Dowling-Degos disease (DDD) is a rare hyperpigmentation disorder with autosomal-dominant inheritance. To date, work by our group and others has identified a total of four DDD sub-phenotypes, which arise secondary to variants in KRT5, POFUT1, POGLUT1, and PSENEN. We postulate that GLMN is a novel fifth gene for DDD that contributes to a hitherto unrecognized DDD sub-phenotype.

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype–phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams.

ABSTRACTBackgroundAcromesomelic chondrodysplasias are a rare subgroup of the clinically and genetically heterogeneous osteochondrodysplasias that are characterised by abnormalities in the limb development and short stature. Here, we report a 2‐year‐old boy, offspring of consanguineous parents, with acromesomelic dysplasia and postaxial polydactyly in which exome sequencing identified a novel homozygous missense variant in BMPR1B. The patient showed skeletal malformation of both hands and feet that included complex brachydactyly with the thumbs most severely affected, postaxial polydactyly of both hands, shortened toes as well as a bilateral hypoplasia of the fibula.MethodsWhole trio exome sequencing was conducted to identify potential genetic variants in the patient.ResultsThe analysis identified the biallelic variant NM_001203.3:c.821A > G;p.(Gln274Arg) in BMPR1B, a gene encoding bone morphogenetic protein receptor 1B.ConclusionThe skeletal phenotype can be brought in line with the phenotypes of previously reported cases of BMPR1B‐associated chondrodysplasias. However, the postaxial polydactyly described here is a novel clinical finding in a BMPR1B‐related case; notably, it has previously been reported in other acromesomelic dysplasia cases caused by homozygous pathogenic variants in GDF5—a gene which encodes for growth differentiation factor 5, a high‐affinity ligand to BMPR1B.

The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.

Background Monilethrix is a rare hereditary hair disorder that is characterized by a beaded hair shaft structure and increased hair fragility. Patients may also present with keratosis pilaris and nail changes. Research has identified three genes responsible for autosomal dominant monilethrix (KRT81, KRT83, KRT86) and one responsible for the autosomal recessive form (DSG4). Objectives To investigate the genetic basis of autosomal dominant monilethrix in families with no pathogenic variants in any of the known monilethrix genes, and to understand the mechanistic basis of variant pathogenicity using a cellular model. Methods Nine affected individuals from four unrelated families were included. A clinical diagnosis of monilethrix was assigned based on clinical examination and/or trichoscopy. Exome sequencing was performed in six individuals to identify pathogenic variants; Sanger sequencing was used for co-segregation and haplotype analyses. Cell culture experiments [immunoblotting, immunofluorescence and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analyses] were used to confirm variant pathogenicity, to determine the expression and subcellular localization of proteins, and to identify possible nonsense-mediated mRNA decay. Results In six affected individuals with clinically suggested monilethrix, exome sequencing led to the identification of the nonsense variant c.1081G>T; p.(Glu361*) in KRT31, which was subsequently identified in other affected members of these families by Sanger sequencing. This variant led to the abolition of both the last three amino acids of the 2B subdomain and the complete C-terminal tail domain of keratin 31. Immunoblotting demonstrated that when co-expressed with its binding partner keratin 85, the truncated keratin 31 was still expressed, albeit less abundantly than the wildtype protein. Immunofluorescence revealed that p.(Glu361*) keratin 31 had an altered cytoskeletal localization and formed vesicular-like structures in the cell cytoplasm near the cell membrane. RT-qPCR analysis did not generate evidence for nonsense-mediated decay of the mutant transcript. Conclusions This study is the first to identify pathogenic variants in KRT31 as a cause of autosomal dominant monilethrix. This highlights the importance of hair keratin proteins in hair biology, and will increase the molecular diagnostic yield for rare ectodermal phenotypes of hair and nail tissues.

Dowling-Degos disease (DDD; MIM 179850, 615327, 615696, and 613736) is a rare, autosomal dominant skin pigmentation disorder ( Degos and Ossipowski, 1954 Degos R. Ossipowski B. Dermatose pigmentaire ŕeticulée des plis (discussion de l'acanthosis nigricans) [Reticulated pigmentary dermatosis of the folds: relation to acanthosis nigricans]. Ann Dermatol Syphiligr (Paris). 1954; 81: 147-151 PubMed Google Scholar ; Dowling and Freudenthal, 1938 Dowling G.B. Freudenthal W. Acanthosis nigricans. Proc R Soc Med. 1938; 31: 1147-1150 PubMed Google Scholar ). Depending on which gene is mutated, affected individuals show progressive, reticulate hyperpigmentation that affects the trunk, face, flexures, large skin folds, genitals, and/or extremities, sometimes accompanied by pruritus. Histopathologic features encompass filiform epithelial downgrowth of the epidermal rete ridges, with deposition of melanin at the tips ( Betz et al., 2006 Betz R.C. Planko L. Eigelshoven S. Hanneken S. Pasternack S.M. Bussow H. et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. 2006; 78: 510-519 Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar ). In 2006, we identified pathogenic variants in keratin 5 (KRT5) ( Betz et al., 2006 Betz R.C. Planko L. Eigelshoven S. Hanneken S. Pasternack S.M. Bussow H. et al. Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease. Am J Hum Genet. 2006; 78: 510-519 Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar ) in patients with DDD who presented with hyperpigmentation in the large body folds, trunk, neck, and face. Subsequently, we and Li et al., 2013 Li M. Cheng R. Liang J. Yan H. Zhang H. Yang L. et al. Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet. 2013; 92: 895-903 Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar identified pathogenic variants in the genes encoding protein O-fucosyltransferase 1 ( Basmanav et al., 2015 Basmanav F.B. Fritz G. Lestringant G.G. Pachat D. Hoffjan S. Fischer J. et al. Pathogenicity of POFUT1 in Dowling-Degos disease: additional mutations and clinical overlap with reticulate acropigmentation of kitamura. J Invest Dermatol. 2015; 135: 615-618 Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar ; Li et al., 2013 Li M. Cheng R. Liang J. Yan H. Zhang H. Yang L. et al. Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease. Am J Hum Genet. 2013; 92: 895-903 Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar ) and protein O-glucosyltransferase 1 (POGLUT1) ( Basmanav et al., 2014 Basmanav F.B. Oprisoreanu A.M. Pasternack S.M. Thiele H. Fritz G. Wenzel J. et al. Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease. Am J Hum Genet. 2014; 94: 135-143 Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar ; Ralser et al., 2019 Ralser D.J. Takeuchi H. Fritz G. Basmanav F.B. Effern M. Sivalingam S. et al. Altered Notch signaling in Dowling-Degos disease: additional mutations in POGLUT1 and further insights into disease pathogenesis. J Invest Dermatol. 2019; 139: 960-964 Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar ). The protein O-fucosyltransferase 1 variants were found in patients in whom hyperpigmentation involved wrists and genitals, whereas the POGLUT1 variants were found in patients in whom it involved extremities. Recently, we reported pathogenic variants in the gene presenilin enhancer, gamma-secretase subunit (PSENEN), which result in hyperpigmentation as well as, in susceptible individuals, concomitant acne inversa ( Ralser et al., 2017 Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al. Mutations in γ-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. J Clin Invest. 2017; 127: 1485-1490 Crossref PubMed Scopus (70) Google Scholar ).

Abstract The de novo pyrimidine biosynthetic pathway is an inducible cellular program which allows the rapid synthesis of pyrimidine nucleotides in proliferating cells, and the final rate-limiting step is catalyzed by cytidine triphosphate synthase (CTPS1 or CTPS2). A CTPS1 loss-of-function mutation in humans has illustrated the essential and non-redundant role of CTPS1 in activated lymphocyte proliferation. Therefore, selective CTPS1 inhibition is an attractive approach to specifically target pathological immune activity in autoimmune and inflammatory disease. Using cryo-EM and structure-based drug design, we have identified a series of potent, orally bioavailable, CTPS1-specific inhibitors, exemplified by the compound NTX-871. In-vitro, NTX-871 significantly inhibits the proliferation of T-cell derived lines and activated primary T-cells. These inhibitory effects are reversed by the addition of exogenous cytidine, illustrating the specificity of NTX-871 for CTPS1 and the de novo pyrimidine synthesis program. NTX-871 was also tested in several mouse in-vivo PD and autoimmune disease models. Oral dosing of NTX-871 significantly reduced T-cell proliferation in an ovalbumin-induced T-cell proliferation model, and QD or BID dosing of NTX-871 significantly improved disease phenotypes in models of delayed-type hypersensitivity, collagen-induced arthritis, and experimental autoimmune encephalomyelitis.

Most individuals with rare diseases initially consult their primary care physician. For a subset of rare diseases, efficient diagnostic pathways are available. However, ultra-rare diseases often require both expert clinical knowledge and comprehensive genetic diagnostics, which poses structural challenges for public healthcare systems. To address these challenges within Germany, a novel structured diagnostic concept, based on multidisciplinary expertise at established university hospital centers for rare diseases (CRDs), was evaluated in the three year prospective study TRANSLATE NAMSE. A key goal of TRANSLATE NAMSE was to assess the clinical value of exome sequencing (ES) in the ultra-rare disease population. The aims of the present study were to perform a systematic investigation of the phenotypic and molecular genetic data of TRANSLATE NAMSE patients who had undergone ES in order to determine the yield of both ultra-rare diagnoses and novel gene-disease associations; and determine whether the complementary use of machine learning and artificial intelligence (AI) tools improved diagnostic effectiveness and efficiency. ES was performed for 1,577 patients (268 adult and 1,309 pediatric). Molecular genetic diagnoses were established in 499 patients (74 adult and 425 pediatric). A total of 370 distinct molecular genetic causes were established. The majority of these concerned known disorders, most of which were ultra-rare. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were delineated, mainly in individuals with neurodevelopmental disorders. To determine the likelihood that ES will lead to a molecular diagnosis in a given patient, based on the respective clinical features only, we developed a statistical framework called YieldPred. The genetic data of a subcohort of 224 individuals that also gave consent to the computer-assisted analysis of their facial images were processed with the AI tool Prioritization of Exome Data by Image Analysis (PEDIA) and showed superior performance in variant prioritization. The present analyses demonstrated that the novel structured diagnostic concept facilitated the identification of ultra-rare genetic disorders and novel gene-disease associations on a national level and that the machine learning and AI tools improved diagnostic effectiveness and efficiency for ultra-rare genetic disorders.

Dowling-Degos disease (DDD) is a rare autosomal-dominant hyperpigmentation disorder caused by mutations in KRT5, POFUT1, POGLUT1 and PSENEN. Our results suggest that dysfunctional Notch signalling in melanocytes plays a key role in DDD pathogenesis, and that altered biogenesis and intracellular trafficking of melanosomes, receptor tyrosine kinase signalling and oestrogen signalling receptor-mediated signalling may represent downstream molecular mechanisms through which decreased Notch signalling leads to hyperpigmentation in DDD. Furthermore, a common downstream pathomechanism for both POGLUT1 and PSENEN mutation carriers can be assumed.

A 1-year-old girl presented with porcelain white fingernails, accidentally discovered when she was referred for an infantile hemangioma consultation. The family reported that the nails had been milky white since birth and her father had similar white finger and toenails. The father remembered that additional family members on his side of the family presented with white nails; however, he could not provide exact information about the number of other relatives affected by this nail abnormality. The girl and her father were the only available family members with white nails presented for this study (Figure 1). The girl presented with leukonychia totalis on all fingernails only, while the father had this abnormality on all finger and toenails (Figure 2). We were not aware of any association with other diseases or features in this family, except hemangioma in the girl. (SKINmed. 2023;21:44-46).

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 21, Issue 5 p. 540-541 LESERBRIEF POGLUT1-Varianten bei Morbus Dowling-Degos - Assoziation mit spezifischen klinischen und histopathologischen Merkmalen? Sheetal Kumar, Sheetal Kumar Institut für Humangenetik undSearch for more papers by this authorJörg Wenzel, Jörg Wenzel Klinik und Poliklinik für Dermatologie und Allergologie, Universität Bonn, Medizinische Fakultät und Universitätsklinikum BonnSearch for more papers by this authorMichael P. Schön, Michael P. Schön Klinik für Dermatologie, Venerologie und Allergologie und Niedersächsisches Institut für Berufsdermatologie, Universitätsmedizin GöttingenSearch for more papers by this authorRegina C. Betz, Regina C. Betz Institut für Humangenetik undGleichberechtigte SeniorautorenschaftSearch for more papers by this authorJorge Frank, Corresponding Author Jorge Frank [email protected] Klinik für Dermatologie, Venerologie und Allergologie undGleichberechtigte Seniorautorenschaft Korrespondenzanschrift Prof. Dr. Jorge Frank, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Robert-Koch-Straße 40, 37075 Göttingen. Email: [email protected]Search for more papers by this author Sheetal Kumar, Sheetal Kumar Institut für Humangenetik undSearch for more papers by this authorJörg Wenzel, Jörg Wenzel Klinik und Poliklinik für Dermatologie und Allergologie, Universität Bonn, Medizinische Fakultät und Universitätsklinikum BonnSearch for more papers by this authorMichael P. Schön, Michael P. Schön Klinik für Dermatologie, Venerologie und Allergologie und Niedersächsisches Institut für Berufsdermatologie, Universitätsmedizin GöttingenSearch for more papers by this authorRegina C. Betz, Regina C. Betz Institut für Humangenetik undGleichberechtigte SeniorautorenschaftSearch for more papers by this authorJorge Frank, Corresponding Author Jorge Frank [email protected] Klinik für Dermatologie, Venerologie und Allergologie undGleichberechtigte Seniorautorenschaft Korrespondenzanschrift Prof. Dr. Jorge Frank, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsmedizin Göttingen, Robert-Koch-Straße 40, 37075 Göttingen. Email: [email protected]Search for more papers by this author First published: 15 May 2023 https://doi.org/10.1111/ddg.15111_g Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. LITERATUR 1Papadopoulou K, Karsai S, Böer-Auer A. Disseminierte papulöse Variante des Morbus Dowling-Degos: Histopathologische Merkmale bei POGLUT1 -Mutation. J Dtsch Dermatol Ges. 2022; 20(11): 1423-29. 2Basmanav FB, Oprisoreanu A-M, Pasternack SM, et al. Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease. Am J Hum Genet. 2014; 94(1): 135-143. 3Betz RC, Planko L, Eigelshoven S, et al. Loss-of-Function Mutations in the Keratin 5 Gene Lead to Dowling-Degos Disease. Am J Hum Genet. 2006; 78(3): 510-519. 4Ralser DJ, Basmanav FBÜ, Tafazzoli A, et al. Mutations in γ-secretase subunit–encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. J Clin Invest. 2017; 127(4): 1485-1490. 5Ralser DJ, Takeuchi H, Fritz G, et al. Altered Notch Signaling in Dowling-Degos Disease: Additional Mutations in POGLUT1 and Further Insights into Disease Pathogenesis. J Invest Dermatol. 2019; 139(4): 960-964 6Hanneken S, Rütten A, Eigelshoven S, Braun-Falco M, Pasternack SM, Ruzicka T, et al. Morbus Galli-Galli: Klinische und histopathologische Untersuchung anhand einer Fallserie von 18 Patienten. Hautarzt. 2011; 62(11): 842-851. 7Schnabel V, Hermasch MA, Wolf S, et al. Eine Frau mit hyperpigmentierten Maculae und Papeln. J Dtsch Dermatol Ges. 2021; 19(11): 1655-1659. 8Shabrawi-Caelen LE, Hofer A, Kerl H. Macro-micro dermatology: Erythematous papules and lentigo-like macules – a new entity? J Dtsch Dermatol Ges. 2007; 5(8): 645-646. 9Sprecher E, Indelman M, Khamaysi Z, et al. Galli-Galli disease is an acantholytic variant of Dowling-Degos disease. Br J Dermatol. 2007; 156(3): 572-574. Volume21, Issue5May 2023Pages 540-541 ReferencesRelatedInformation

Importance Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far. Objective To elucidate the genetic spectrum of UHS. Design, Setting, and Participants This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes. Results The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions and Relevance This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.