Special Issue "Genetic Disease in Mediterranean Region"

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 (1 May 2021).

Special Issue Editors

Prof. Dr. Munis Dundar
E-Mail Website
Guest Editor
Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri 38280, Turkey
Interests: clinical genetics; dysmorphology; biotechnology and applications; rare diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Mahmut Cerkez Ergoren
E-Mail
Guest Editor
1. Department of Medical Biology, Faculty of Medicine, Near East University, Nicosia 99138, Cyprus
2. DESAM Institute, Near East University, Nicosia 99138, Cyprus
Interests: rare disease; population genetics and diversity; molecular medicine; mutation databases; precise medicine; genome editing

Special Issue Information

Dear Colleagues,

The first human genome sequence was established at the beginning of the third millennium. Since then, advanced molecular sciences has been shaping the economy and societies. A recent high-throughput sequencing technology has dramatically changed the nature of biomedical research and molecular diagnosis. When applied to individuals with genetic conditions, diverse approaches of this technology allow scientists to identify genetic variants and to understand genome structure and function better.

In the past two decades, exome sequencing has emerged as a comprehensive and cost-effective approach to identify pathogenic variants in the protein-coding regions of the genome. Nearly half of the genes causing 8,000 rare monogenic disorders, which are often difficult to diagnose based solely on symptoms, have been identified. More than 50% of individuals with rare genetic disorders are yet to be diagnosed and treated in order to improve their life quality.  Generally, suggestive clinical features can be used to distinguish one condition from another; however, in some cases these clinical features may overlap with several other genetic conditions, whereas exome-sequencing fails to identify potential pathogenic variants in patients. International and national genetic variation databases are now helping to elucidate disease-causing variants putative effects on gene function, estimate the frequency of alleles within populations, differentiate among subtypes of diseases, trace how genes may predispose to or protect against illnesses, and improve precise medical therapies.

The demic complexity of the Mediterranean Basin, an important intersection among three continents where different people and cultures have met over time, has shaped the genetic variability of the Mediterranean populations. Migrations, together with cultural exchanges and environmental factors, gave rise to present-day genomes structures of Mediterranean populations. The identification of pathogenic genetic variations and susceptibility factors such as rare, common, and complex genetic-related diseases has been well studies in many populations; however, there is much more to be done in terms of identifying a particular population for immediate use in accurate diagnosis, to gain an improved understanding of the underlying molecular mechanisms and develop effective preventive medicine strategies.

In this Special Issue, ‘’Genetic Disease in Mediterranean Region’’, we would like to contribute to the growing list of reported pathogenic genetic variations and genetic risk alleles to better understand the genotype and phenotype correlations of human diseases. We welcome studies of any design (e.g., rare diseases, candidate genes, genetic epidemiology, case reports, cohorts, meta-analysis, and genome editing and treatment) that have been performed on any genetic disease in Mediterranean Region.

Prof. Munis Dundar
Dr. Mahmut Cerkez Ergoren
Guest Editors

Manuscript Submission Information

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Keywords

  • rare disease
  • novel variants
  • Mediterranean
  • common genetic disease
  • novel gene

Published Papers (5 papers)

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Article
A Homozygous Synonymous Variant Likely Cause of Severe Ciliopathy Phenotype
Genes 2021, 12(6), 945; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12060945 - 21 Jun 2021
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Abstract
Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report [...] Read more.
Joubert syndrome (OMIM #213300) is a rare neurodevelopmental disease characterized by abnormal breathing patterns, intellectual impairment, ocular findings, renal cysts, and hepatic fibrosis. It is classified as a ciliopathy disease, where cilia function or structure in various organs are affected. Here, we report a 17-year-old male whose main clinical findings are oculomotor apraxia and truncal ataxia. Magnetic resonance imaging revealed the characteristic molar tooth sign of Joubert syndrome. He also has obsessive–compulsive disorder concomitantly, which is not a known feature of Joubert syndrome. Molecular genetic analysis revealed a homozygous c.2106G>A (p.(Thr702=)) variation in the Abelson helper integration 1 (AHI1) gene and another homozygous c.1739C>T (p.Thr580Ile) variation in the coiled-coil and C2 domain-containing protein 1A (CC2D1A) gene. Even though certain AHI1 variations were previously associated with Joubert syndrome (JS), c.2106G>A (p.(Thr702=)) was only reported in one patient in trans with another known pathogenic JS variant. The CC2D1A c.1739C>T (p.Thr580Ile) variation, on the other hand, has been reported to cause autosomal recessive nonsyndromic mental retardation, but there are conflicting interpretations about its pathogenicity. Overall, to our knowledge, this is the first patient representing a severe ciliopathy phenotype caused by a homozygous synonymous AHI1 variation. Further investigations should be performed to determine any involvement of the CC2D1A gene in ciliopathy phenotypes such as Joubert syndrome. Full article
(This article belongs to the Special Issue Genetic Disease in Mediterranean Region)
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Article
Clinical and Mutational Spectrum of Xeroderma Pigmentosum in Egypt: Identification of Six Novel Mutations and Implications for Ancestral Origins
Genes 2021, 12(2), 295; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020295 - 20 Feb 2021
Cited by 1 | Viewed by 576
Abstract
Xeroderma pigmentosum is a rare autosomal recessive skin disorder characterized by freckle-like dry pigmented skin, photosensitivity, and photophobia. Skin and ocular symptoms are confined to sun exposed areas of the body. Patients have markedly increased risk for UV-induced skin, ocular, and oral cancers. [...] Read more.
Xeroderma pigmentosum is a rare autosomal recessive skin disorder characterized by freckle-like dry pigmented skin, photosensitivity, and photophobia. Skin and ocular symptoms are confined to sun exposed areas of the body. Patients have markedly increased risk for UV-induced skin, ocular, and oral cancers. Some patients develop neurodegenerative symptoms, including diminished tendon reflexes and microcephaly. In this study, we describe clinical and genetic findings of 36 XP patients from Egypt, a highly consanguineous population from North Africa. Thorough clinical evaluation followed by Sanger sequencing of XPA and XPC genes were done. Six novel and seven previously reported mutations were identified. Phenotype-genotype correlation was investigated. We report clinical and molecular findings consistent with previous reports of countries sharing common population structure, and geographical and historical backgrounds with implications on common ancestral origins and historical migration flows. Clinical and genetic profiling improves diagnosis, management, counselling, and implementation of future targeted therapies. Full article
(This article belongs to the Special Issue Genetic Disease in Mediterranean Region)
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Article
Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey
Genes 2021, 12(2), 206; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12020206 - 31 Jan 2021
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Abstract
Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been [...] Read more.
Background: Cystic fibrosis (CF) is the most common worldwide, life-shortening multisystem hereditary disease, with an autosomal recessive inheritance pattern caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The national newborn screening (NBS) program for CF has been initiated in Turkey since 2015. If the immunoreactive trypsinogen (IRT) is elevated (higher than 70 μg/L in the second control) and confirmed by sweat test or clinical findings, genetic testing is performed. The aims of this study are to emphasize the effect of NBS on the status of genetic diagnosis centers with the increasing numbers of molecular testing methods, and to determine the numbers and types of CFTR mutations in Turkey. Methods: The next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) results of 1595 newborns, who were referred to Cukurova University Adana Genetic Diseases Diagnosis and Treatment Center (AGENTEM) for molecular genetic testing, were evaluated with positive CF NBS program results since 2017. Results: According to the results; 560 (35.1%) of the 1595 patients carried at least 1 (one) CF-related variant, while 1035 patients (64.9%) had no mutation. Compound heterozygosity for two mutations was the most common in patients, while two detected variants were homozygote in 14 patients. A total of 161 variants were detected in 561 patients with mutations. Fifteen novel variants that have not been previously reported were found. Moreover, p.L997F was identified as the most frequent pathogenic mutation that might affect the IRT measurements used for the NBS. The distribution of mutation frequencies in our study showed a difference from those previously reported; for example, the well-known p.F508del was the third most common (n = 42 alleles), rather than the first. The most striking finding is that 313 cases had a pathogenic variant together with the V470M variant, which might have a cumulative effect on CF perpetuation. Conclusion: This study is the first to determine the mutational spectrum of CFTR in correlation with the NBS program in the Turkish population. NBS for CF raises issues regarding screening in diverse populations, both medical and non-medical benefits, and carrier identification. Through the lens of NBS, we focused on the integrated diagnostic algorithms and their effect on the results of genetic testing. Full article
(This article belongs to the Special Issue Genetic Disease in Mediterranean Region)
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Article
Effect of Mutations on mRNA and Globin Stability: The Cases of Hb Bernalda/Groene Hart and Hb Southern Italy
Genes 2020, 11(8), 870; https://0-doi-org.brum.beds.ac.uk/10.3390/genes11080870 - 31 Jul 2020
Cited by 1 | Viewed by 726
Abstract
We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in cis to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that [...] Read more.
We identified two unstable variants in the third exon of α-globin genes: Hb Bernalda/Groene Hart (HBA1:c.358C>T), and Hb Caserta (HBA2:c.79G>A) in cis to Hb Sun Prairie (HBA2:c.391G>C), also named Hb Southern Italy. These mutations occurred in the H helix of the α-globin that is involved in heme contacting, specific recognition of α-hemoglobin-stabilizing protein (AHSP), and α1β1 interactions. The carriers showed α-thalassemia phenotype, but one also jaundice and cholelithiasis. Molecular identification of clusters of families in Southern Italy encouraged molecular characterization of mRNA, globin chain analyses, molecular modeling studies, and comparison with globin variants to understand the mechanisms causing the α-thalassemia phenotype. A normal amount of Hb Bernalda/Groene Hart mRNA were found, and molecular modeling highlighted additional H bonds with AHSP. For Hb Southern Italy, showing an unexpected α/β biosynthetic ratio typical of the β-thalassemia type, two different molecular mechanisms were shown: Reduction of the variant mRNA, likely due to the No-Go Decay for the presence of unused triplet ACG at cod 26, and protein instability due to the impairment of AHSP interaction. The UDP glucuronosyltransferase 1A (UGT1A1) genotyping was conclusive in the case of jaundice and cholelithiasis. Multiple approaches are needed to properly identify the mechanisms leading to unstable variants and the effect of a mutation. Full article
(This article belongs to the Special Issue Genetic Disease in Mediterranean Region)
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Case Report
Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency
Genes 2021, 12(5), 703; https://0-doi-org.brum.beds.ac.uk/10.3390/genes12050703 - 08 May 2021
Cited by 1 | Viewed by 975
Abstract
Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in [...] Read more.
Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of ETFDH and PHGDH genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the ETFDH gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the PHGDH gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation. Full article
(This article belongs to the Special Issue Genetic Disease in Mediterranean Region)
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