Current Issue

Spring/Summer 2025, Vol. 32 No. 1

Hong Kong J. Dermatol. Venereol. (2025) 32, 42-50

Review Article

Genodermatoses: improving diagnostics and patient care

遺傳性皮膚病：診斷與病患照護之進展

YR Lee 李昱融, PC Lin 林培琪, HC Cheng 鄭慧卿, PC Hou 侯秉宸, CK Hsu 許釗凱, JA McGrath

Abstract

Genetic skin diseases (genodermatoses) are rare, clinically complex conditions which present both diagnostic and therapeutic challenges. Historically, diagnosis for most dermatologists often depended on clinical familiarity or clues from skin biopsy assessment by light, electron or immunofluorescence microscopy. With the advent of gene discovery in the 1990s, Sanger sequencing of candidate genes led to molecular diagnostics for a few disorders. However, the introduction of next generation sequencing in 2008 heralded a new era of diagnostic improvements. This review focuses on recent advances in diagnostics for genodermatoses, illustrating the beneficial impact on genetic counselling and treatments for patients and their families.

遺傳性皮膚病是一群罕見且臨床表現極為複雜的疾病，無論在診斷或治療上都構成重大挑戰。過去，多數皮膚科醫師主要依賴臨床經驗，搭配光學顯微鏡、電子顯微鏡及免疫螢光染色等皮膚切片檢查進行診斷。自1990年代起，隨著致病基因陸續被發現，桑格定序技術開始用於特定疾病的分子診斷。然而，2008年次世代定序技術的問世，開啟了基因診斷的新紀元。本文回顧近年來在遺傳性皮膚病診斷技術的重大進展，並透過臨床案例說明這些技術如何促進基因諮詢與個人化治療，進而提升患者及其家庭的整體照護品質。

Keywords: Genodermatoses, Next-generation sequencing, Personalised medicine, RNA sequencing. Whole exome sequencing, Whole genome sequencing

關鍵詞: 遺傳性皮膚病、次世代定序、個人化醫療、RNA定序、全外顯子定序、全基因體定序

Introduction

In human genetics there are approximately 8000 Mendelian disorders, at least 1000 of which affect the skin. Within most of these cutaneous entities, the skin is the major organ involved and thus this sub-group of conditions is referred to as "genodermatoses". However, genodermatoses are clinically and genetically heterogeneous, which often creates diagnostic challenges for dermatologists. Until the late 1980s, diagnosing genodermatoses was mainly done using clinical skills complemented by skin biopsy assessment, such as the use of transmission electron microscopy for assessing inherited skin fragility (epidermolysis bullosa, EB) or abnormal epidermal structure (mostly ichthyoses).¹ Assessment was refined following the introduction of immunofluorescence microscopy using antibodies to target skin antigens (e.g. for severe forms of EB), but all these tests were only applicable to a select group of genodermatoses and thus the diagnostic challenges still prevailed.

The first genetic breakthrough for genodermatoses only occurred in 1987, when microdeletions were discovered in the STS gene (steroid sulphatase) in X-linked ichthyosis.² After that, during the 1990s, genetic linkage studies led to the discovery of the keratin 5 and 14 genes (KRT5 and KRT14) in EB simplex,³ the transglutaminase 1 gene (TGM1) in autosomal recessive congenital ichthyosis,⁴ and the type VII collagen gene (COL7A1) in dystrophic EB.⁵ The 1990s also saw a big uptick in Sanger sequencing (first invented in the late 1970s) in which individual exons and flanking introns of genes could be sequenced to find pathogenic variants using a chain termination method of chemical labelling of DNA.⁶

The giant leap forward in diagnostic methodology for genodermatoses, however, occurred around 2008 with the introduction of next-generation sequencing (NGS). One form of NGS, known as whole exome sequencing (WES), has led to the discovery of more than 140 genodermatosis genes and approximately 40 brand new genodermatoses.⁷ Indeed, the first successful application of WES in dermatology was in 2011 with identification of the major pustular psoriasis gene (IL36RN), encoding the receptor antagonist of IL-36.⁸

In this review, we reflect on the approach to assessing patients with genodermatoses to establish rapid and accurate molecular diagnoses. We also illustrate two cases to demonstrate clinical benefits in improving genetic counselling and treatment options.

Diagnostic approaches in genodermatoses

1. Clinical and pathological data
Clinical and pathological data are important in diagnosing genodermatoses, as they provide a foundation for interpreting genetic findings. The clinical presentation, including the onset, distribution, and progression of skin lesions, along with associated systemic features, offers clues for narrowing down differential diagnoses. Pathological data obtained from skin biopsies can reveal hallmark features such as epidermal abnormalities, specific inflammatory patterns, or defects in dermal or adnexal structures, which are often characteristic of certain genodermatoses.⁹ Integrating these data with genetic analyses enhances diagnostic accuracy, as clinical and pathological insights help prioritise gene targets and interpretation of genetic variants. Thus, for dermatologists, the key message – even in an era of molecular diagnostics – is to continue to take a full history and always consider the possible insights a skin biopsy can provide.

2. Family pedigree
The family pedigree is pivotal in diagnosing genodermatoses, as it provides a record of genetic inheritance patterns across multiple generations, helping determine autosomal dominant, autosomal recessive, X-linked, or mitochondrial inheritance. This information facilitates targeted genetic testing, and aids in distinguishing hereditary conditions from sporadic or acquired ones. Moreover, pedigrees assist in identifying at-risk individuals within families, allowing for early diagnosis and preventive interventions. Creating a pedigree is important even if there is only a single affected individual, as involving both unaffected parents (as a "trio") may be necessary for any genetic studies (e.g. in distinguishing autosomal recessive from de novo autosomal dominant inheritance).

3. Sanger sequencing
Nowadays, Sanger sequencing remains a reliable method for genetic testing. Known for its accuracy and sensitivity, it is ideal for analysing genomic regions up to 1,000 base pairs and detecting single nucleotide variants (SNVs), small indels, and base pair-level changes. Despite advancements in NGS technology, Sanger sequencing is widely used for variant confirmation, family segregation analysis, and cost-effective diagnostics. For genodermatosis diagnostics, Sanger sequencing is used to sequence a polymerase chain reaction product often spanning an individual exon and flanking introns (or a few closely packed exons) but is considered too costly and laborious for more comprehensive gene screening. For example, before NGS, to examine the 118 exons of the COL7A1 gene in dystrophic EB, Sanger sequencing of more than 70 PCR products was required.¹⁰

4. Next-generation sequencing (NGS)
Next-generation sequencing encompasses advanced genetic testing methods, including WES, whole genome sequencing (WGS), and RNA sequencing. Since 2008, these approaches have revolutionised the diagnostic landscape by providing high-throughput, precise, and comprehensive analyses of genetic variants.¹¹ For dermatologists, samples for such tests involve blood collection in EDTA (purple top) tubes or saliva (multiple commercial kits available, e.g. see dnagenotek.com).

(A) Whole exome sequencing (WES): This method focuses on the protein-coding regions of the genome, which comprise about 1.5% of the genome but contain nearly 85% of disease-causing variants.¹² WES has proven particularly valuable in medical genetics, including genodermatoses, due to its ability to identify SNVs, small insertions, and deletions that often underlie many rare genetic disorders. These disorders, frequently characterised by diverse phenotypes, multiple causative genes, or overlapping symptoms - such as EB,¹³ ichthyosis,¹⁴ and palmoplantar keratoderma (PPK),¹⁵ present diagnostic challenges that WES effectively addresses. To reduce costs and speed the diagnostic process, WES data may also be filtered into specific gene panels according to clinical data or likely diagnosis. Such panels often form the basis of current diagnostic services in healthcare settings.

(B) Whole genome sequencing (WGS): Unlike WES, WGS provides a comprehensive view of the entire genome, including coding and non-coding regions. This method is particularly advantageous for detecting structural variations, deep intronic mutations, and complex rearrangements. While more expensive than WES, WGS offers a higher diagnostic yield and is invaluable for conditions with atypical presentations or previously undetected gene pathology.¹⁶ Acquiring personal data on an individual's 3.2 billion nucleotide in their genomic DNA through WGS may also provide an investment in future healthcare, as the disease relevance of other health and disease associated variants (currently of unknown significance) become apparent when new insights into the human genome emerge.

(C) RNA sequencing (RNA-Seq): RNA-Seq analyzes the transcriptome, providing insights into gene expression levels, alternative splicing, and the functional impact of genetic variants. This approach is useful for detecting pathogenic variants in regulatory regions or identifying aberrant splicing events that may not be evident in DNA-based analyses. It complements WES and WGS by adding a functional layer to the genetic data.¹⁷ Thus, RNA-seq has double-value potential – it can identify the pathogenic variant and, by also appreciating its impact on gene (and likely protein) function, it generates greater insights into disease pathobiology.

(D) Integrated strategies for variant pathogenicity assessment: After genetic testing, the interpretation of a variant necessitates a systematic and standardised approach, guided by the ACMG/AMP (American College of Medical Genetics and Genomics/Association for Molecular Pathology) guidelines.¹⁸ These guidelines provide a comprehensive framework for classifying variants into categories such as "pathogenic," "likely pathogenic," "uncertain significance," "likely benign," and "benign", and may be numbered from 5 to 1, respectively, in molecular genetics reports. Dermatologists need to become familiar with these definitions and their clinical significance, such that reading a molecular report should be no different from interpreting a dermatopathology report.

To assess whether a variant has been previously reported and its classification, clinical database analysis is employed, utilising resources like ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/), VarSome (https://varsome.com/), HGMD (https://www.hgmd.cf.ac.uk/), and OMIM (https://omim.org/). Furthermore, population frequency assessments through databases such as gnomAD (https://gnomad.broadinstitute.org/) and 1000 Genomes (https://www.internationalgenome.org/) help determine if the variant is sufficiently rare to be considered pathogenic. In addition, computational prediction tools like PolyPhen-2, SIFT, and CADD are utilised to perform in silico evaluations of the variant's likely pathogenicity.¹⁹

Although not typically needed for molecular diagnostic laboratory reporting, new variants may require characterisation through functional studies at the RNA level, such as RT-PCR and RNA sequencing, to identify splicing defects and alterations in gene expression. At the protein level, analyses like Western blotting, immunohistochemistry, and mass spectrometry assess changes in protein expression, stability, and function. Family segregation analysis through targeted Sanger sequencing in both affected and unaffected relatives helps determine whether a variant co-segregates with the disease phenotype to underscore disease relevance.

5. Array comparative genomic hybridisation (aCGH) and multiplex ligation-dependent probe amplification (MLPA)
These methods are used to detect copy number variations (CNVs) and other structural changes in the genome. aCGH compares patient DNA to a reference genome to identify deletions and duplications, while MLPA provides a targeted approach to analyse specific genomic regions for CNVs or methylation abnormalities.^20,21 For genodermatoses, MLPA might be used to assess a case of suspected X-linked ichthyosis in which a large genomic deletion may be present.²²

Case studies of genodermatoses

Case 1: Unveiling hidden risks through genetic testing
A 40-year-old male presented with longstanding asymptomatic erythematous papules and nodules on the left post-auricular region (Figure 1a). Histopathological analysis confirmed leiomyomas, characterised by spindle cells with cigar-shaped nuclei (Figures 1b and 1c). Based on the clinicopathological features, we performed Sanger sequencing of the FH gene, the only known causative gene. We identified a heterozygous 5-bp germline deletion (c.395_399delTAAAT; p.Leu132Ter) in exon 4 (Figure 1d). He was the only currently clinically affected individual in his family, although segregation analysis revealed the same variant in his father and two of his three children (Figure 1e).

Figure 1 Clinical, histopathological, and genetic analysis in a patient with multiple cutaneous and uterine leiomyomatosis (MCUL) (a) Clinical appearances showing erythematous papules and nodules on the patient's left neck. (b) Histopathological study shows a relatively well-defined nodule composed of spindle cells in the upper two-thirds of the dermis. (Haematoxylin and eosin (H&E) staining, x40) (c) Higher magnification showing spindle cells with cigar-shaped vesicular nuclei. (H&E staining, x100) (d) Sanger sequencing of genomic DNA from peripheral blood of the proband (II-2) reveals a 5-base pair germline deletion (c.395_399del; p.Leu132_Asn133delinsTer) in exon 4 of the FH gene, as shown in the upper panel. (e) Family pedigree of the proband. Genotypes (+/−, −/−) indicate heterozygous and homozygous variants, respectively.

Multiple cutaneous and uterine leiomyomatosis (MCUL, OMIM #150800), known as Reed's syndrome, is caused by pathogenic variants in FH, which encodes fumarate hydratase, a key enzyme in the Krebs cycle. This is an autosomal dominant condition with variable penetrance.²³ The key questions arising from the molecular findings are (a) what are the health implications for our patient and (b) what is the relevance of the data to other family members with this FH variant?

Apart from the painful lumps in his skin, one other consideration is the future risk of renal cancer, given data showing estimated lifetime risk of renal cell carcinoma development in FH variant carriers being around 15%, with a mean age of around 40 years.²⁴ Annual renal imaging using magnetic resonance imaging is recommended for the patient and their variant-positive family members,²⁵ since the tumours are often iso-echoic and hard to detect by ultrasound. This renal screening advice is also relevant to his father and two of his three children. Regarding the skin, although the carrier individuals have no cutaneous leiomyomas, they are all potentially at risk from developing such benign but often painful lumps. Also relevant to his daughter (III-2 in the pedigree shown in Figure 1e) is the risk of uterine fibroids, Cutaneous leiomyomas typically manifest in the late teens or early twenties, whereas uterine fibroids in females usually develop in the late twenties, which may have implications for fertility and family planning.²⁶

Case 2: From genetic diagnosis to personalised treatment
A 40-year-old male presented with asymptomatic thickening and hardening of the palms and soles since childhood, characterised by prominent wrinkling upon water immersion and limited benefits from conventional treatments. Lesional skin biopsy revealed hyperkeratosis with epidermal hyperplasia and sparse superficial perivascular infiltrates, consistent with PPK. WES identified compound heterozygous variants in the SERPINB7 gene: c.455G>T; p.Gly152Val in exon 6 and c.647_650del; p.Ser217Leufs*7 in exon 7. The missense variant (p.Gly152Val) was evaluated using VarSome and ClinVar and classified as likely pathogenic (class 4 variant), whereas the frameshift (c.647_650del) results in a premature stop codon (class 5 pathogenic variant); both variants have been previously reported.^27,28

Nagashima-type PPK (NPPK, OMIM #615598) is an autosomal recessive disorder and the most common type of PPK in East Asia. It is caused by biallelic variants in SERPINB7, which impair epidermal differentiation and keratinocyte homeostasis, leading to diffuse acral hyperkeratosis, hyperhidrosis, and spongy white changes after water exposure.²⁸

Traditionally, treatments for PPK rely on symptomatic relief with emollients and keratolytics. A recent breakthrough in the management of NPPK, however, involves gentamicin readthrough therapy, a targeted approach that addresses the underlying genetic defect. Gentamicin is an aminoglycoside antibiotic that facilitates translational readthrough of premature termination codons (PTCs) arising from nonsense mutations.²⁹ Two investigator-blinded or double-blinded studies have demonstrated significant clinical improvement in gentamicin-treated areas, reinforcing the potential of this approach in NPPK management.^30,31 Notably, more than 90% of NPPK cases in East Asian descent carry a founder nonsense mutation c.796C>T (p.Arg266∗), and it is these individuals for whom gentamicin may improve their PPK.³⁰ However, such treatment is not appropriate for all NPPK patients. For instance, in our case, the patient had one missense and one frameshift mutation in SERPINB7, making him unsuitable for gentamicin readthrough therapy. Thus, the molecular data help avoid inadvertent prescribing of a treatment that would not work in our patient.

Figure 2 Clinical presentation, family pedigree and genetic study of a patient with Nagashima-type palmoplantar keratoderma (NPPK). (a) Clinical photographs showing diffuse thickening of the palms (left) and the soles (middle) The condition extends beyond the edges of the soles, a phenomenon known as transgrediens (right). (b) Pedigree of the affected family (c) WES visualization with the integrative genomics viewer (IGV), showing compound heterozygous variants in SERPINB7: c.455G>T missense variant in the upper panel and c.647_650del frameshift variant in the lower panel.

Discussion

Ideally, for patients with genodermatoses identifying an underlying genetic abnormality would lead directly to a targeted form of gene therapy. Despite some progress in this endeavour, such as the approval of topical COL7A1 gene therapy in 2023 for patients with dystrophic EB,³² the delivery of gene therapy for genodermatoses is ongoing work, and other treatment benefits are perhaps less tangible (but still important to patients). The two cases presented here highlight the value of obtaining a personal genetic diagnosis, notably with implications for genetic counselling as well as appropriateness of therapy. But advances in characterising genodermatoses are having much more widespread benefits for patients, particularly when implication of a certain gene in disease pathobiology leads to the prescription of a disease modifying or symptom alleviating drug. One recent example of such therapeutic progress is in the genetically heterogeneous disorder ILVEN (inflammatory linear verrucous epidermal naevus), which exhibits similar clinical features but arises from variants in any one of seven genes (CARD14, GJA1, PMVK, NSDHL, KRT10, HRAS or ABCA12).^33,34 However, these genes have been linked to potential bespoke treatments. Notably, if caused by CARD14 variants, then ustekinumab may be helpful;³⁵ or if associated with PMVK/NSDHL variants, the best treatment could be a topical cholesterol/statin combination;³⁶ or if the gene screening reveals ABCA12 variants, a janus kinase inhibitor may be appropriate to prescribe.³⁷ Another significant advance is in the autosomal dominant mutilating form of PPK, Olmsted syndrome, in which characterisation of the epidermal hyperplasia revealed activation of epidermal growth factor receptor (EGFR) signalling.³⁸ Thereafter, treatment with an EGFR inhibitor, such as low dose oral erlotinib, has been effective in substantially reducing the keratoderma.³⁸

Gleaning benefits from DNA sequencing for many patients with genodermatoses, however, remains a challenging enterprise, despite the significant advancements in genetic testing technologies. The high cost and limited accessibility of these tools hinder widespread application, particularly in low-resource settings. Moreover, the interpretation of variants of unknown significance remains a complex task, often requiring functional validation and expert consensus, which can delay clinical decision-making.³⁹ Future efforts should focus on increasing access to genetic diagnostics, streamlining variant interpretation through advanced bioinformatics, and addressing the societal implications of genetic testing to maximise its potential benefits.

Beyond these technical and logistical challenges, the ethical and psychosocial dimensions of genetic testing also demand attention. Issues such as informed consent, privacy concerns, and the risk of genetic discrimination must be navigated responsibly. By addressing barriers to accessibility and ethical considerations, we can ensure that the benefits of genetic testing and personalised medicine reach all patients, ultimately transforming the care landscape for genodermatoses.

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