RORC p.Arg10* variant is a stop codong gain that truncates the protein from the 10th amino acid (CADD Phred-like score=36). This variant affects two unrelated HS individuals in our cohort, including the youngest daughter (II:2) in the family with the NCSTN W300 mutation. The father (I:1) and the other daughter (II:1) (Hurley II) do not carry this RORC variant, whereas the youngest daughter (II:2) has a more severe form of the disease (Hurley III). The GJB2 variant is a missense mutation with a CADD Phred-like score of 20.8, affecting a sporadic case of HS. The NOD2 variant is a missense mutation with a CADD Phred-like score of 25.5 and the most deleterious SIFT and PolyPhen-2 scores (0 and 1, respectively). Complementary analyses using missense3D and AlphaMissense describe this mutation as “neutral” and “likely benign” effect. This variant affects two unrelated individuals.
Additionally, we highlight two other high-impact variants among the 29 genes reported in the literature and do not affect the individuals in our control cohort. These are two frameshift variants: one affecting SLC46A2 (rs1841700210 - p.Ala326GlyfsTer133) and the other affecting NOTCH3 (rs749829137 - p.Cys43LeufsTer32). As expected, their CADD Phred-like scores are close to 30.

3. Discussion

We analyzed WES data from 100 HS patients, predominantly non-syndromic cases, with a focus on genes already reported to be mutated in HS. We identified 15 variants in the γ-secretase complex, including 12 with rare frequencies (<1%) in the general population. These 12 variants were found in 15 patients, including a family of three individuals affected by the W300 variant. Thus, 15% of the sporadic cases in our HS cohort have a variant in the γ-secretase complex with a predicted moderate to strong effect.
A detailed literature review allowed us to compile a catalogue of potentially HS-causing variants in the γ-secretase complex. Table 2 lists 91 and eight new variants, over two-third of which are predicted to have a significant impact on γ-secretase function (e.g., nonsense mutations, frameshifts leading to premature truncation, alternative splicing or elongation). Approximately 40% of these variants are documented in gnomAD (v. 4.1-exome), an additional 11% are known in dbSNP, and the remaining 49% of variants are described only in articles. Among these, only four variants have an alternative allele frequency greater than 1% in the general population and non-Finnish Europeans: c.436+129A>G (NCSTN), c.1180-5C>G (NCSTN), c.868+16G>T (PSEN1), and c.953A>G (PSEN1; p.E318G), with frequencies of 3.6, 5.1, 57.6, and 1.8%, respectively. These variants have been previously reported [42,54,55] with noted frequencies in the general population or in intrafamilial non-HS controls. Functional studies of some of these variants, such as p.Val75Ile [29], p.Asp185Asn [30], p.Pro211Arg [31] and p.Gln216Pro [29], have shown no impact on γ-secretase activity, suggesting that they are unlikely to be implicated in HS. These findings underscore the necessity for functional studies to elucidate the functional impact of these variants.
Despite its relatively small size of 101 amino acids, the PEN-2 protein has 20 identified variants in the PSENEN gene, with 95% of these having a strong effect. The literature describes that the four proteins of the γ-secretase complex are crucial for its proper function, and deregulation of any single protein can destabilize the entire complex [124]. For instance, PEN-2 is necessary for PS1 endoproteolysis [125], and PS1 mediates NCSTN maturation and intracellular trafficking [124]. Therefore, a strong-effect variant in one of the γ-secretase subunits is likely to have functional consequences. It has been demonstrated that knockdown of NCSTN in HaCaT cells disrupts the interaction between PEN-2 and PS1, impairing γ-secretase activity and leading to abnormal keratinocyte differentiation [64].
In the article by de Oliveira et al. [97], the authors demonstrate that the heterozygous nonsense mutation c.131T>A (p.L44*) in NCSTN gene activates the NMD mechanism, which degrades the aberrant transcript. This degradation can be reversed by the addition of gentamicin, restoring the expression of the truncated NCSTN protein. The resulting haploinsufficiency can affect the expression of genes related to the type I interferon response pathway [126]. Moreover, based on the pLI, pRec and pNull scores (respectively the probabilities of intolerance to loss-of-function, being a recessive gene or being an unconstrained gene) associated with the genes described in this article, NCSTN is among the genes most prone to haploinsufficiency (Supp. Figure S4). However, Pink et al. [87] still assert that haploinsufficiency alone is not sufficient to cause HS.
Among the γ-secretase complex variants reported in this article, there are five heterozygous nonsense or frameshift variants that could potentially lead to the degradation of APH1B and NCSTN RNA. Therefore, these variants warrant further functional analysis to assess their potential role in HS.
Finally, variants affecting proteins other than those of the γ-secretase complex primarily concern syndromic cases of HS or cases with co-morbidities (as noted in Supp. Figure S1). Variants in GJB2 are more commonly associated with the Follicular Occlusion Triad (FO3) and Keratitis-Ichthyosis-Deafness syndrome (KID), KRT17 variants with the Follicular Occlusion Tetrad (FO4), KRT6A and KRT17 variants with Pachyonychia Congenita (PC), MEFV variants with PASH and PAPASH syndromes, OCRL variants with Dent Disease 2 (DD2), POFUT1 and POGLUT1 variants with Dowling Degos Disease (DDD), and PSTPIP1 variants with PASH and PAPASH syndromes. In these cases, it is even more challenging to establish the causative role of the variants in HS. For example, the p.D50N mutation is associated with HS patients who also have KID syndrome [19]. This variant is also found in KID patients without HS, underscoring the importance of careful interpretation of variant data. The two variants that we include in this catalog concern the NOTCH3 and SLC46A2 genes. The first gene is directly involved in the Notch signaling pathway, the second gene is involved in the activation of NOD (nucleotide oligomerization domain) receptors in epithelial cells and initiate an anti-inflammatory response [127]. Both genes are highly deregulated in the lesional tissues of HS patients [128,129]
In conclusion, our study has identified and cataloged 179 new and previously known variants in the γ-secretase complex and other genes potentially associated with HS. These findings underscore the complex genetic landscape of HS, proposing both common and rare variants that may contribute to its pathogenesis. Our analysis emphasizes the potential role of rare variants in the disease’s development and suggests that both haploinsufficiency and more complex genetic interactions are maybe involved. Notably, the presence of multiple low-impact common variants may create a genetic predisposition that, in combination with environmental factors and lifestyle conditions (e.g., smoking behavior or obesity), facilitates the onset of the disease. Further functional studies are necessary to elucidate the precise mechanisms by which these genetic alterations influence HS. Understanding these mechanisms may provide new insights into targeted therapeutic strategies, offering hope for more effective treatments for individuals affected by this debilitating condition.

4. Materials and Methods

4.1. Sample Collection

This article combines data from three independent cohorts: the HS1 cohort, which includes 75 PBMC samples from HS patients; the HS2 cohort, comprising 25 diverse samples (PBMC, keratinocytes, ORS cells in culture, as well as total dermal cells); and the CTL cohort, consisting of 100 non-HS control individuals from the public French Exome consortium [50,51] (http://lysine.univ-brest.fr/FrExAC/). We maintained exactly the same male-to-female ratio between the HS and CTL cohorts. The characteristics of the 100 HS patients are summarized in Table 1. The ethics committee of Henri Mondor Hospital (CPP n°10-026) in agreement with the Declaration of Helsinki approved this study, and written informed consent was received from participants before inclusion in the study.

4.2. Whole Exome Sequencing

Whole Exome sequencing was performed using the Illumina HiSeq2500 sequencer for the HS1 cohort, the HiSeq4000 for the HS2 cohort, and the HiSeq2000 for the CTL cohort according to the following specifications:
Cohort Agilent WES Kit Protocol Library size
HS1 SureSelectXT Human All Exon V5+UTR 2 2 x 100 bp
HS2 SureSelectXT Human All Exon V6 2 x 150 bp ~70M
CTL SureSelectXT Human All Exon V4+UTR 2 x 100 bp ~60M

4.3. Variant Calling and Annotation

The individual .g.vcf files were obtained through an in-house pipeline using the following tools: bwa-mem (v. 2.2.1) [130,131], PicardTools (v. 2.26.9) [132], Samtools (v. 1.16) [133], Sambamba (v. 0.8.1) [134], GATK (v. 4.2.3.0) [135,136], and bedtools (v. 2.30.0) [137]. The alignment was done on the reference genome GRCh38. The .g.vcf files were aggregated and then transformed into .vcf files using the GATK HaplotypeCaller and GenotypeGVCFs modules. The variants were then limited to the regions captured by the kits (extended from 10 to 100bp) and filtered according to the commonly used criteria [138]: (1) for SNVs: QD < 2, QUAL < 30, SOR > 3, FS > 60, MQ < 40, MQRankSum < -12.5, and ReadPosRankSum < -8; (2) for Indels: QD < 2, QUAL < 30, FS > 200, and ReadPosRankSum < -20. We annotated our variants with the gnomAD (v. 4.1-exome) and dbSNP 2.0 (v. 152) [139] databases using the SnpEff tool [140] and its SnpSift module (v. 4.5) [141]. We complemented missing data with the online tool CADD (v. 1.7) [142]. Variant allele frequencies and deleteriousness scores (using various tools) are provided by gnomAD (v. 4.1). The thresholds used to assess the deleteriousness of a variant according to the tools are as follows:
  • CADD Phred-like score ≥ 30: among the 0.1% most deleterious variants
  • REVEL ≥ 0.5: deleterious missense
  • SIFT < 0.05: deleterious missense
  • AlphaMissense > 0.564: possibly deleterious
  • PolyPhen-2 ≥ 0.85: probably damaging missense
  • SpliceAI ≥ 0.8: variant with the probability of altering splicing
  • Pangolin ≥ 0.8: variant with the probability of altering splicing
  • PhyloP (mammals) < 1.5: fast evolution of the locus in mammals

4.4. Variant Validation

Each variant of the literature was validated manually. The data retrieved from the articles (electrophoregrams, sequences, genome used, HGVS, dbSNP identifier, transcript concerned, gene position, etc.) were compared with the Ensembl and/or NCBI databases and MANE reference transcripts to harmonize the data. Where data was missing, it was complemented (e.g., if position or exon information was absent, these details were incorporated into the final tables). The tools and databases used were mainly LitVar² (v. 2.0) [143], MutationTaster (v. 2021) [144], gnomAD (v. 2.1.1, v. 3.1.2 & v. 4.1.0-exome) [145], CADD (v. 1.7) [142], dbSNP (v. 156 and previous versions) [139], AlphaMissense (v.04-2024) [146,147], and LiftOver [148].

4.5. Protein Folding

Protein models of NCSTN, PS1 (PSEN1 gene), PEN-2 (PSENEN gene) and APH-1B (APH1B gene) were generated from the canonical Ensembl translated transcripts (i.e., ENST00000294785.10, ENST00000324501.10, ENST00000587708.7 and ENST00000261879.10, respectively) using the AlphaFold tool (v. 2.1.2) [149], which is freely available on the Galaxy France server (https://usegalaxy.fr/ - v. 22.01). The mutated models were processed in the same way, although we aknowledge the limitations of this tool for predicting the consequences of missense mutations [150,151]; it remains the best tool for predicting three-dimensional structures. The visualization and manipulation of the .pdb files was done via the RasTop tool (v.2.2) [152], and their annotation was a mix between InterPro (v.90.0) [153] predictions and cryo-EM structures of γ-secretase (models 2KR6 [154], 6IYC [155] & 5FN [2,3,4,5,154]) available on RCSB Protein Data Bank [156].

Supplementary Materials

The following supporting information can be downloaded at the website of this paper posted on Preprints.org. Figure S1: Comorbidities of HS and its involvement in various autoinflammatory syndromes; Figure S2: All γ-secretase exonic variants identified in our HS1 & HS2 cohorts; Figure S3: Protein network of all genes discussed in this article, according to STRING; Figure S4: Distribution of pLI (probability of intolerance to loss of function), pRec (probability of being recessive) and pNull (probability of being unconstrained) gene scores; Table S1: Complete table of all 179 variants found in the literature, including our new variants; Table S2: Example of a mutation presented in 9 distinct articles; Table S3: Additional polymorphisms in other genes associated with HS (78) in the literature, including the two new variants identified in our cohort; Data S1: Complete catolog of variants in a .vcf file left-normalized.

Author Contributions

Conceptualization, S.H., Y.L.; methodology, K.M., C.D.R., V.L.G.; software, K.M., V.L.G., F.S., L.M.; validation, K.M.; formal analysis, C.D.R., K.M., V.L.G., E.L.F.; resources, S.H., J.F.D., J.L.C., B.B., P.W., C.H., F.J.L., D.D., R.O.; investigation, K.M., V.L.G., L.M.; data curation, S.H., K.M., F.J.L.; writing – original draft preparation, K.M.; writing – review and editing, K.M., S.H., J.F.D., E.B.; visualization, K.M.; supervision, S.H., J.F.D., E.B., V.M.; project administration, S.H., J.F.D., E.B., V.M., K.M., Y.L.; funding acquisition, S.H., J.F.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partly supported by the French “Agence Nationale de la Recherche” (ANR) under project ANR-20-CE17-0019.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Henri Mondor Hospital (protocol code 10-026 – 13 septembre 2010).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Acknowledgments

We would like to acknowledge the French Exome Consortium for granting us access to their cohort as the control group for this study.

Conflicts of Interest

The authors declare no conflict of interest.

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Preprints 114390 g001
Figure 1. Computational models of the NCSTN protein. In cyan, red, and grey: the cytosolic, transmembrane (TM), and extracellular regions or domains. In pink: the signal peptide responsible for adressing the protein to the membrane. In green: the small lobe that would interact with the substrate. In dark blue: the large lobe. (a) Reference (WT), (b) p.Ala300TrpfsTer20 (W300), (c) p.Arg429*, and (d) p.Trp648* variant models.
Figure 1. Computational models of the NCSTN protein. In cyan, red, and grey: the cytosolic, transmembrane (TM), and extracellular regions or domains. In pink: the signal peptide responsible for adressing the protein to the membrane. In green: the small lobe that would interact with the substrate. In dark blue: the large lobe. (a) Reference (WT), (b) p.Ala300TrpfsTer20 (W300), (c) p.Arg429*, and (d) p.Trp648* variant models.
Preprints 114390 g001
Table 1. Characteristics of the 100 HS patients.
Table 1. Characteristics of the 100 HS patients.
Individual characteristics Male Female All ND
 N 36 64 100 -
 Age (mean ± sd) 33.8 ± 12.2 34.6 ± 11.1 34.0 ± 11.5 2
 BMI (mean ± sd) 26.1 ± 4.5 27.1 ± 5.1 26.8 ± 4.8 4
 Smoking status 21 (67.7%) 44 (72.1%) 65 (70.6%) 8
 Familial case 7 (36.8%) 21 (37.5%) 28 (37.3%) 25
 IBD history 0 1 (1.8%) 1 (1.3%) 25
 Rhumatological history 0 2 (3.6%) 2 (2.7%) 25
Hurley
 I (mild) 4 (12.5%) 11 (17.2%) 15 (15.6%) 4
 II (moderate) 12 (37.5%) 30 (46.9%) 42 (43.7%)
 III (severe) 16 (50.0%) 23 (35.9%) 39 (40.6%)
Table 2. All 91 γ-secretase variants found in the literature, including the eight new variants identified in our cohort.
Table 2. All 91 γ-secretase variants found in the literature, including the eight new variants identified in our cohort.
Gene ID Position (GRCh38) Ex. c/p.HGVS Eff. rsID R. Or. F/S Association
APH1A (ENST00000369109) 1 1:150267780 3 p.D98E mis|spl rs996158631 0 div. – –
APH1B (ENST00000261879) 2°N 15:63277702 1 p.T27A mis rs77834210 0 FR* S –
3°N 15:63279258 2 p.L71V mis – 0 FR* S –
4 15:63302375 5 p.H170R mis rs139355584 2 div. F –
5°N 15:63302416 5 p.K185Sfs*10 fs rs745918508 0 FR* S –
6 15:63305770 6 p.R255C mis rs142676640 0 div. – –
NCSTN (ENST00000294785) 7 1:160343408 1 p.G6Vfs*22 fs rs1266104510 0 div. – –
8 1:160343434 1 p.G13Efs*15 fs – 3 DE S AC
9°N 1:160343443 1 p.L17Sfs*30 fs – 0 FR* S –
10 1:160344733 2 p.G33R mis|spl – 6 JP F –
11 1:160344767 2 p.L44* non – 0 BR F DDD
12 1:160344818 2 p.G61V mis – 3 FR*|MT* F –
13 1:160349018 3 p.V72Yfs*16 fs rs1243425689 10 CN F –
14 1:160349031 3 p.V75I mis rs12045198 10 CN F –
15° 1:160349039 3 p.E77D mis rs35603924 0 div.|FR* S –
16 1:160349086 3 p.P93Lfs*15 fs – 8 CN FS SAPHO
17 1:160349578 4 p.T115Nfs*20 fs – 9 FR* – PASH
18 1:160349583 4 p.R117* non rs387906896 10 CN|US*|AfUS F –
19 1:160349799 4-5 c.436+129A>G int rs2274184 0 SG FS –
20 1:160350115 5 p.N150Ifs*52 fs – 2 CN F –
21 1:160350118 5 p.S151Qfs*48 fs – 4 CN F –
22 1:160350145 5 p.C159* non – 9 CN|GR* F –
23 1:160350150 5 p.I162Yfs*40 fs – 1 IT* S PASH/SAPHO
24 1:160350155 5 p.Q163Sfs*39 fs – 10 FR F –
25 1:160350165 5 p.S166* non – 6 CN F –
26 1:160350221 5 p.D185N mis rs201293070 9 GB* S Diab
27 1:160350251 5-6 c.582+1del(G) spl* – 10 JP F –
28 1:160350251 5-6 c.582+1G>A spl rs1373027391 0 SG FS –
29 1:160351256 6 p.S206* non – 7 CN* F –
30 1:160351271 6 p.P211R mis – 10 CN S –
31 1:160351286 6 p.Q216P mis – 9 CN|MT* F –
32 1:160351310 6 p.V224_T227del del – 3 MT F –
33 1:160351325 6 p.C230Pfs*32 fs – 8 CN|IN F AC
34 1:160351713 7 p.L251Vfs*2 fs – 3 CN F Com
35 1:160351755 7 p.T265Nfs*8 fs – 2 CN F –
36 1:160352097 8 p.E296G mis rs758910156 7 CN|MT* F –
37°N 1:160352104 8 p.A300Wfs*20 fs – 0 FR* F –
38 1:160352154 8 p.A315V mis rs1553210405 9 CN F –
39 1:160352188 8 p.M326Ifs*31 fs – 5 SG – –
40 1:160352207 8-9 p.E333Q367del(x9) spl* – 5 GB F –
41 1:160352213 8-9 c.996+7G>A int rs202046846 9 GB*|FR* S AC|Diab
42 1:160352992 9-10 c.1101+1G>A spl rs1347055289 10 GB F –
43 1:160353001 9-10 c.1101+10A>G int rs1048828525 9 GB* S –
44 1:160353198 10 p.D381Sfs*7 fs – 1 IT* S PAPASH
45° 1:160354113 10-11 c.1180-5C>G int rs7528638 5 GB|FR* F –
46 1:160354167 11 p.A410V mis rs147225198 6 US* S –
47° 1:160354187 11 p.N417Y mis rs143039637 0 div.|FR* S –
48 1:160354190 11 p.Q418* non – 0 div. – –
49 1:160354196 11 p.Q420* non – 10 CN|SG|div. F –
50° 1:160354223 11 p.R429* non rs771414318 5 JP|FR* F –
51 1:160354232 11 p.R432* non – 3 CN* FS KTS
52 1:160354238 11 p.R434* non rs1085307081 10 CN|ES*|FR F DDD
53 1:160354263 11 p.D443Lfs*6 fs – 3 ES* – DDD
54 1:160354291 11-12 c.1352+1G>A spl – 9 CN F –
55 1:160354194 11 c.1381del(C) fs – 2 FR* F –
56 1:160355941 13 p.Q512* non – 3 CN* F –
57 1:160355959 13-14 p.A486_T517del(x13) spl* rs1553210984 9 CN F –
58 1:160356263 14 p.T519Nfs*10 fs – 3 CN S –
59 1:160356343 14 p.Y545* non – 8 IR F PASH
60 1:160356655 15 p.Y565* non – 10 CN F –
61 1:160356662 15 p.Q568* non – 9 JP F –
62 1:160356687 15 p.G576V mis – 3 FR*|MT* F –
63 1:160356707 15 p.R583* non – 3 IT* F DDD
64 1:160356712 15 p.E584Dfs*44 fs rs1553211087 10 CN F –
65 1:160356728 15 p.S590G/p.S590Afs*3 mis|spl – 10 FR F –
66 1:160357046 16 p.Y600* fs – 6 CN|IN FS AC
67 1:160357122 16 p.R626* non – 3 ES*|IN F DDD|AC
68 1:160357161 16 p.Q639Gfs*31 fs – 5 NL F –
69°N 1:160357189 16 p.W648* non – 0 FR* S –
70 1:160358788 3’ c.*517_*518del(CA) utr rs141849450 4 CN S –
PSEN1 (ENST00000324501) 71 14:73186897 6 p.S178Ffs*10 fs rs1174374799 0 div. – –
72 14:73192820 7 p.P242Lfs*11 fs rs1595035030 10 CN F –
73° 14:73198145 8-9 c.868+16G>T int rs165932 4 CN|div.|FR* S Ps
74° 14:73206470 9 p.E318G mis|spl rs17125721 8 GB|div.|FR* F –
75°N 14:73211786 10 p.Q325E mis – 0 FR* S –
76 14:73217163 11 p.S390Efs*20 fs – 3 FR* F Crohn
77° 14:73217252 11-12 c.1248+8T>C int rs362382 0 div.|FR* S –
PSEN2 (ENST00000366783) 78°N 1:226882007 4 p.G34S mis rs200636353 0 FR* S –
79 1:226894073 12 p.T380K mis rs143912759 0 div. – –
PSENEN (ENST00000587708) 80 19:35745943 2 p.R5* non – 3 CN F –
81 19:35745965 2 p.L12* non rs1555738763 5 DE – DDD
82 19:35745973 2 p.C15Pfs*101 fs – 5 JP F AC
83 19:35746418 2-3 p.G21_Y56del(x3) spl* rs1555738836 4 IN F DDD
84 19:35746418 2-3 c.62-1G>T spl – 5 IN* F DDD
85 19:35746423 3 p.F23Vfs*98 fs rs1555738837 10 GB*|FR* FS DDD
86 19:35746423 3 p.F23Lfs*46 fs rs1555738837 10 CN FS DDD|Ps
87 19:35746441 3 p.L29Sfs*92 fs – 3 TH F DDD
88 19:35746472 3 p.R39* non – 5 DE – DDD
89 19:35746525 3-4 p.G21_Y56del(x3) spl* rs1970575677 5 FR F DDD
90 19:35746706 3-4 c.167-2A>G spl rs1555738903 7 CN F DDD
91 19:35746709 4 p.Y56* non rs751542345 8 Jash|FR* F DDD|IBD|PS
92 19:35746735 4 p.L65R mis rs1555738906 7 CN F Com|DDD
93 19:35746756 4 p.S73Pfs*72 fs – 1 DE – DDD
94 19:35746769 4 p.I77Hfs*45 fs – 1 CN F PASH
95 19:35746770 4 p.I77Tfs*45 fs – 4 CN* F DDD
96 19:35746812 4 p.Y91Tfs*54 fs – 2 div. F –
97 19:35746819 4 p.F94Sfs*51 fs rs1555738943 9 CN F –
98 19:35746833 4 p.L98Wfs*47 fs – 2 div. F –
99 19:35746845 4 p.*102Rxt*50 elg – 3 FR* – DDD|Diab
This table concerning γ-secretase genes: APH1A [17], APH1B [16,17,36], NCSTN [12,17,24,36,41,42,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101], PSEN1 [17,36,54,55,59,73,102], PSEN2 [17], PSENEN [16,17,56,59,73,91,102,103,104,105,106,107,108,109,110,111,112,113]. The lines with an (°) and in bold correspond to the above-mentioned variants (15) found in our HS cohorts. Those with an (N) are the new ones (8), not mentionned in the literature. Ex.: exons; Eff.: effect (del, elg, fs, int, mis, non, spl, spl*, and utr meaning respectively deletion with no frameshift, elongation, frameshift, intronic variant, missense, nonsense, splice site, known alternative splicing event, and untranslated region variant); R.: number of studied reviews [13,59,78,88,100,114,115,116,117,118,119] (out of 11) citing this mutation; Or.: origin. The two-letter country code was used for the various studies (BR:Brazil; CN:China; DE:Germany; ES:Spain; FR:France; GB:United Kingdom; IN:India; IR:Iran; IT:Italy; JP:Japan; MT:Malta; NL:Netherlands; SG:Singapour; TH:Thailand; US:United States and AfUS and Jash for African-American and Jewish Ashkenazi populations). When the code is followed by an asterisk (*), it indicates that the population is not explicitly mentioned in the article, and the country is inferred based on the authors’ affiliations ; F/S: familial and/or sporadic case. The last column lists the disease and/or syndrome associations mentioned in the articles — all acronyms are defined in Supplementary Figure S1.
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Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
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