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Molecular Basis of Rare Diseases
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Molecular Basis of Rare Diseases

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 November 2022) | Viewed by 30804

Special Issue Editors

Dr. Jair Tenorio

E-Mail Website
Guest Editor
1. INGEMM—Institute of Medical and Molecular Genetics Hospital Universitario La Paz–IdiPAZ, 261-28046 Madrid, Spain
2. Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, 28029 Madrid, Spain
Interests: rare diseases; human genetics; whole genome sequencing
Special Issues, Collections and Topics in MDPI journals
Dr. Pablo Lapunzina

E-Mail Website
Guest Editor
INGEMM—Institute of Medical and Molecular Genetics Hospital Universitario La Paz – IdiPAZ, 261-28046 Madrid, Spain
Interests: genomic medicine; gain of function and loss of function mutations; overgrowth syndromes; imprinting disorders; novel genes associated to intellectual disabilities; Sotos syndrome; Becwith–Wiedemann syndrome; Simpson–Golabi–Behmel syndrome; WGS and WES in genetic diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We would like to invite you to participate in this Special Issue, “Molecular Basis of Rare Diseases”.

There are about 7000 known genetic-based diseases, many of them with a known molecular basis. However, there are still many pathologies whose molecular cause is not known or the mechanisms through which the disease manifests itself are poorly understood.

Knowing the molecular mechanisms through which genetic diseases manifest themselves is of tremendous interest for the diagnosis of individuals and the development of new targeted therapies.

The aim of this special volume is to present original papers and reviews on the molecular basis of genetic diseases, with special interest in those papers that present new genes and/or new molecular mechanisms associated with genetic diseases.

Dr. Jair Tenorio
Dr. Pablo Lapunzina
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • human genetics
  • rare diseases
  • next generation serquencing
  • massive paralleled sequencing
  • genomic medicine
  • whole genome sequencing
  • whole exome sequencing
  • diseases ontologies

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Published Papers (10 papers)

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Research

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15 pages, 1851 KiB  
Article
Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature
by Alejandro Parra, Rachel Rabin, John Pappas, Patricia Pascual, Mario Cazalla, Pedro Arias, Natalia Gallego-Zazo, Alfredo Santana, Ignacio Arroyo, Mercè Artigas, Harry Pachajoa, Yasemin Alanay, Ozlem Akgun-Dogan, Lyse Ruaud, Nathalie Couque, Jonathan Levy, Gloria Liliana Porras-Hurtado, Fernando Santos-Simarro, Maria Juliana Ballesta-Martinez, Encarna Guillén-Navarro, Hugo Muñoz-Hernández, Julián Nevado, Spanish OverGrowth Registry Initiative, Jair Tenorio-Castano and Pablo Lapunzinaadd Show full author list remove Hide full author list
Genes 2023, 14(6), 1179; https://doi.org/10.3390/genes14061179 - 29 May 2023
Cited by 4 | Viewed by 3436
Abstract
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan–Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin–Pappas syndrome (RAPAS). LLS [MIM #616831] is an [...] Read more.
SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan–Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin–Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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21 pages, 1547 KiB  
Article
Chromosomal Microarray in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital
by Ana Karen Sandoval-Talamantes, María Ángeles Mori, Fernando Santos-Simarro, Sixto García-Miñaur, Elena Mansilla, Jair Antonio Tenorio, Carolina Peña, Carmen Adan, María Fernández-Elvira, Inmaculada Rueda, Pablo Lapunzina and Julián Nevado
Genes 2023, 14(4), 820; https://doi.org/10.3390/genes14040820 - 29 Mar 2023
Cited by 2 | Viewed by 3273
Abstract
Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with [...] Read more.
Autism spectrum disorders (ASD) comprise a group of neurodevelopmental disorders (NDD) characterized by deficits in communication and social interaction, as well as repetitive and restrictive behaviors, etc. The genetic implications of ASD have been widely documented, and numerous genes have been associated with it. The use of chromosomal microarray analysis (CMA) has proven to be a rapid and effective method for detecting both small and large deletions and duplications associated with ASD. In this article, we present the implementation of CMA as a first-tier test in our clinical laboratory for patients with primary ASD over a prospective period of four years. The cohort was composed of 212 individuals over 3 years of age, who met DSM-5 diagnostic criteria for ASD. The use of a customized array-CGH (comparative genomic hybridization) design (KaryoArray®) found 99 individuals (45.20%) with copy number variants (CNVs); 34 of them carried deletions (34.34%) and 65 duplications (65.65%). A total of 28 of 212 patients had pathogenic or likely pathogenic CNVs, representing approximately 13% of the cohort. In turn, 28 out of 212 (approximately 12%) had variants of uncertain clinical significance (VUS). Our findings involve clinically significant CNVs, known to cause ASD (syndromic and non-syndromic), and other CNVs previously related to other comorbidities such as epilepsy or intellectual disability (ID). Lastly, we observed new rearrangements that will enhance the information available and the collection of genes associated with this disorder. Our data also highlight that CMA could be very useful in diagnosing patients with essential/primary autism, and demonstrate the existence of substantial genetic and clinical heterogeneity in non-syndromic ASD individuals, underscoring the continued challenge for genetic laboratories in terms of its molecular diagnosis. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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16 pages, 7652 KiB  
Article
Proteomic and Transcriptomic Landscapes of Alström and Bardet–Biedl Syndromes
by Urszula Smyczynska, Marcin Stanczak, Miljan Kuljanin, Aneta Włodarczyk, Ewelina Stoczynska-Fidelus, Joanna Taha, Bartłomiej Pawlik, Maciej Borowiec, Joseph D. Mancias, Wojciech Mlynarski, Piotr Rieske, Wojciech Fendler and Agnieszka Zmysłowska
Genes 2022, 13(12), 2370; https://doi.org/10.3390/genes13122370 - 15 Dec 2022
Cited by 5 | Viewed by 2161
Abstract
Alström syndrome (ALMS) and Bardet–Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and retinal degeneration. ALMS and BBS belong to the ciliopathies, which are known to have the expression products of genes, encoding [...] Read more.
Alström syndrome (ALMS) and Bardet–Biedl syndrome (BBS) are rare genetic diseases with a number of common clinical features ranging from early-childhood obesity and retinal degeneration. ALMS and BBS belong to the ciliopathies, which are known to have the expression products of genes, encoding them as cilia-localized proteins in multiple target organs. The aim of this study was to perform transcriptomic and proteomic analysis on cellular models of ALMS and BBS syndromes to identify common and distinct pathological mechanisms present in both syndromes. For this purpose, epithelial cells were isolated from the urine of patients and healthy subjects, which were then cultured and reprogrammed into induced pluripotent stem (iPS) cells. The pathways of genes associated with the metabolism of lipids and glycosaminoglycan and the transport of small molecules were found to be concomitantly downregulated in both diseases, while transcripts related to signal transduction, the immune system, cell cycle control and DNA replication and repair were upregulated. Furthermore, protein pathways associated with autophagy, apoptosis, cilium assembly and Gli1 protein were upregulated in both ciliopathies. These results provide new insights into the common and divergent pathogenic pathways between two similar genetic syndromes, particularly in relation to primary cilium function and abnormalities in cell differentiation. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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18 pages, 3054 KiB  
Article
Challenges in Gene Therapy for Somatic Reverted Mosaicism in X-Linked Combined Immunodeficiency by CRISPR/Cas9 and Prime Editing
by Yujuan Hou, Guillermo Ureña-Bailén, Tahereh Mohammadian Gol, Paul Gerhard Gratz, Hans Peter Gratz, Alicia Roig-Merino, Justin S. Antony, Andrés Lamsfus-Calle, Alberto Daniel-Moreno, Rupert Handgretinger and Markus Mezger
Genes 2022, 13(12), 2348; https://doi.org/10.3390/genes13122348 - 13 Dec 2022
Cited by 5 | Viewed by 2619
Abstract
X-linked severe combined immunodeficiency (X-SCID) is a primary immunodeficiency that is caused by mutations in the interleukin-2 receptor gamma (IL2RG) gene. Some patients present atypical X-SCID with mild clinical symptoms due to somatic revertant mosaicism. CRISPR/Cas9 and prime editing are two advanced genome [...] Read more.
X-linked severe combined immunodeficiency (X-SCID) is a primary immunodeficiency that is caused by mutations in the interleukin-2 receptor gamma (IL2RG) gene. Some patients present atypical X-SCID with mild clinical symptoms due to somatic revertant mosaicism. CRISPR/Cas9 and prime editing are two advanced genome editing tools that paved the way for treating immune deficiency diseases. Prime editing overcomes the limitations of the CRISPR/Cas9 system, as it does not need to induce double-strand breaks (DSBs) or exogenous donor DNA templates to modify the genome. Here, we applied CRISPR/Cas9 with single-stranded oligodeoxynucleotides (ssODNs) and prime editing methods to generate an in vitro model of the disease in K–562 cells and healthy donors’ T cells for the c. 458T>C point mutation in the IL2RG gene, which also resulted in a useful way to optimize the gene correction approach for subsequent experiments in patients’ cells. Both methods proved to be successful and were able to induce the mutation of up to 31% of treated K–562 cells and 26% of treated T cells. We also applied similar strategies to correct the IL2RG c. 458T>C mutation in patient T cells that carry the mutation with revertant somatic mosaicism. However, both methods failed to increase the frequency of the wild-type sequence in the mosaic T cells of patients due to limited in vitro proliferation of mutant cells and the presence of somatic reversion. To the best of our knowledge, this is the first attempt to treat mosaic cells from atypical X-SCID patients employing CRISPR/Cas9 and prime editing. We showed that prime editing can be applied to the formation of specific-point IL2RG mutations without inducing nonspecific on-target modifications. We hypothesize that the feasibility of the nucleotide substitution of the IL2RG gene using gene therapy, especially prime editing, could provide an alternative strategy to treat X-SCID patients without revertant mutations, and further technological improvements need to be developed to correct somatic mosaicism mutations. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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11 pages, 814 KiB  
Article
Description of Two New Cases of AQP1 Related Pulmonary Arterial Hypertension and Review of the Literature
by Natalia Gallego-Zazo, Alejandro Cruz-Utrilla, María Jesús del Cerro, Nuria Ochoa Parra, Julián Nevado Blanco, Pedro Arias, Pablo Lapunzina, Pilar Escribano-Subias and Jair Tenorio-Castaño
Genes 2022, 13(5), 927; https://doi.org/10.3390/genes13050927 - 22 May 2022
Cited by 4 | Viewed by 2695
Abstract
Pulmonary arterial hypertension (PAH) is a severe clinical condition characterized by an increase in mean pulmonary artery pressure, which leads to a right ventricular hypertrophy and potentially heart failure and death. In the last several years, many genes have been associated with PAH, [...] Read more.
Pulmonary arterial hypertension (PAH) is a severe clinical condition characterized by an increase in mean pulmonary artery pressure, which leads to a right ventricular hypertrophy and potentially heart failure and death. In the last several years, many genes have been associated with PAH, particularly in idiopathic and heritable forms but also in associated forms. Here we described the identification of two unrelated families in which the AQP1 variant was found from a cohort of 300 patients. The variants were identified by whole exome sequencing (WES). In the first family, the variant was detected in three affected members from a hereditary PAH, and in the second family the proband had PAH associated with scleroderma. In addition, we have reviewed all cases published in the literature thus far of patients with PAH and AQP1 variants. Functional studies have led to some contradictory conclusions, and the evidence of the relationship of AQP1 and PAH is still limited. However, we describe two further families with PAH and variants in AQP1, expanding both the number of cases and the clinically associated phenotype. We provide further evidence of the association of AQP1 and the development of hereditary and associated forms of PAH. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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17 pages, 2918 KiB  
Article
Complex Changes in the Efficiency of the Expression of Many Genes in Monogenic Diseases, Mucopolysaccharidoses, May Arise from Significant Disturbances in the Levels of Factors Involved in the Gene Expression Regulation Processes
by Zuzanna Cyske, Lidia Gaffke, Karolina Pierzynowska and Grzegorz Węgrzyn
Genes 2022, 13(4), 593; https://doi.org/10.3390/genes13040593 - 26 Mar 2022
Cited by 11 | Viewed by 2338
Abstract
Monogenic diseases are primarily caused by mutations in a single gene; thus, they are commonly recognized as genetic disorders with the simplest mechanisms. However, recent studies have indicated that the molecular mechanisms of monogenic diseases can be unexpectedly complicated, and their understanding requires [...] Read more.
Monogenic diseases are primarily caused by mutations in a single gene; thus, they are commonly recognized as genetic disorders with the simplest mechanisms. However, recent studies have indicated that the molecular mechanisms of monogenic diseases can be unexpectedly complicated, and their understanding requires complex studies at the molecular level. Previously, we have demonstrated that in mucopolysaccharidoses (MPS), a group of monogenic lysosomal storage diseases, several hundreds of genes reveal significant changes in the expression of various genes. Although the secondary effects of the primary biochemical defect and the inefficient degradation of glycosaminoglycans (GAGs) might be considered, the scale of the changes in the expression of a large fraction of genes cannot be explained by a block in one biochemical pathway. Here, we demonstrate that in cellular models of 11 types of MPS, the expression of genes coding for proteins involved in the regulation of the expression of many other genes at various stages (such as signal transduction, transcription, splicing, RNA degradation, translation, and others) is significantly disturbed relative to the control cells. This conclusion was based on transcriptomic studies, supported by biochemical analyses of levels of selected proteins encoded by genes revealing an especially high level of dysregulation in MPS (EXOSC9, SRSF10, RPL23, and NOTCH3 proteins were investigated). Interestingly, the reduction in GAGs levels, through the inhibition of their synthesis normalized the amounts of EXOSC9, RPL23, and NOTCH3 in some (but not all) MPS types, while the levels of SRSF10 could not be corrected in this way. These results indicate that different mechanisms are involved in the dysregulation of the expression of various genes in MPS, pointing to a potential explanation for the inability of some therapies (such as enzyme replacement therapy or substrate reduction therapy) to fully correct the physiology of MPS patients. We suggest that the disturbed expression of some genes, which appears as secondary or tertiary effects of GAG storage, might not be reversible, even after a reduction in the amounts of the storage material. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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17 pages, 3346 KiB  
Article
Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency
by Yujuan Hou, Hans Peter Gratz, Guillermo Ureña-Bailén, Paul G. Gratz, Karin Schilbach-Stückle, Tina Renno, Derya Güngör, Daniel A. Mader, Elke Malenke, Justin S. Antony, Rupert Handgretinger and Markus Mezger
Genes 2022, 13(1), 35; https://doi.org/10.3390/genes13010035 - 23 Dec 2021
Cited by 11 | Viewed by 4075
Abstract
Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T−B+NK− phenotype as a result of dysfunctional γC [...] Read more.
Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T−B+NK− phenotype as a result of dysfunctional γC-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the IL2RG gene have been described causing atypical SCID with a milder phenotype. Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts. The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation. Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients. Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls. Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3+, CD4+ and CD8+ T cells. Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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Review

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13 pages, 1902 KiB  
Review
State of the Science for Kidney Disorders in Phelan-McDermid Syndrome: UPK3A, FBLN1, WNT7B, and CELSR1 as Candidate Genes
by Megan D. McCoy, Sara M. Sarasua, Jane M. DeLuca, Stephanie Davis, Katy Phelan, Roger Curtis Rogers and Luigi Boccuto
Genes 2022, 13(6), 1042; https://doi.org/10.3390/genes13061042 - 10 Jun 2022
Cited by 7 | Viewed by 2618
Abstract
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by chromosomal rearrangements affecting the 22q13.3 region or by SHANK3 pathogenic variants. The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the [...] Read more.
Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by chromosomal rearrangements affecting the 22q13.3 region or by SHANK3 pathogenic variants. The scientific literature suggests that up to 40% of individuals with PMS have kidney disorders, yet little research has been conducted on the renal system to assess candidate genes attributed to these disorders. Therefore, we first conducted a systematic review of the literature to identify kidney disorders in PMS and then pooled the data to create a cohort of individuals to identify candidate genes for renal disorders in PMS. We found 7 types of renal disorders reported: renal cysts, renal hypoplasia or agenesis, hydronephrosis, vesicoureteral reflux, kidney dysplasia, horseshoe kidneys, and pyelectasis. Association analysis from the pooled data from 152 individuals with PMS across 22 articles identified three genomic regions spanning chromosomal bands 22q13.31, 22q13.32, and 22q13.33, significantly associated with kidney disorders. We propose UPK3A, FBLN1, WNT7B, and CELSR1, located from 4.5 Mb to 5.5 Mb from the telomere, as candidate genes. Our findings support the hypothesis that genes included in this region may play a role in the pathogenesis of kidney disorders in PMS. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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15 pages, 3540 KiB  
Review
MICAL1 Monooxygenase in Autosomal Dominant Lateral Temporal Epilepsy: Role in Cytoskeletal Regulation and Relation to Cancer
by Sipan Haikazian and Michael F. Olson
Genes 2022, 13(5), 715; https://doi.org/10.3390/genes13050715 - 19 Apr 2022
Cited by 5 | Viewed by 2957
Abstract
Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy associated with mutations in the LGI1, RELN, and MICAL1 genes. A previous study linking ADLTE with two MICAL1 mutations that resulted in the substitution of a highly conserved glycine residue for [...] Read more.
Autosomal dominant lateral temporal epilepsy (ADLTE) is a genetic focal epilepsy associated with mutations in the LGI1, RELN, and MICAL1 genes. A previous study linking ADLTE with two MICAL1 mutations that resulted in the substitution of a highly conserved glycine residue for serine (G150S) or a frameshift mutation that swapped the last three C-terminal amino acids for 59 extra residues (A1065fs) concluded that the mutations increased enzymatic activity and promoted cell contraction. The roles of the Molecule Interacting with CasL 1 (MICAL1) protein in tightly regulated semaphorin signaling pathways suggest that activating MICAL1 mutations could result in defects in axonal guidance during neuronal development. Further studies would help to illuminate the causal relationships of these point mutations with ADLTE. In this review, we discuss the proposed pathogenesis caused by mutations in these three genes, with a particular emphasis on the G150S point mutation discovered in MICAL1. We also consider whether these types of activating MICAL1 mutations could be linked to cancer. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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Other

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9 pages, 1547 KiB  
Brief Report
Identification of Frameshift Variants in POLH Gene Causing Xeroderma Pigmentosum in Two Consanguineous Pakistani Families
by Ghazala Y. Zamani, Ranjha Khan, Noreen Karim, Zubair M. Ahmed and Muhammad Naeem
Genes 2022, 13(3), 543; https://doi.org/10.3390/genes13030543 - 19 Mar 2022
Viewed by 2873
Abstract
Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by severe sensitivity of skin to sunlight and an increased risk of skin cancer. XP variant (XPV), a milder subtype, is caused by variants in the POLH gene. POLH encodes an error-prone [...] Read more.
Xeroderma pigmentosum (XP) is a rare autosomal recessive genetic disorder characterized by severe sensitivity of skin to sunlight and an increased risk of skin cancer. XP variant (XPV), a milder subtype, is caused by variants in the POLH gene. POLH encodes an error-prone DNA-polymerase eta (pol eta) which performs translesion synthesis past ultraviolet photoproducts. The current study documents the clinical and genetic investigations of two large consanguineous Pakistani families affected with XPV. In family 1, whole exome sequencing (WES) revealed a novel frameshift variant, c.1723dupG (p.(Val575Glyfs*4)), of POLH, which is predicted to cause frameshift and premature truncation of the encoded enzyme. Indeed, our ex vivo studies in HEK293T cells confirmed the truncation of the encoded protein due to the c.1723dupG variant. In family 2, Sanger sequencing of POLH exons, revealed a recurrent nonsense variant, c.437dupA (p.Tyr146*). POLH forms a hetero-tetrameric POLZ complex with REV3L, REV7, POLD2 and POLD3. Next, we performed in silico analysis of POLH and other POLZ complex genes expression in publicly available single cell mRNAseq datasets from adult human healthy and aging skin. We found overlapping expression of POLH, REV3L and POLD2 in multiple cell types including differentiated and undifferentiated keratinocytes, pericytes and melanocytes in healthy skin. However, in aging human skin, POLH expression is reduced in compare to its POLZ complex partners. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of POLH-related XPV. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Diseases)
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