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Identifying the Molecular Basis of Rare Genetic Diseases
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Identifying the 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 (25 August 2023) | Viewed by 14772

Special Issue Editor

Prof. Dr. Paulo Ricardo Gazzola Zen

E-Mail Website
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

Special Issue Information

Dear Colleagues,

According to the World Health Organization, rare diseases are those that affect 65 out of every 100,000 individuals. Around 80% of rare diseases are genetic, and the majority already present clinical manifestations in childhood.

Currently, there is already specific treatment for several genetic diseases that improve life expectancy and quality and reduce mortality. Knowledge of the molecular basis of rare diseases is important, both for making the appropriate diagnosis and for developing specific therapy. 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 the molecular basis of rare diseases are welcome.

Prof. Dr. Paulo Ricardo Gazzola Zen
Guest Editor

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Keywords

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

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Published Papers (6 papers)

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Research

21 pages, 1984 KiB  
Article
NGS Custom Panel Implementation in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital
by Ana Karen Sandoval-Talamantes, Jair Antonio Tenorio-Castaño, Fernando Santos-Simarro, Carmen Adán, María Fernández-Elvira, Laura García-Fernández, Yolanda Muñoz, Pablo Lapunzina and Julián Nevado
Genes 2023, 14(11), 2091; https://doi.org/10.3390/genes14112091 - 17 Nov 2023
Viewed by 1647
Abstract
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by deficiencies in communication, social interaction, and repetitive and restrictive behaviors. The discovery of genetic involvement in the etiology of ASD has made this condition a strong candidate for genome-based diagnostic tests. [...] Read more.
Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by deficiencies in communication, social interaction, and repetitive and restrictive behaviors. The discovery of genetic involvement in the etiology of ASD has made this condition a strong candidate for genome-based diagnostic tests. Next-generation sequencing (NGS) is useful for the detection of variants in the sequence of different genes in ASD patients. Herein, we present the implementation of a personalized NGS panel for autism (AutismSeq) for patients with essential ASD over a prospective period of four years in the clinical routine of a tertiary hospital. The cohort is composed of 48 individuals, older than 3 years, who met the DSM-5 (The Diagnostic and Statistical Manual of Mental Disorders) diagnostic criteria for ASD. The NGS customized panel (AutismSeq) turned out to be a tool with good diagnostic efficacy in routine clinical care, where we detected 12 “pathogenic” (including pathogenic, likely pathogenic, and VUS (variant of uncertain significance) possibly pathogenic variations) in 11 individuals, and 11 VUS in 10 individuals, which had previously been negative for chromosomal microarray analysis and other previous genetic studies, such as karyotype, fragile-X, or MLPA/FISH (Multiplex Ligation dependent Probe Amplification/Fluorescence in situ hybridization) analysis. Our results demonstrate the high genetic and clinical heterogeneity of individuals with ASD and the current difficulty of molecular diagnosis. Our study also shows that an NGS-customized panel might be useful for diagnosing patients with essential/primary autism and that it is cost-effective for most genetic laboratories. Full article
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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19 pages, 2175 KiB  
Article
Genotype–Phenotype Correlations in 293 Russian Patients with Causal Fabry Disease Variants
by Kirill Savostyanov, Alexander Pushkov, Ilya Zhanin, Natalya Mazanova, Alexander Pakhomov, Elena Trufanova, Alina Alexeeva, Dmitry Sladkov, Ludmila Kuzenkova, Aliy Asanov and Andrey Fisenko
Genes 2023, 14(11), 2016; https://doi.org/10.3390/genes14112016 - 28 Oct 2023
Cited by 2 | Viewed by 1646
Abstract
Background: Fabry disease (FD) is a rare hereditary multisystem disease caused by variants of the GLA gene. Determination of GLA gene variants and identification of genotype–phenotype correlations allow us to explain the features of FD associated with predominant damage of one or another [...] Read more.
Background: Fabry disease (FD) is a rare hereditary multisystem disease caused by variants of the GLA gene. Determination of GLA gene variants and identification of genotype–phenotype correlations allow us to explain the features of FD associated with predominant damage of one or another system, both in the classical and atypical forms of FD, as well as in cases with late manifestation and involvement of one of the systems. Methods: The study included 293 Russian patients with pathogenic variants of the GLA gene, which were identified as a result of various selective screening programs. Screening was carried out for 48,428 high-risk patients using a two-step diagnostic algorithm, including the determination of the concentration of the biomarker lyso-Gb3 as a first-tier test. Screening of atypical FD among patients with HCM was carried out via high-throughput sequencing in another 2427 patients. Results: 102 (0.20%) cases of FD were identified among unrelated patients as a result of the study of 50,855 patients. Molecular genetic testing allowed us to reveal the spectrum and frequencies of 104 different pathogenic variants of the GLA gene in 293 examined patients from 133 families. The spectrum and frequencies of clinical manifestations in patients with FD, including 20 pediatric patients, were described. Correlations between the concentration of the lyso-Gb3 biomarker and the type of pathogenic variants of the GLA gene have been established. Variants identified in patients with early stroke were described, and the association of certain variants with the development of stroke was established. Conclusions: The results of a large-scale selective FD screening, as well as clinical and molecular genetic features, in a cohort of 293 Russian patients with FD are described. Full article
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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9 pages, 919 KiB  
Article
A Spanish Family with Gordon Syndrome Due to a Variant in the Acidic Motif of WNK1
by Ramón Peces, Carlos Peces, Laura Espinosa, Rocío Mena, Carolina Blanco, Jair Tenorio-Castaño, Pablo Lapunzina and Julián Nevado
Genes 2023, 14(10), 1878; https://doi.org/10.3390/genes14101878 - 27 Sep 2023
Cited by 1 | Viewed by 1458
Abstract
(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) [...] Read more.
(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS. Full article
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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11 pages, 951 KiB  
Article
Molecular Genetic Analysis of Russian Patients with Coagulation Factor FVII Deficiency
by Olesya Pshenichnikova, Daria Selivanova, Ekaterina Shchemeleva, Tatiana Abramova, Nadezhda Zozulya and Vadim Surin
Genes 2023, 14(9), 1767; https://doi.org/10.3390/genes14091767 - 6 Sep 2023
Cited by 2 | Viewed by 1404
Abstract
Coagulation factor VII (proconvertin) is one of the proteins starting the blood coagulation cascade. Plasma FVII concentration is regulated by different factors. A low level of FVII could also be a result of FVII deficiency (MIM# 227500), the rare autosomal recessive inherited disease [...] Read more.
Coagulation factor VII (proconvertin) is one of the proteins starting the blood coagulation cascade. Plasma FVII concentration is regulated by different factors. A low level of FVII could also be a result of FVII deficiency (MIM# 227500), the rare autosomal recessive inherited disease caused by pathogenic variants in the F7 gene. The aim of this study was to describe a mutation spectrum of the F7 gene and genotype–phenotype relationship in patients with FVII deficiency in Russia for the first time. We studied the primary structure of the F7 gene of 54 unrelated patients with FVII deficiency by direct Sanger sequencing. Pathogenic variants in the F7 gene were detected in 37 (68.5%) of them. We identified 24 different mutations located mostly in the serine protease domain. Five pathogenic variants had never been reported before. A major mutation in the Russian population was c.1391delC (p. Pro464Hisfs*32), linked with rs36209567 and rs6046 functional polymorphisms, that is widely distributed in East Europe. As in other countries, the F7 genotypes poorly correlated with the severity of clinical manifestations but were quite well associated with FVII levels. Minor alleles of functional polymorphisms rs510335, rs5742910, rs561241, rs36209567, and rs6046 could also participate in the F7 genotype and influence FVII levels. Full article
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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13 pages, 2249 KiB  
Article
16p11.2 Microduplication Syndrome with Increased Fluid in the Cisterna: Coincidence or Phenotype Extension?
by Lívia Polisseni Cotta Nascimento, Rafaella Mergener, Marcela Rodrigues Nunes, Victória Feitosa Muniz, Juliana Rossi Catao, Ana Kalise Böttcher da Silveira, Luiza Emy Dorfman, Carla Graziadio and Paulo Ricardo Gazzola Zen
Genes 2023, 14(8), 1583; https://doi.org/10.3390/genes14081583 - 3 Aug 2023
Cited by 2 | Viewed by 3312
Abstract
We report the first case of a child with 16p11.2 microduplication syndrome with increased fluid in the cisterna magna seen on magnetic resonance imaging (MRI). This finding may correspond to a Blake’s Pouch Cyst (BPC) or a Mega Cisterna Magna (MCM), being impossible [...] Read more.
We report the first case of a child with 16p11.2 microduplication syndrome with increased fluid in the cisterna magna seen on magnetic resonance imaging (MRI). This finding may correspond to a Blake’s Pouch Cyst (BPC) or a Mega Cisterna Magna (MCM), being impossible to differentiate through image examination. The molecular duplication was diagnosed using chromosomal microarray analysis with single nucleotide polymorphism (SNP). We review the clinical and neuroimaging features in published case reports in order to observe the findings described in the literature so far and present a skull three-dimensional model to contribute to a better understanding. Despite the variable expressivity of the syndrome being well known, there is no case described in the available literature that mentions the association of 16p11.2 microduplication and the presence of BPC or MCM seen in neuroimaging exams. This finding may represent an extension of the phenotype not yet reported or may present itself as a coincidence in a child with various malformations. Full article
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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15 pages, 2536 KiB  
Article
Hereditary Tyrosinemia Type 1 Mice under Continuous Nitisinone Treatment Display Remnants of an Uncorrected Liver Disease Phenotype
by Jessie Neuckermans, Sien Lequeue, Paul Claes, Anja Heymans, Juliette H. Hughes, Haaike Colemonts-Vroninks, Lionel Marcélis, Georges Casimir, Philippe Goyens, Geert A. Martens, James A. Gallagher, Tamara Vanhaecke, George Bou-Gharios and Joery De Kock
Genes 2023, 14(3), 693; https://doi.org/10.3390/genes14030693 - 11 Mar 2023
Cited by 1 | Viewed by 4700
Abstract
Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic [...] Read more.
Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC. Full article
(This article belongs to the Special Issue Identifying the Molecular Basis of Rare Genetic Diseases)
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