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Variations of Rare Genetic Diseases
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Variations 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: 25 December 2024 | Viewed by 10094

Special Issue Editors

Dr. Rajech Sharkia

E-Mail Website
Guest Editor
1. Unit of Human Biology and Genetics, Triangle Regional Research and Development Center, Kfar Qari’ 3007500, Israel
2. Beit-Berl Academic College, Beit-Berl 4490500, Israel
Interests: genetic disorders; community genetics; consanguinity; public health; health education
Dr. Abdelnaser Zalan

E-Mail Website
Co-Guest Editor
Unit of Human Biology and Genetics, Triangle Regional Research and Development Center, Kfar Qari’ 3007500, Israel
Interests: genetic disorders; community genetics; consanguinity; public health; health education
Dr. Muhammad Mahajnah

E-Mail Website
Co-Guest Editor
1. Pediatrics Neurology and Child Development Institute, Hillel-Yaffe Medical Center, Hadera 38100, Israel
2. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3200003, Israel
Interests: pediatric neurogenetic disorders; neurodevelopmental disorders; pediatric neurology; public health

Special Issue Information

Dear Colleagues,

Genetic diseases, especially autosomal recessive diseases, are rare in the general population. However, they become unusually frequent in certain communities worldwide as a result of genetic isolation due to social, geographic, or religious factors. When a new mutation is inserted in such a population it spreads rapidly, leading to an increased prevalence of carriers and many homozygous individuals being affected. There are high frequencies of genetic diseases and congenital disorders among many communities worldwide, especially wherever high rates of consanguineous marriages exist. It is estimated that around 80% of rare diseases are genetic, and most of them clinically present during childhood. Therefore, an investigation of hereditary disorders is vital for improving health care. This can be achieved by identifying and diagnosing their molecular genetic basis to develop preventive intervention measures aimed at reducing the occurrence of these inherited genetic disorders.

This Special Issue aims to focus on rare genetic diseases that include genotype–phenotype correlations, disease gene discovery, pathogenetic mechanisms, novel gene variants, and phenotypic expansion. We welcome various original articles and reviews that address these topics.

Dr. Rajech Sharkia
Dr. Abdelnaser Zalan
Dr. Muhammad Mahajnah
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

  • rare genetic diseases
  • genotype–phenotype correlations
  • gene variants
  • whole-exome sequencing
  • genes
  • neurogenetic diseases
  • neurodegenerative diseases

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Published Papers (9 papers)

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Research

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13 pages, 269 KiB  
Article
Exploring the Impact of Genetics in a Large Cohort of Moebius Patients by Trio Whole Exome Sequencing
by Giada Moresco, Maria Francesca Bedeschi, Marco Venturin, Roberta Villa, Jole Costanza, Alessia Mauri, Carlo Santaniello, Odoardo Picciolini, Laura Messina, Fabio Triulzi, Monica Rosa Miozzo, Ornella Rondinone and Laura Fontana
Genes 2024, 15(8), 971; https://doi.org/10.3390/genes15080971 - 23 Jul 2024
Viewed by 1093
Abstract
Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is [...] Read more.
Moebius syndrome (MBS) is a rare congenital disorder characterized by non-progressive facial palsy and ocular abduction paralysis. Most cases are sporadic, but also rare familial cases with autosomal dominant transmission and incomplete penetrance/variable expressivity have been described. The genetic etiology of MBS is still unclear: de novo pathogenic variants in REV3L and PLXND1 are reported in only a minority of cases, suggesting the involvement of additional causative genes. With the aim to uncover the molecular causative defect and identify a potential genetic basis of this condition, we performed trio-WES on a cohort of 37 MBS and MBS-like patients. No de novo variants emerged in REV3L and PLXND1. We then proceeded with a cohort analysis to identify possible common causative genes among all patients and a trio-based analysis using an in silico panel of candidate genes. However, identified variants emerging from both approaches were considered unlikely to be causative of MBS, mainly due to the lack of clinical overlap. In conclusion, despite this large cohort, WES failed to identify mutations possibly associated with MBS, further supporting the heterogeneity of this syndrome, and suggesting the need for integrated omics approaches to identify the molecular causes underlying MBS development. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
16 pages, 5599 KiB  
Article
SCAPER-Related Autosomal Recessive Retinitis Pigmentosa with Intellectual Disability: Confirming and Extending the Phenotypic Spectrum and Bioinformatics Analyses
by Rajech Sharkia, Abdelnaser Zalan, Amit Kessel, Wasif Al-Shareef, Hazar Zahalka, Holger Hengel, Ludger Schöls, Abdussalam Azem and Muhammad Mahajnah
Genes 2024, 15(6), 791; https://doi.org/10.3390/genes15060791 - 16 Jun 2024
Viewed by 1169
Abstract
Mutations in the gene SCAPER (S phase Cyclin A-Associated Protein residing in the Endoplasmic Reticulum) have recently been associated with retinitis pigmentosa (RP) and intellectual disability (ID). In 2011, a possible involvement of SCAPER in human diseases was discovered for the first time [...] Read more.
Mutations in the gene SCAPER (S phase Cyclin A-Associated Protein residing in the Endoplasmic Reticulum) have recently been associated with retinitis pigmentosa (RP) and intellectual disability (ID). In 2011, a possible involvement of SCAPER in human diseases was discovered for the first time due to the identification of a homozygous mutation causing ID in an Iranian family. Later, five studies were published in 2019 that described patients with autosomal recessive syndromic retinitis pigmentosa (arRP) accompanied by ID and attention-deficit/hyperactivity disorder (ADHD). This present study describes three patients from an Arab consanguineous family in Israel with similar clinical features of the SCAPER syndrome. In addition, new manifestations of ocular symptoms, nystagmus, glaucoma, and elevator palsy, were observed. Genetic testing of the patients and both parents via whole-exome sequencing revealed the homozygous mutation c.2023–2A>G in SCAPER. Phenotypic and genotypic descriptions for all available cases described in the literature including our current three cases (37 cases) were carried out, in addition to a bioinformatics analysis for all the genetic variants that was undertaken. Our study confirms and extends the clinical manifestations of SCAPER-related disorders. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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11 pages, 731 KiB  
Article
Whole-Genome Sequencing Identified a Novel Mutation in the N-Terminal Domain of KIF5A in Chinese Patients with Familial Amyotrophic Lateral Sclerosis
by Hui Wang, Liping Guan, Xiaojuan Ma, Yiying Wang, Jinhao Wang, Peipei Zhang and Min Deng
Genes 2024, 15(6), 680; https://doi.org/10.3390/genes15060680 - 24 May 2024
Viewed by 1149
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive damage to both upper and lower motor neurons. Genetic factors are known to play a crucial role in ALS, as genetic studies not only advance our comprehension of disease mechanisms but also help unravel the complex phenotypes exhibited by patients. To gain further insights into the genetic landscape of ALS in the Chinese population and explore genotype–phenotype correlations among individuals, we conducted whole-genome sequencing to screen genes in 34 Chinese familial ALS (FALS) probands lacking the most common ALS-associated genes. Within this cohort, we identified a rare heterozygous missense mutation in the N-terminal domain of KIF5A (c.86A>G) in one of the probands. This finding is significant as mutations in the KIF5A gene have been implicated in ALS in European cohorts since 2018, predominantly characterized by C-terminal mutations. Analysis of the clinical phenotype within this familial lineage revealed a delayed onset of symptoms, an extended survival duration, and initial manifestations in both upper limbs. These observations underscore the clinical heterogeneity observed in ALS patients harboring KIF5A mutations. In conclusion, our study contributes to the growing body of evidence linking KIF5A to ALS and enhances our understanding of the intricate genetic landscape of this disease. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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14 pages, 1867 KiB  
Article
Recessive GNE Mutations in Korean Nonaka Distal Myopathy Patients with or without Peripheral Neuropathy
by Nasrin Tamanna, Byung Kwon Pi, Ah Jin Lee, Sumaira Kanwal, Byung-Ok Choi and Ki Wha Chung
Genes 2024, 15(4), 485; https://doi.org/10.3390/genes15040485 - 11 Apr 2024
Viewed by 1918
Abstract
Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of [...] Read more.
Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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Review

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13 pages, 1929 KiB  
Review
Hotspots for Disease-Causing Mutations in the Mitochondrial TIM23 Import Complex
by Sahil Jain, Eyal Paz and Abdussalam Azem
Genes 2024, 15(12), 1534; https://doi.org/10.3390/genes15121534 - 28 Nov 2024
Viewed by 523
Abstract
The human mitochondrial proteome comprises approximately 1500 proteins, with only 13 being encoded by mitochondrial DNA. The remainder are encoded by the nuclear genome, translated by cytosolic ribosomes, and subsequently imported into and sorted within mitochondria. The process of mitochondria-destined protein import is [...] Read more.
The human mitochondrial proteome comprises approximately 1500 proteins, with only 13 being encoded by mitochondrial DNA. The remainder are encoded by the nuclear genome, translated by cytosolic ribosomes, and subsequently imported into and sorted within mitochondria. The process of mitochondria-destined protein import is mediated by several intricate protein complexes distributed among the four mitochondrial compartments. The focus of this mini-review is the translocase of the inner membrane 23 (TIM23) complex that assists in the import of ~60% of the mitochondrial proteome, which includes the majority of matrix proteins as well as some inner membrane and intermembrane space proteins. To date, numerous pathogenic mutations have been reported in the genes encoding various components of the TIM23 complex. These diseases exhibit mostly developmental and neurological defects at an early age. Interestingly, accumulating evidence supports the possibility that the gene for Tim50 represents a hotspot for disease-causing mutations among core TIM23 complex components, while genes for the mitochondrial Hsp70 protein (mortalin) and its J domain regulators represent hotspots for mutations affecting presequence translocase-associated motor (PAM) subunits. The potential mechanistic implications of the discovery of disease-causing mutations on the function of the TIM23 complex, in particular Tim50, are discussed. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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Other

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10 pages, 219 KiB  
Case Report
A Novel Pathogenic Sense Variant in Exon 7 of the HK1 Gene in a Patient with Hexokinase Deficiency and Gilbert Syndrome
by Magdalena Bartnik, Weronika Pawlik, Beata Burzyńska, Konrad Wasilewski, Elżbieta Kamieńska and Tomasz Urasiński
Genes 2024, 15(12), 1576; https://doi.org/10.3390/genes15121576 - 7 Dec 2024
Viewed by 474
Abstract
Background: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase [...] Read more.
Background: Hexokinase (HK) deficiency is a rare autosomal recessively inherited disease manifested by chronic nonspherocytic hemolytic anemia. Most patients present with a mild to severe course of the disease (fetal hydrocephalus, neonatal hyperbilirubinemia, severe anemia). We reviewed 37 cases of patients with hexokinase deficiency described so far, focusing on the severity of the disease, clinical presentation, treatment applied, and genetic test results. Methods: We present a 10-year-old girl who initially presented with symptoms of weakness, excessive fatigue, and yellowing of the skin and sclerae. Genetic testing detected the (TA)7 variant in both alleles of the UGT1A1 gene and diagnosed Gilbert’s disease. In the follow-up, red cell hemolysis was observed. The diagnosis was extended, and tests for red cell enzymopathy were performed and a reduced level of hexokinase—0.65 IU/gHb (normal 0.78–1.57) was found. Next-generation sequencing revealed a new sense-change variant in exon 7 in the hexokinase gene not previously reported in databases. Results: Up to this date, only around 37 cases of hexokinase deficiency associated with hereditary nonspherocytic hemolytic anemia have been documented around the world. Diagnosing hexokinase deficiency involves clinical evaluation, laboratory testing, and genetic analysis. Management focuses on treating symptoms and preventing complications; there is no cure for the underlying enzyme deficiency. In patients with severe anemia, the treatment is multiple blood transfusions followed by iron chelation therapy. Conclusions: Understanding and diagnosing hexokinase deficiency is critical for providing appropriate care and improving the quality of life for affected individuals. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
10 pages, 1130 KiB  
Case Report
Segregation of the COL6A2 Variant (c.1817-3C>G) in a Consanguineous Saudi Family with Bethlem Myopathy
by Hitham Aldharee and Hamdan Z. Hamdan
Genes 2024, 15(11), 1405; https://doi.org/10.3390/genes15111405 - 30 Oct 2024
Viewed by 1154
Abstract
Introduction: Bethlem myopathy is a rare genetic disease caused by a variant mapped to 21q22, which harbors the collagen type VI alpha 2 chain (COL6A2) and collagen type VI alpha 1 chain (COL6A1) genes, and 2q37, which harbors the collagen type VI [...] Read more.
Introduction: Bethlem myopathy is a rare genetic disease caused by a variant mapped to 21q22, which harbors the collagen type VI alpha 2 chain (COL6A2) and collagen type VI alpha 1 chain (COL6A1) genes, and 2q37, which harbors the collagen type VI alpha 3 chain (COL6A3) gene. Disease onset can occur at any age, and the symptoms are related to those of muscular dystrophy. Since Bethlem myopathy is a rare disease, no previous studies have been conducted in Arab countries, including Saudi Arabia. Its variable presentation of nonspecific muscular contractions and severity represents a diagnostic dilemma. Case presentation: Here, we report a Saudi pediatric patient, who is 9 years old (proband), brought to the pediatric clinic of King Saud’s Hospital by his mother. The boy presented with difficulty standing, walking, and running with his classmates and unaffected siblings. He has a younger sibling, aged 6 years old, who reported having a limping gait and difficulty bending his right knee. Laboratory results for the proband were unremarkable except for a slight increase in creatine kinase (CK). Whole-exome sequencing (WES) was performed for five family members, including the proband and his symptomatic brother, their mother and two asymptomatic siblings. A very rare 3′ splice site acceptor intronic variant, NM_001849.4: c.1817-3C>G, located three nucleotides before exon 25, was identified in COL6A2. Bioinformatics tools (SpliceAI, dbscSNV, FATHMM-MKL, and MaxEntScan) predicted this variant as pathogenic. The proband and his 6-year-old sibling presented a homozygous genotype for the variant, whereas the mother and one asymptomatic sibling were heterozygous, and the other sibling carried homozygous wild-type alleles. Conclusions: This is the first study to report a case of Bethlem myopathy confirmed by WES in Saudi Arabia and all Arab nations. The identified variant is rare, and its segregation pattern suggests autosomal recessive inheritance. The segregation pattern and bioinformatics tool results may qualify this variant to be annotated as pathogenic, addressing the reported uncertainty of its classification. Our findings contribute to linking and filling the knowledge gap of diagnosing and managing patients with collagen VI-related myopathies, providing greater clinical and genetic understanding to the existing knowledge. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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8 pages, 1289 KiB  
Case Report
A Novel Pathogenic Large Duplication in EXT1 Identified in a Family with Multiple Osteochondromas
by Isabella Bartolotti, Klaudia Sobul, Serena Corsini, Davide Scognamiglio, Alice Moroni, Maria Gnoli, Luca Sangiorgi and Elena Pedrini
Genes 2024, 15(9), 1169; https://doi.org/10.3390/genes15091169 - 5 Sep 2024
Viewed by 823
Abstract
Multiple osteochondromas (MO) is an autosomal dominant disorder and the most common genetic skeletal dysplasia, characterized by the growth of bone outgrowths capped by cartilage, called osteochondromas. Most MO cases are caused by mutations in the exostosin-1 (EXT1) and exostosin-2 ( [...] Read more.
Multiple osteochondromas (MO) is an autosomal dominant disorder and the most common genetic skeletal dysplasia, characterized by the growth of bone outgrowths capped by cartilage, called osteochondromas. Most MO cases are caused by mutations in the exostosin-1 (EXT1) and exostosin-2 (EXT2) genes. Only 5% of MO-causative variants are represented by single or multiple exon deletions; to date, no pathogenic large duplication has been described in the literature. In the present study, we describe the novel in-tandem intragenic duplication c.(1128_1202)_(1284+29_1344)dup involving exon 4 of EXT1 (NM_000127.2), detected in a three-generation family with MO. The variant has been detected by MLPA (multiplex ligation-dependent probe amplification) and then confirmed with qPCR (quantitative PCR). Our finding expands the spectrum of MO-causing variants describing a pathogenic large duplication, underlying the importance of quantitative analysis in patients with negative sequencing. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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8 pages, 763 KiB  
Case Report
A New Case Report of Traboulsi Syndrome: A Literature Review and Insights Into Genotype–Phenotype Correlations
by Marisol Ibarra-Ramírez, Luis D. Campos-Acevedo, Aristides Valenzuela-Lopez, Luis Arturo López-Villanueva, Marissa Fernandez-de-Luna and Jibran Mohamed-Noriega
Genes 2024, 15(9), 1120; https://doi.org/10.3390/genes15091120 - 25 Aug 2024
Viewed by 828
Abstract
Traboulsi syndrome is a rare genetic disorder characterized by facial dysmorphism, lens subluxation, anterior segment anomalies, and spontaneous filtering blebs. The syndrome is due to mutations in the ASPH gene, which plays a crucial role in the development and maintenance of the lens. [...] Read more.
Traboulsi syndrome is a rare genetic disorder characterized by facial dysmorphism, lens subluxation, anterior segment anomalies, and spontaneous filtering blebs. The syndrome is due to mutations in the ASPH gene, which plays a crucial role in the development and maintenance of the lens. This case report describes the clinical and genetic findings in a Mexican male with Traboulsi syndrome, highlighting the identification of a novel ASPH variant. A 21-year-old male presented with trauma to the right eye while playing soccer. He had a history of lens subluxation and dysmorphic facial features. Ophthalmic examination revealed right eye lens subluxation into the anterior chamber (with signs of a previous episode of acute angle closure) and left eye posterior and inferior lens subluxation with sectorial iris atrophy. Genetic analysis identified a pathogenic ASPH variant (NM_004318.3:c.1892G>A, p.Trp631*) and a novel likely pathogenic variant (deletion of exons 20–21), confirming Traboulsi syndrome. This is the first instance of Traboulsi syndrome in the Mexican population. The absence of spontaneous filtering blebs in this patient supports previous reports of the wide phenotypic variability that could be related to the type of mutation. This novel ASPH variant expands the known genetic heterogeneity of Traboulsi syndrome. Full article
(This article belongs to the Special Issue Variations of Rare Genetic Diseases)
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