Evidence map›Paper›PMID 39501396›Full record

ArticleOrphanet journal of rare diseases2024

Molecular analysis of inherited disorders of cornification in polish patients show novel variants and functional data and provokes questions on the significance of secondary findings.

Katarzyna Wertheim-Tysarowska, Katarzyna Osipowicz, Katarzyna Woźniak, Justyna Sawicka, Adrianna Mika, Anna Kutkowska-Kaźmierczak, Katarzyna Niepokój, Agnieszka Sobczyńska-Tomaszewska, Bartłomiej Wawrzycki, Aldona Pietrzak and 34 more

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Article in Orphanet journal of rare diseases, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. A standardized approach to test missenseJID innovations : skin science from molecules to population health · 2026
    Article
  2. Palmoplantar Keratoderma: A Mechanism-Based Disease Classification.Clinical, cosmetic and investigational dermatology · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

44 authors.

Katarzyna Wertheim-TysarowskaDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland. katarzyna.wertheim@imid.med.pl.ORCID 0000-0001-9911-3811
Katarzyna OsipowiczDepartment of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland.
Katarzyna WoźniakDepartment of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland.
Justyna SawickaDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Adrianna MikaDepartment of Pharmaceutical Biochemistry, Medical University of Gdansk, Gdansk, 80-211, Poland.
Anna Kutkowska-KaźmierczakDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Katarzyna NiepokójDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Agnieszka Sobczyńska-TomaszewskaMedgen - MedGen Diagnostic Laboratory, MedGen Medical Center, ul. Wiktorii Wiedeńskiej 9a, Warsaw, 02- 954, Poland.
Bartłomiej WawrzyckiDepartment of Dermatology, Venereology, and Paediatric Dermatology, Medical University of Lublin, Staszica 11, Lublin, 20-080, Poland.
Aldona PietrzakDepartment of Dermatology, Venereology, and Paediatric Dermatology, Medical University of Lublin, Staszica 11, Lublin, 20-080, Poland.
Robert ŚmigielDepartment of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases, Wroclaw Medical University, Wroclaw, Poland.
Bartosz WojtaśLaboratory of Sequencing, Nencki Institute of Experimental Biology, Wroclaw, Poland.
Bartłomiej GielniewskiLaboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Wroclaw, Poland.
Alicja Szabelska-BeresewiczDepartment of Mathematical and Statistical Methods, Poznań University of Life Sciences, Poznań, 60-637, Poland.
Joanna Zyprych-WalczakDepartment of Mathematical and Statistical Methods, Poznań University of Life Sciences, Poznań, 60-637, Poland.
Agnieszka Magdalena RygielDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Alicja DomaszewiczDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Natalia Braun-WalickaDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Alicja GrabarczykDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Sylwia Rzońca-NiewczasDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Ruszkowska LidiaMiędzyleski Specialistic Hospital In Warsaw, Bursztynowa 2, Warsaw, 04-749, Poland.
Mateusz DawidziukDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Dominik DomańskiMass Spectrometry Laboratory, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Tomasz GambinDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Monika JackiewiczDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Katarzyna DukDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Barbara DorożkoDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Orest SzczygielskiClinic of Surgery of Children and Adolescents, Institute of Mother and Child, Warsaw, Poland.
Natalia KrześniakDepartment of Plastic and Reconstructive Surgery, Centre of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland.
Bartłomiej H NoszczykDepartment of Plastic and Reconstructive Surgery, Centre of Postgraduate Medical Education, Prof. W. Orlowski Memorial Hospital, Warsaw, Poland.
Ewa ObersztynDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Jolanta WierzbaDepartment of Internal and Pediatric Nursing, Institute of Nursing and Midwifery, Medical University of Gdańsk, Gdańsk, Poland.
Artur BarczykDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Jennifer CastanedaDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Anna Eckersdorf-MastalerzMedical Center Fundacja PoMoc, ul. Dąbrowskiego 87, Łódź, 93-271, Poland.
Anna Jakubiuk-TomaszukMedical Genetics Unit, Mastermed Medical Center, Bialystok, Poland.
Paweł WłasienkoDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Ilona JaszczukDepartment of Cancer Genetics with Cytogenetic Laboratory, Medical University of Lublin, Lublin, Poland.
Aleksandra Jezela-StanekDepartment of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, 26 Plocka str, Warsaw, 01-138, Poland.
Jakub KlapeckiDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Michel van GeelDepartment of Dermatology, Maastricht University Medical Centre +, Maastricht, The Netherlands.
Cezary KowalewskiDepartment of Dermatology, Immunodermatology and Venereology, Medical University of Warsaw, Warsaw, 02-008, Poland.
Jerzy BalDepartment of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
Antoni GostyńskiDepartment of Dermatology, Maastricht University Medical Centre +, Maastricht, The Netherlands.

Funding

Narodowe Centrum Nauki 2014/13/D/NZ5/03304
6 · The paper itself

Abstract

backgroundThe Mendelian Disorders of Cornification (MeDOC) comprise a large number of disorders that present with either localised (palmoplantar keratoderma, PPK) or generalised (ichthyoses) signs. The MeDOC are highly heterogenic in terms of genetics and phenotype. Consequently, diagnostic process is challenging and before implementation of the next generation sequencing, was mostly symptomatic, not causal, which limited research on those diseases. The aim of the study was to genetically characterise a cohort of 265 Polish patients with MeDOC and to get insight into the skin lesions using transcriptome and lipid profile analyses.

resultsWe detected causal variants in 85% (226/265) patients. In addition to the primary gene defect, a pathogenic variant in another gene involved in MeDOC pathology was identified in 23 cases. We found 150 distinct variants in 33 genes, including 32 novel and 16 recurrent (present in > 5 alleles). In 43 alleles large rearrangements were detected, including deletions in the STS, SPINK5, CERS3 and recurrent duplication of exons 10-14 in TGM1. The RNA analysis using samples collected from 18 MeDOC patients and 22 controls identified 1377 differentially expressed genes - DEG. The gene ontology analysis revealed that 114 biological processes were upregulated in the MeDOC group, including i.e. epithelial cell differentiation, lipid metabolic process; homeostasis; regulation of water loss via skin; peptide cross-linking. The DEG between TGM1 and ALOX12B patients, showed that RNA profile is highly similar, though fatty acid profile in epidermal scrapings of those patients showed differences e.g. for the very long chain fatty acids (VLCFAs; FAs ≥ C20), the very long-chain monounsaturated fatty acids (VLC-MUFAs, FAs ≥ C20:1) and the n6 polyunsaturated fatty acids (n6 PUFAs).

conclusionOur results show that NGS-based analysis is an effective MeDOC diagnostic tool. The Polish MeDOC patients are heterogenic, however recurrent variants are present. The novel variants and high number of TGM1 and SPINK5 copy number variations give further insight into molecular pathology of MeDOC. We show that secondary variants in MeDOC-related genes are present in a significant group of patients, which should be further investigated in the context of phenotype modifiers. Finally, we provide novel RNA and lipid data that characterise molecularly MeDOC epidermis.

Indexed as

Serine Peptidase Inhibitor Kazal-Type 5AdultFemaleHigh-Throughput Nucleotide SequencingHumansIchthyosisMaleMutationPolandTransglutaminasesSerine Peptidase Inhibitor Kazal-Type 5SPINK5 protein, humantransglutaminase 1TransglutaminasesGenesGenodermatosesIchthyosesMeDOCPPKRNAseqSecondary findingsVariants

Identifiers

PMID39501396
PMCPMC11536877

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