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Molecular Basis of Rare Genetic Diseases
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Molecular Basis of Rare Genetic 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 (15 March 2025) | Viewed by 10811

Special Issue Editors

Prof. Dr. Paulo Ricardo Gazzola Zen

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Guest Editor
Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
Interests: rare genetic diseases; epidemiology; genes; molecular basis; genomic medicine; cytogenetics
Special Issues, Collections and Topics in MDPI journals
Dr. Rafaella Mergener

E-Mail Website
Guest Editor Assistant
Graduate Program in Pathology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil
Interests: rare genetic diseases; epidemiology; genes; molecular basis; genomic medicine; cytogenetics

Special Issue Information

Dear Colleagues,

According to the World Health Organization, rare diseases affect 65 out of 100,000 individuals. Around 80% of rare diseases are genetic, and the majority clinically manifest in childhood.

Currently, specific treatment are available for several genetic diseases that improve the patients’ life expectancy and quality and reduce the mortality risk. Knowledge of the molecular basis of rare diseases is important, both for making appropriate diagnoses and for developing specific therapies. In addition, early diagnosis is also important so that specific or supportive therapies can be started as early as possible.

In this Special Issue, we will bring together contributions that help to identify the molecular basis of rare diseases. Review or original articles that address this are welcome. 

Prof. Dr. Paulo Ricardo Gazzola Zen
Guest Editor

Dr. Rafaella Mergener
Guest Editor Assistant

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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

  • rare diseases
  • genetic disorders
  • whole-exome sequencing
  • genome analysis
  • genes

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Published Papers (7 papers)

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Research

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10 pages, 258 KiB  
Article
Variants of the PTPN11 Gene in Mexican Patients with Noonan Syndrome
by Paola Montserrat Zepeda-Olmos, Eduardo Esparza-García, Kiabeth Robles-Espinoza, Juan Ramón González-García, Perla Graciela Rodríguez Gutiérrez and María Teresa Magaña-Torres
Genes 2024, 15(11), 1379; https://doi.org/10.3390/genes15111379 - 25 Oct 2024
Viewed by 1235
Abstract
Background/Objectives: Noonan syndrome (NS) is a genetic multisystem disease characterized by distinctive facial features, short stature, chest deformity, and congenital heart defects. NS is caused by gene variants of the RAS/MAPK pathway, with PTPN11 accounting for about 50% of cases. This study aimed [...] Read more.
Background/Objectives: Noonan syndrome (NS) is a genetic multisystem disease characterized by distinctive facial features, short stature, chest deformity, and congenital heart defects. NS is caused by gene variants of the RAS/MAPK pathway, with PTPN11 accounting for about 50% of cases. This study aimed to identify PTPN11 pathogenic variants in Mexican patients with NS to enhance our understanding of the disease in this population. Methods: This study included 91 probands and 60 relatives, all of which were clinically evaluated by a geneticist. Sanger sequencing was used to screen the entire PTPN11 gene. Results: Twenty-one previously reported pathogenic variants were identified in 47.3% of the probands. The most frequently occurring were p.Asn308Asp (16.3%) and p.Met504Val (16.3%). Variants p.Tyr279Cys and p.Thr468Met were found exclusively in patients with lentiginosis. Eighty-three percent of patients carried a variant in one of the three exons (3, 8, or 13) where the greatest genetic diversity was observed. Common clinical findings identified in probands included short stature (82%), cardiac anomalies (70.7%), short neck (68.4%), and pectus excavatum (63.2%), although features represented by only one patient each were also detected. Conclusions: This study confirmed the clinical diagnosis of NS in 43 probands and 11 relatives, and further genetic analysis of the remaining 48 probands is required to identify the causal variant. The genetic and clinical variability observed in our cohort was consistent with reports from other populations, underscoring the importance of comprehensive care for all patients. This research provides the most extensive clinical and molecular characterization of NS in Mexican patients, identifying pathogenic variants of PTPN11. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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12 pages, 2224 KiB  
Article
invdup(8)(8q24.13q24.3)—A Complex Alteration and Its Clinical Consequences
by Rafaella Mergener, Marcela Rodrigues Nunes, Ana Kalise Böttcher, Monique Banik Siqueira, Helena Froener Peruzzo, Milene Carvalho Merola, Mariluce Riegel and Paulo Ricardo Gazzola Zen
Genes 2024, 15(7), 910; https://doi.org/10.3390/genes15070910 - 12 Jul 2024
Viewed by 1483
Abstract
Structural variation is a source of genetic variation that, in some cases, may trigger pathogenicity. Here, we describe two cases, a mother and son, with the same partial inverted duplication of the long arm of chromosome 8 [invdup(8)(q24.21q24.21)] of 17.18 Mb, showing different [...] Read more.
Structural variation is a source of genetic variation that, in some cases, may trigger pathogenicity. Here, we describe two cases, a mother and son, with the same partial inverted duplication of the long arm of chromosome 8 [invdup(8)(q24.21q24.21)] of 17.18 Mb, showing different clinical manifestations: microcephaly, dorsal hypertrichosis, seizures and neuropsychomotor development delay in the child, and a cleft lip/palate, down-slanted palpebral fissures and learning disabilities in the mother. The deleterious outcome, in general, is reflected by the gain or loss of genetic material. However, discrepancies among the clinical manifestations raise some concerns about the genomic configuration within the chromosome and other genetic modifiers. With that in mind, we also performed a literature review of research published in the last 20 years about the duplication of the same, or close, chromosome region, seeking the elucidation of at least some relevant clinical features. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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15 pages, 1980 KiB  
Article
Deafness DFNB128 Associated with a Recessive Variant of Human MAP3K1 Recapitulates Hearing Loss of Map3k1-Deficient Mice
by Rabia Faridi, Rizwan Yousaf, Sayaka Inagaki, Rafal Olszewski, Shoujun Gu, Robert J. Morell, Elizabeth Wilson, Ying Xia, Tanveer Ahmed Qaiser, Muhammad Rashid, Cristina Fenollar-Ferrer, Michael Hoa, Sheikh Riazuddin and Thomas B. Friedman
Genes 2024, 15(7), 845; https://doi.org/10.3390/genes15070845 - 27 Jun 2024
Viewed by 1647
Abstract
Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 [...] Read more.
Deafness in vertebrates is associated with variants of hundreds of genes. Yet, many mutant genes causing rare forms of deafness remain to be discovered. A consanguineous Pakistani family segregating nonsyndromic deafness in two sibships were studied using microarrays and exome sequencing. A 1.2 Mb locus (DFNB128) on chromosome 5q11.2 encompassing six genes was identified. In one of the two sibships of this family, a novel homozygous recessive variant NM_005921.2:c.4460G>A p.(Arg1487His) in the kinase domain of MAP3K1 co-segregated with nonsyndromic deafness. There are two previously reported Map3k1-kinase-deficient mouse models that are associated with recessively inherited syndromic deafness. MAP3K1 phosphorylates serine and threonine and functions in a signaling pathway where pathogenic variants of HGF, MET, and GAB1 were previously reported to be associated with human deafness DFNB39, DFNB97, and DFNB26, respectively. Our single-cell transcriptome data of mouse cochlea mRNA show expression of Map3k1 and its signaling partners in several inner ear cell types suggesting a requirement of wild-type MAP3K1 for normal hearing. In contrast to dominant variants of MAP3K1 associated with Disorders of Sex Development 46,XY sex-reversal, our computational modeling of the recessive substitution p.(Arg1487His) predicts a subtle structural alteration in MAP3K1, consistent with the limited phenotype of nonsyndromic deafness. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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13 pages, 2853 KiB  
Article
Presentation of Rare Phenotypes Associated with the FKBP10 Gene
by Elena S. Merkuryeva, Tatiana V. Markova, Vladimir M. Kenis, Olga E. Agranovich, Ivan M. Dan, Yulia Y. Kotalevskaya, Olga A. Shchagina, Oxana P. Ryzhkova, Sergei S. Fomenko, Elena L. Dadali and Sergey I. Kutsev
Genes 2024, 15(6), 674; https://doi.org/10.3390/genes15060674 - 23 May 2024
Viewed by 1355
Abstract
Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. [...] Read more.
Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. This study analyzed the clinical-genetic characteristics of patients with these conditions, focusing on both known and newly identified FKBP10 variants. We examined data from 15 patients, presenting symptoms of OI and joint contractures. Diagnostic methods included genealogical analysis, clinical assessments, radiography, whole exome sequencing, and direct automated Sanger sequencing. We diagnosed 15 patients with phenotypes due to biallelic FKBP10 variants—4 with OI Type XI, 10 with BS I, and 1 with the AG-like phenotype—demonstrating polymorphism in disease severity. Ten pathogenic FKBP10 variants were identified, including three novel ones, c.1373C>T (p.Pro458Leu), c.21del (p.Pro7fs), and c.831_832insCG (p.Gly278Argfs), and a recurrent variant, c.831dup (p.Gly278Argfs). Variant c.1490G>A (p.Trp497Ter) was found in two unrelated patients, causing OI XI in one and BS I in the other. Additionally, two unrelated patients with BS I and epidermolysis bullosa shared identical homozygous FKBP10 and KRT14 variants. This observation illustrates the diversity of FKBP10-related pathology and the importance of considering the full spectrum of phenotypes in clinical diagnostics. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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Review

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25 pages, 933 KiB  
Review
The Molecular Basis of Multiple Morphological Abnormalities of Sperm Flagella and Its Impact on Clinical Practice
by Yujie Zhou, Songyan Yu and Wenyong Zhang
Genes 2024, 15(10), 1315; https://doi.org/10.3390/genes15101315 - 13 Oct 2024
Cited by 3 | Viewed by 2303
Abstract
Multiple morphological abnormalities of the sperm flagella (MMAF) is a specific form of severe flagellar or ciliary deficiency syndrome. MMAF is characterized by primary infertility with abnormal morphology in the flagella of spermatozoa, presenting with short, absent, bent, coiled, and irregular flagella. As [...] Read more.
Multiple morphological abnormalities of the sperm flagella (MMAF) is a specific form of severe flagellar or ciliary deficiency syndrome. MMAF is characterized by primary infertility with abnormal morphology in the flagella of spermatozoa, presenting with short, absent, bent, coiled, and irregular flagella. As a rare disease first named in 2014, studies in recent years have shed light on the molecular defects of MMAF that comprise the structure and biological function of the sperm flagella. Understanding the molecular genetics of MMAF may provide opportunities for the development of diagnostic and therapeutic strategies for this rare disease. This review aims to summarize current studies regarding the molecular pathogenesis of MMAF and describe strategies of genetic counseling, clinical diagnosis, and therapy for MMAF. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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Other

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14 pages, 1031 KiB  
Case Report
Example of Intrafamilial Clinical Polymorphism in a Family with Osteogenesis Imperfecta
by Varvara A. Galkina, Tatyana A. Vasilyeva, Inna S. Tebieva, Zolina K. Getoeva, Andrey V. Marakhonov, Vitaly V. Kadyshev, Sergey I. Kutsev and Rena A. Zinchenko
Genes 2025, 16(5), 475; https://doi.org/10.3390/genes16050475 - 23 Apr 2025
Viewed by 211
Abstract
Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with [...] Read more.
Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with most cases inherited in an autosomal dominant manner, while others follow autosomal recessive or X-linked recessive inheritance patterns. Accurate DNA testing is essential for precise medical and genetic counseling, ensuring reliable prognostic assessments for patients’ descendants and siblings. As part of a medical genetic study of the population of the Republic of the North Ossetia Alania, specifically in the Mozdok district, specialists from the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG) examined a family with 13 affected individuals with OI across four generations. Methods: A comprehensive clinical assessment was performed, followed by molecular genetic analysis using whole-exome sequencing (WES). Segregation analysis within the family was conducted via Sanger sequencing. Results: Clinical evaluation suggested a diagnosis of OI, which was subsequently confirmed by genetic testing. The severity and spectrum of symptoms varied considerably among affected family members and were influenced by age and specific nuclear family lineage. Molecular analysis in the proband identified a heterozygous pathogenic variant in the COL1A1 gene variant (c.1243C>T, p.(Arg415*)), confirming a diagnosis of OI type IV. The variant was found to co-segregate with the disease within the family. Conclusions: Molecular diagnosis enabled precise risk assessment for affected offspring in family members with mild phenotypic manifestations. Additionally, pediatric patients were referred for standard bisphosphonate therapy to manage the condition effectively. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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9 pages, 2249 KiB  
Case Report
Phenotypic Variability in Camurati–Engelmann Disease: A Case Report of a Family with the c.653G>A Pathogenic Variant in the TGFB1 Gene
by Talyta Campos, Elza Uchoa, Victor Santos, Raffael Zatarin, Rosenelle Benício, Clayson Gomes and Aparecido da Cruz
Genes 2024, 15(11), 1354; https://doi.org/10.3390/genes15111354 - 22 Oct 2024
Viewed by 1456
Abstract
Camurati–Engelmann Disease (CED), or Progressive Diaphyseal Dysplasia, is a rare autosomal dominant disorder caused by heterozygous mutations in the TGFB1 Gene, essential for bone regeneration. This study examines the genotype–phenotype relationship in a family diagnosed with CED, specifically focusing on a missense variant [...] Read more.
Camurati–Engelmann Disease (CED), or Progressive Diaphyseal Dysplasia, is a rare autosomal dominant disorder caused by heterozygous mutations in the TGFB1 Gene, essential for bone regeneration. This study examines the genotype–phenotype relationship in a family diagnosed with CED, specifically focusing on a missense variant (c.653G>A, p.Arg218Cys). The family comprised a mother and her two children, all of whom were found to carry the same disease-causing variant. The second child exhibited severe symptoms by age six, including progressive weakness and joint pain, leading to wheelchair dependency. The mother displayed milder symptoms with preserved independence. The firstborn son, initially asymptomatic, developed gait abnormalities and pain during adolescence. Clinical evaluations revealed characteristic hyperostosis of long bones, with significant variability in symptom onset and severity among family members, potentially indicative of genetic anticipation. This case underscores the importance of genetic testing and interdisciplinary management in CED, as traditional treatments, including corticosteroids and NSAIDs, often yield limited efficacy and notable side effects. Our findings contribute to the understanding of CED’s pathophysiology and highlight the necessity for tailored therapeutic approaches. The identification of the common TGFB1 variant in this family reinforces the critical role of TGFB1 in bone metabolism and suggests avenues for further research into targeted therapies. Such reports enhance awareness and provide valuable insights for healthcare professionals managing rare genetic disorders. Full article
(This article belongs to the Special Issue Molecular Basis of Rare Genetic Diseases)
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