Aug 2026· International Journal of Molecular Sciences· 0 citations· 27 references
TL;DR
Overall, this review synthesizes the molecular basis of all four major EB types across 16+ classical genes, highlights the paradigm shift where NGS achieves a diagnostic yield exceeding 90%, and critically assesses recent therapeutic milestones—ranging from the first FDA-approved topical gene therapy to precision RNA and genome-editing modalities.
Abstract
Epidermolysis bullosa (EB) is a heterogeneous group of inherited disorders characterised by skin fragility, caused by pathogenic variants in genes encoding structural components of the dermo-epidermal junction. With the advent of next-generation sequencing (NGS), the diagnostic paradigm has shifted from a morphological to a genotype-oriented approach. This review summarises the genetic architecture of EB, the types of mutations and genotype–phenotype relationships, the challenges in interpreting variants of unknown significance (VUS), and therapeutic strategies targeting specific mutational mechanisms, including read-through approaches, exon skipping and genome editing. The role of modifier genes and epigenetic factors in clinical variability is also discussed. The focus is on the translational potential of genomics for personalized therapy in EB. Overall, this review synthesizes the molecular basis of all four major EB types across 16+ classical genes, highlights the paradigm shift where NGS achieves a diagnostic yield exceeding 90%, and critically assesses recent therapeutic milestones—ranging from the first FDA-approved topical gene therapy to precision RNA and genome-editing modalities.
Inherited genodermatoses are a heterogeneous group of rare monogenic disorders. Among these, epidermolysis bullosa (EB) and ichthyoses represent paradigmatic disorders characterized by severe skin fragility and hyperkeratosis, respectively, and impaired barrier function, often with profound effects on quality of life and systemic health. Current management remains largely palliative, underscoring the urgent need for disease-modifying therapies. Over the past 2 decades, advances in epithelial stem cell biology, vector engineering and genome editing technologies have transformed the therapeutic landscape for genodermatoses.
Ex vivo
gene therapy has provided the first proof that genetically corrected epidermal stem cells can achieve long-term tissue regeneration in EB skin patients, establishing a new paradigm for regenerative medicine. In parallel, the emergence of programmable genome engineering platforms, including CRISPR/Cas nucleases, base editors and prime editors, have enabled increasingly precise strategies for mutation-specific correction in both recessive and dominant disorders. Furthermore, the development of
in vivo
topical approaches is expanding the possibility of directly targeting the skin. Despite these advances, substantial translational barriers continue to limit broad clinical implementation. Efficient and durable targeting of epidermal stem cells within a highly regenerative tissue, together with safe delivery across the skin barrier, stringent control of off-target activity, scalable manufacturing and demonstration of long-term safety, remain major challenges for the clinical translation of these approaches. In this Review, we discuss the current state of gene therapy for genodermatoses, highlighting key clinical milestones, emerging genome editing technologies and next-generation delivery systems. We further examine the biological and regulatory challenges that need to be overcome to bridge the gap between experimental innovation and clinically accessible therapies for patients with inherited skin diseases.
A. Fabrizi, Marta Valenti, Silvia Zacchino et al.· Frontiers in Bioengineering...· 0 citations
Hypospadias is one of the most common birth defects in China and a key feature of differences in sex development (DSD), yet its genetic etiology remains largely unresolved. Current diagnostic approaches using DSD-targeted gene panels have a low rate of definitive diagnoses (5.5%), highlighting the need for more comprehensive genetic investigation. In this study, we performed next-generation sequencing (NGS) on the largest trio-based cohort of hypospadias to date, comprising 106 pediatric cases and their parents (92 trios). We achieved a definitive genetic diagnosis in 6.6% of patients, identifying pathogenic variants in canonical DSD genes such as AR, NR5A1 and WT1. By incorporating a broader spectrum of potentially clinically significant variants, we increased the overall genetic identification rate to 33.0% (35/106). Strikingly, trio analysis uncovered a significant burden of de novo loss-of-function (LoF) variants (2.2-fold enrichment, P=0.001), primarily driven by variants in genes associated with ciliopathies (10.35-fold, P=0.016), a previously underappreciated gene class in hypospadias. Furthermore, we identified and functionally validated two high-confidence risk genes, PRKCZ and HRNR, based on recurrent de novo variants. Functional assays confirmed that these variants disrupt key biological mechanisms, including cell proliferation, migration, and androgen signaling. Our large-scale trio approach substantially expands the genetic landscape of hypospadias, demonstrates the critical value of trio-based sequencing for improving diagnostic yield, and decisively implicates ciliary genes in its pathogenesis.
Yanqin You, Yingliu Luo, Honghui Zhou et al.· Science China Life Sciences· 0 citations
ABSTRACT Junctional epidermolysis bullosa (JEB) is a hereditary skin disorder caused by defects in proteins responsible for dermal‐epidermal adhesion. We investigated the genetic cause of JEB in three related mixed‐breed puppies presenting with congenital skin blistering and ulceration. Whole‐genome sequencing of one affected dog followed by comparison with 1538 control genomes identified a private candidate variant, XM_038543644.1:c.5690_5691ins240, in LAMA3, a known JEB‐associated gene. Visual inspection of the short‐read alignments and Sanger sequencing revealed a homozygous 240‐bp SINE insertion in exon 45 that had initially been miscalled as a heterozygous short insertion. Fragment length analysis confirmed complete co‐segregation of the variant with the disease phenotype within the available family. The SINE insertion is flanked by a 16‐bp target site duplication, contains a 45‐nt poly(A) tail, and is predicted to remain in‐frame, introducing an additional 80 amino acids into the laminin α3 coiled‐coil domain without introducing a premature stop codon. Although the molecular consequences were not functionally investigated, the insertion is expected to disrupt normal laminin‐332 heterotrimer assembly and secretion. This study expands the spectrum of pathogenic LAMA3 variants associated with canine JEB and highlights the importance of visual inspection of short‐read sequencing data for the detection and correct interpretation of structurally complex variants such as transposable element insertions.
S. Kiener, R. Kaufmann, Ori Brenner et al.· Animal Genetics· 0 citations
Rothmund-Thomson syndrome (RTS) represents a paradigm of the intricate intersection between dermatologic phenomics, genomic instability, and oncologic predisposition. This comprehensive review synthesizes current knowledge regarding this ultra-rare autosomal recessive genodermatosis, which classically manifests with the pathognomonic triad of poikiloderma, juvenile cataracts, and skeletal dysplasias, while conferring a substantially elevated lifetime risk for osteosarcoma and cutaneous malignancies. Over the past decade, significant nosological refinement has emerged from the elucidation of biallelic pathogenic variants in RECQL4 and ANAPC1 as the primary molecular etiologies underlying RTS type 2 and type 1, respectively. However, the recent identification of DNA2 and CRIPT variants in affected individuals without identifiable alterations in the canonical genes has further unraveled the genetic heterogeneity of this condition, challenging traditional classification paradigms and expanding the continuum of RECQL4-related disorders. We critically examine the evolving landscape of RTS molecular diagnostics, emphasizing the genotype-phenotype correlations that distinguish RECQL4-associated multisystemic involvement—characterized by radial ray defects, patellar hypoplasia, and a striking predisposition to osteosarcoma—from the ANAPC1-related subtype wherein cataracts predominate without malignant transformation. The role of RECQL4 as a cornerstone of genomic maintenance through its participation in replication fork stabilization, double-strand break repair, and telomere homeostasis is explored in depth, providing mechanistic insights into the cellular fragility that underlies the premature aging phenotype and neoplastic progression. Current evidence regarding surveillance protocols, including the contentious role of routine imaging for osteosarcoma screening and the utility of pulsed dye laser therapy for telangiectatic lesions, is critically appraised. Furthermore, we highlight emerging therapeutic avenues, including the potential for targeted DNA damage response modulation and the importance of genotype-informed cancer risk stratification. By integrating the most recent case series, molecular discoveries, and longitudinal outcome data, this review aims to provide clinicians with a practical framework for early recognition, diagnostic confirmation, and multidisciplinary management of this often-elusive syndrome, while identifying critical knowledge gaps that warrant future investigation.
Ilse Nájera Basurto, J. G. Rodríguez, Josselin Rocha Martinez et al.· International Journal of Med...· 0 citations
Heterotaxy (HTX) is a rare condition characterized by complex congenital heart defects and a wide spectrum of extracardiac abnormalities that significantly impact survival. While molecular diagnosis is essential for clinical management, next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%-30% of HTX cases. To address this diagnostic gap, we collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam. In parallel, we conducted a systematic review of 108 published cases to refine genotype-phenotype correlations. We identified seven variants in four key genes: DNAH9, PKD1L1, MMP21, and GDF1. The findings revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations, such as the association of MMP21 and GDF1 variants with severe conotruncal malformations. Two unreported variants were identified, further expanding the mutational spectrum of laterality defects. By integrating fetopathological data with advanced genomic analyses, we further delineate the phenotypic spectrum of these conditions. Ultimately, this work underscores the high diagnostic value of NGS in prenatal and neonatal cardiology, enabling earlier diagnosis and more personalized clinical management.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical Genetics· 0 citations
The findings on somatic instability in HD suggest that neurodegeneration in HD is an asynchronous DNA process for >95% of a neuron's life, with majority of neurons in all disease stages having a HTT gene which is not biologically harmful.
M. Ostrožovičová, M. Škorvánek· Current Neurology and Neuros...· 0 citations
