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Advances in Molecular Genetics of Rare Disorders
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Advances in Molecular Genetics of Rare Disorders

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

Deadline for manuscript submissions: 20 March 2027 | Viewed by 2250

Editor

Dr. Miriam Lucia Carriero

E-Mail Website
Guest Editor
Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, 00133 Rome, Italy
Interests: neurodevelopmental disorders; CRISPR-Cas9 gene editing; disease modeling; rare diseases; molecular genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rare diseases affect a small portion of the population, but collectively impact millions worldwide. Approximately 80% of rare diseases have a genetic basis, making molecular genetics a crucial field for understanding their etiologies, improving diagnoses, and developing targeted therapies. Advances in next-generation sequencing, genome-wide association studies, and functional genomics have transformed our approach to understanding these conditions and significantly enhanced our ability to identify disease-causing variants, uncover novel gene–disease associations, and elucidate pathogenic mechanisms.

This Special Issue, Advances in Molecular Genetics of Rare Disorders, aims to highlight recent progress in the genetic and molecular characterization of rare disorders. We welcome original research and review articles covering novel disease gene discoveries, expanded phenotypic spectra, genotype–phenotype correlations, disease mechanisms, and therapeutic strategies. Contributions focusing on innovative diagnostic methodologies, including bioinformatics approaches, functional studies, and model systems, are also encouraged.

By bringing together cutting-edge studies in molecular genetics, this Special Issue seeks to advance our understanding of rare diseases, ultimately facilitating more accurate diagnoses and improved treatment options for affected individuals.

Dr. Miriam Lucia Carriero
Guest Editor

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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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
  • molecular genetics
  • gene–disease associations
  • genotype–phenotype correlation
  • targeted gene therapy
  • next-generation sequencing
  • whole-genome sequencing
  • genome-wide association studies
  • functional genomics

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Published Papers (4 papers)

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Research

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14 pages, 272 KB  
Article
PURA-Related Neurodevelopmental Disorder: Insight from Eight New Cases
by Agnieszka Madej-Pilarczyk, Marzena Gawlik, Beata Chałupczyńska, Jagoda Błaszkiewicz, Dorota Wicher, Agata Cieślikowska, Anila Babameto-Laku, Krystyna Chrzanowska and Elżbieta Ciara
Genes 2026, 17(7), 765; https://doi.org/10.3390/genes17070765 - 30 Jun 2026
Viewed by 517
Abstract
Background: PURA-related neurodevelopmental disorder (PURA-NDD; OMIM #616158) is a rare autosomal dominant condition caused by pathogenic variants in the PURA gene encoding Purα, a multifunctional protein involved in DNA replication, transcriptional regulation, and RNA transport. Since its initial description [...] Read more.
Background: PURA-related neurodevelopmental disorder (PURA-NDD; OMIM #616158) is a rare autosomal dominant condition caused by pathogenic variants in the PURA gene encoding Purα, a multifunctional protein involved in DNA replication, transcriptional regulation, and RNA transport. Since its initial description in 2014, PURA-NDD has been increasingly recognized as a distinct clinical entity with early onset and a broad phenotypic spectrum. The clinical presentation is characterized primarily by neonatal hypotonia, global developmental delay, intellectual disability, feeding difficulties, and epilepsy, along with additional features such as respiratory insufficiency, movement disorders, hypersomnolence, and variable dysmorphic traits. Despite a relatively recognizable core phenotype, marked inter-individual variability often limits the ability to establish a definitive clinical diagnosis based on phenotype alone. This underscores the essential role of molecular genetic testing in the differential diagnosis of rare neurodevelopmental disorders. Patients and methods: We report a cohort of eight individuals (four males and four females) aged 17 months to 15.5 years with PURA-related neurodevelopmental disorder (PURA-NDD), evaluated using a genotype-first diagnostic strategy supported by comprehensive genomic testing, including next-generation sequencing (NGS) panels and whole-genome sequencing (WGS). Patients were referred for the evaluation of nonspecific neurodevelopmental features, including neonatal hypotonia, respiratory distress, and epilepsy, in the absence of a definitive clinical diagnosis. Results: Molecular analysis identified eight heterozygous variants in PURA, of which four (50%) were novel: c.311T>G p.(Met104Arg), c.406_407del p.(Gln136Glyfs64), c.515A>C p.(Gln172Pro), and c.885delinsGC p.(His296Profs21). The remaining variants included previously reported missense and frameshift changes associated with PURA-NDD, as well as one variant previously reported in ClinVar. Conclusions: Our findings not only confirm the core clinical features of PURA-related neurodevelopmental disorder but also contribute to a more comprehensive delineation of its phenotypic spectrum. The detailed characterization of our cohort broadens the range of recognized clinical manifestations and further highlights the marked phenotypic heterogeneity of PURA-NDD. In addition, the identification of both novel and previously reported pathogenic variants expands the mutational spectrum of PURA and underscores the importance of integrating clinical, molecular, and bioinformatic data for accurate variant interpretation. Although genotype–phenotype correlations remain incompletely understood, emerging evidence suggests potential associations between variant type or location and clinical severity, warranting further investigation in larger cohorts. The recognition of characteristic neonatal features may facilitate earlier diagnosis and implementation of supportive multidisciplinary management. Overall, this study illustrates how genomic technologies not only improve diagnostic yield in rare disorders but also refine disease definition, enhance the understanding of underlying pathogenic mechanisms, and support the development of more precise genotype–phenotype correlations. Further studies involving larger cohorts and long-term follow-up are needed to better define the full clinical and molecular spectrum of PURA-NDD. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Rare Disorders)
13 pages, 3796 KB  
Article
Clinical Variability Within the PLOD2-Associated Phenotypic Continuum: Three Novel Variants in Four Patients from a Descriptive Case Series
by Elena S. Merkuryeva, Evgeniya A. Melnik, Vladimir M. Kenis, Svetlana I. Trofimova, Olga E. Agranovich, Yuri V. Buklemishev, Khushnud K. Rustamov, Denis V. Chistol, Tatiana S. Nagornova, Viktoriia V. Zabnenkova and Tatiana V. Markova
Genes 2026, 17(5), 556; https://doi.org/10.3390/genes17050556 - 5 May 2026
Viewed by 585
Abstract
Background/Objectives: Bruck syndrome type 2 (BS2) is an ultra-rare autosomal recessive disorder within the osteogenesis imperfecta (OI) spectrum caused by biallelic pathogenic variants in PLOD2, which encodes lysyl hydroxylase 2 (LH2), an enzyme essential for bone-specific collagen cross-linking. Marked clinical heterogeneity [...] Read more.
Background/Objectives: Bruck syndrome type 2 (BS2) is an ultra-rare autosomal recessive disorder within the osteogenesis imperfecta (OI) spectrum caused by biallelic pathogenic variants in PLOD2, which encodes lysyl hydroxylase 2 (LH2), an enzyme essential for bone-specific collagen cross-linking. Marked clinical heterogeneity complicates diagnosis, particularly in patients with atypical or incomplete presentations. We aimed to further delineate the clinical and molecular spectrum of PLOD2-associated disease. Methods: In this descriptive case series, we performed clinical, radiological, and molecular evaluations of four patients from three unrelated families, including two previously reported siblings. Molecular testing comprised targeted next-generation sequencing or whole-exome sequencing, followed by Sanger sequencing for variant confirmation and familial segregation analysis where feasible. Results: Four PLOD2 variants (NM_182943.3) were identified: homozygous c.1885A > G (p.Thr629Ala) in two siblings; c.8dup (p.(Cys4MetfsTer35)) and c.2222G > A (p.(Gly741Glu)) in one patient; and homozygous c.2027A > C (p.(Tyr676Ser)) in one infant. Three variants were previously unreported. Two missense variants remained classified as variants of uncertain significance, and the phase of the two heterozygous variants detected in one patient could not be established because a paternal sample was unavailable. Clinical severity was variable: age at first fracture ranged from 3 months to 4 years, and cumulative fracture burden ranged from 3 to multiple recurrent fractures. One 10-year-old patient had a severe OI-like phenotype without congenital contractures. Older patients showed additional axial and pelvic involvement, including craniovertebral junction abnormalities and acetabular protrusion. Conclusions: This case series broadens the range of clinical presentations observed in PLOD2-associated disease and indicates that severe bone fragility may occur in the absence of congenital contractures. These findings support inclusion of PLOD2 in the differential diagnosis of patients with unexplained bone fragility and progressive skeletal deformities. Additional well-characterized cases and functional studies are needed to refine genotype–phenotype correlations and clarify the clinical significance of newly identified variants. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Rare Disorders)
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Review

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16 pages, 2746 KB  
Review
The Neurobehavioral Profile of Phelan–McDermid Syndrome: Suggestions for Assessment Tools in Light of the 2023 Consensus Guidelines
by Emily Payne, Sara M. Sarasua, Curtis Rogers, Rebekah Martin, Katy Phelan, Laura Beamer and Luigi Boccuto
Genes 2026, 17(8), 923; https://doi.org/10.3390/genes17080923 - 5 Aug 2026
Viewed by 147
Abstract
Objectives and Background: Individuals with Phelan–McDermid Syndrome (PMS) present with a variety of symptoms, including a breadth of behavioral issues. Clinically assessing behavior in PMS remains challenging due to the overabundance of behavioral assessments and the lack of tools validated explicitly for use [...] Read more.
Objectives and Background: Individuals with Phelan–McDermid Syndrome (PMS) present with a variety of symptoms, including a breadth of behavioral issues. Clinically assessing behavior in PMS remains challenging due to the overabundance of behavioral assessments and the lack of tools validated explicitly for use in individuals with intellectual disability (ID) and neurodevelopmental disorders. This review sought to suggest which assessment tools would best clinically assess behavior in individuals with PMS. Methods: Validated behavioral assessment tools were identified using a systematic search of the literature, and relevant data for each assessment were extracted. The consensus guidelines for PMS were reviewed. Results: This review identified 131 validated assessment tools that were categorized by the intended age group and into specific behavioral domains: Autism spectrum disorder (ASD) screening, adaptive behavior, restricted and repetitive behaviors, challenging/disruptive behaviors, mental health screening, and other miscellaneous behaviors such as avoidance and impulsivity. Discussion: Based on the 2023 consensus guidelines, suggestions were given on which tools would be best for assessing various symptoms and behaviors in PMS. Choosing the best assessment tools to appraise behavior and related symptoms in individuals with PMS will aid clinicians in decision-making and lead to more personalized treatment plans. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Rare Disorders)
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Other

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8 pages, 188 KB  
Case Report
Neuropsychiatric Phenotype in a Patient with Neurodevelopmental Disorder with or Without Early-Onset Generalized Epilepsy (NEDEGE)
by Dominika Szczęśniak, Anna Wilczek and Magdalena Mroczek
Genes 2026, 17(6), 713; https://doi.org/10.3390/genes17060713 - 21 Jun 2026
Viewed by 363
Abstract
We report the oldest female identified to date with a pathogenic NBEA variant who has been followed longitudinally. She presented with a complex, diagnostically inconclusive psychiatric phenotype extending in adulthood and a suspected mild neurodevelopmental impairment. The 64-year-old patient experienced recurrent episodes of [...] Read more.
We report the oldest female identified to date with a pathogenic NBEA variant who has been followed longitudinally. She presented with a complex, diagnostically inconclusive psychiatric phenotype extending in adulthood and a suspected mild neurodevelopmental impairment. The 64-year-old patient experienced recurrent episodes of mental state decompensation characterized predominantly by persecutory and health-related delusional ideation and anxiety. Her most recent psychiatric diagnosis was mixed conversion disorder. Although she never underwent formal cognitive testing, mild intellectual disability was suspected based on her educational attainment, occupational history, and social functioning. Additionally, the patient presented with a likely coincidental tremor. A history of childhood epilepsy could not be confirmed, as detailed epilepsy records were unavailable. Furthermore, the patient declined neuroimaging, precluding assessment of a possible relationship with the identified EXT2 deletion. This case expands the currently recognized neuropsychiatric spectrum possibly associated with pathogenic NBEA variants, highlights the importance of extending phenotypic characterization in later adulthood, and underscores the value of longitudinal follow-up. Full article
(This article belongs to the Special Issue Advances in Molecular Genetics of Rare Disorders)
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