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Advances in Human Hereditary Diseases: Genetics and Genomics Research

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 15244

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Special Issue Editor

Dr. Ekaterina Zakharova

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Guest Editor

Research Centre for Medical Genetics, Moskvorechye st., 1, 115522 Moscow, Russia
Interests: hereditary metabolic diseases; medical genetics; selective screening; biochemical markers of hereditary metabolic diseases

Special Issue Information

Dear Colleagues,

Hereditary diseases are one of the main causes of infant morbidity, mortality, and long-term childhood disability worldwide. Genetic heterogeneity and a broad spectrum of clinical manifestations significantly complicate prompt confirmatory diagnosis, and frequently lead to prolonged diagnostic odysseys. In recent years, new genetic technologies—mainly multiplex ones, such as next-generation sequencing (NGS)—have significantly changed our understanding of the genetic heterogeneity of hereditary diseases and their genotype–phenotype correlations. The improvement and expansion of genetic technologies have shed light on our understanding of different molecular mechanisms underlying human hereditary diseases that may become potential therapeutic targets in the future. This development has addressed fundamental ideas of the types of disease inheritance, brought differential diagnostics to a new level, and led us to the discovery of novel disease-associated genes. Finally, NGS has led to a process known as reverse phenotyping and highlighted the role of somatic mosaicism in the development of inherited diseases.

This Special Issue is dedicated to the application of NGS technology, exome and genome studies in unraveling complex diagnostic cases, the identification of new genetic variants affecting gene splicing and expression, new data on genotype–phenotype correlations, as well as clinical cases of patients diagnosed with multiple rare diseases or diseases of digenic inheritance. The Special Issue is also dedicated to new insights into the limitations and challenges associated with NGS as well as the role of different NGS-based approaches in diagnostic workflows.

Being a journal of molecular sciences, this Special Issue of IJMS welcomes original research studies and case reports on molecular and genetic aspects, underlying human hereditary diseases, their potential therapeutic targets, epidemiological data as well as the expansion of differential diagnostic technologies. Descriptions of clinical manifestations of these diseases are admitted only in addition to the aforementioned experimental results.

Dr. Ekaterina Zakharova
Guest Editor

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Keywords

hereditary diseases
genomic technologies
NGS
genotype–phenotype correlation
molecular medicine

Published Papers (11 papers)

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Research

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12 pages, 249 KiB

Open AccessArticle

Genetic Landscape and Clinical Features of Hyperphenylalaninemia in North Ossetia-Alania: High Frequency of P281L and P211T Genetic Variants in the PAH Gene

by Inna S. Tebieva, Polina V. Mishakova, Yulia V. Gabisova, Alana V. Khokhova, Tamara G. Kaloeva, Andrey V. Marakhonov, Olga A. Shchagina, Alexander V. Polyakov, Evgeny K. Ginter, Sergey I. Kutsev and Rena A. Zinchenko

Int. J. Mol. Sci. 2024, 25(9), 4598; https://doi.org/10.3390/ijms25094598 - 23 Apr 2024

Viewed by 479

Abstract

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

15 pages, 1223 KiB

Open AccessArticle

Implementing a New Algorithm for Reinterpretation of Ambiguous Variants in Genetic Dilated Cardiomyopathy

by Alexandra Pérez-Serra, Rocío Toro, Estefanía Martinez-Barrios, Anna Iglesias, Anna Fernandez-Falgueras, Mireia Alcalde, Mónica Coll, Marta Puigmulé, Bernat del Olmo, Ferran Picó, Laura Lopez, Elena Arbelo, Sergi Cesar, Coloma Tiron de Llano, Alipio Mangas, Josep Brugada, Georgia Sarquella-Brugada, Ramon Brugada and Oscar Campuzano

Int. J. Mol. Sci. 2024, 25(7), 3807; https://doi.org/10.3390/ijms25073807 - 29 Mar 2024

Viewed by 586

Abstract

Dilated cardiomyopathy is a heterogeneous entity that leads to heart failure and malignant arrhythmias. Nearly 50% of cases are inherited; therefore, genetic analysis is crucial to unravel the cause and for the early identification of carriers at risk. A large number of variants remain classified as ambiguous, impeding an actionable clinical translation. Our goal was to perform a comprehensive update of variants previously classified with an ambiguous role, applying a new algorithm of already available tools. In a cohort of 65 cases diagnosed with dilated cardiomyopathy, a total of 125 genetic variants were classified as ambiguous. Our reanalysis resulted in the reclassification of 12% of variants from an unknown to likely benign or likely pathogenic role, due to improved population frequencies. For all the remaining ambiguous variants, we used our algorithm; 60.9% showed a potential but not confirmed deleterious role, and 24.5% showed a potential benign role. Periodically updating the population frequencies is a cheap and fast action, making it possible to clarify the role of ambiguous variants. Here, we perform a comprehensive reanalysis to help to clarify the role of most of ambiguous variants. Our specific algorithms facilitate genetic interpretation in dilated cardiomyopathy. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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12 pages, 1586 KiB

Open AccessArticle

Disease-Causing TIMP3 Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation

by Andrea Vergaro, Monika Pankievic, Jana Jedlickova, Lubica Dudakova, Marie Vajter, Michel Michaelides, Martin Meliska, Pavel Nemec, Daniela Babincova, Bohdan Kousal and Petra Liskova

Int. J. Mol. Sci. 2024, 25(7), 3744; https://doi.org/10.3390/ijms25073744 - 27 Mar 2024

Viewed by 685

Abstract

We aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported TIMP3 pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination and retinal imaging, including optical coherence tomography angiography. The DNA of the first proband was screened using a targeted ocular gene panel, while, in the second proband, direct sequencing of the TIMP3 coding region was performed. Sanger sequencing was also used for segregation analysis within the families. All the previously reported TIMP3 variants were reviewed using the American College of Medical Genetics and the Association for Molecular Pathology interpretation framework. A novel heterozygous variant, c.455A>G p.(Tyr152Cys), in TIMP3 was identified in both families and potentially de novo in one. Optical coherence tomography angiography documented in one patient the development of a choroidal neovascular membrane at 54 years. Including this study, 23 heterozygous variants in TIMP3 have been reported as disease-causing. Application of gene-specific criteria denoted eleven variants as pathogenic, eleven as likely pathogenic, and one as a variant of unknown significance. Our study expands the spectrum of TIMP3 pathogenic variants and highlights the importance of optical coherence tomography angiography for early detection of choroidal neovascular membranes. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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17 pages, 5730 KiB

Open AccessArticle

Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity

by Tatiana Usenko, Anastasia Bezrukova, Margarita M. Rudenok, Katerina Basharova, Maria I. Shadrina, Petr A. Slominsky, Ekaterina Zakharova and Sofya Pchelina

Int. J. Mol. Sci. 2023, 24(15), 12164; https://doi.org/10.3390/ijms241512164 - 29 Jul 2023

Cited by 1 | Viewed by 1548

Abstract

Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson’s disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-β-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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9 pages, 2217 KiB

Open AccessCommunication

Clinical Characterization of Alagille Syndrome in Patients with Cholestatic Liver Disease

by Natalia Semenova, Elena Kamenets, Eleonora Annenkova, Andrey Marakhonov, Elena Gusarova, Nina Demina, Daria Guseva, Inga Anisimova, Anna Degtyareva, Natalia Taran, Tatiana Strokova and Ekaterina Zakharova

Int. J. Mol. Sci. 2023, 24(14), 11758; https://doi.org/10.3390/ijms241411758 - 21 Jul 2023

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Abstract

Alagille syndrome (ALGS) is a multisystem condition characterized by cholestasis and bile duct paucity on liver biopsy and variable involvement of the heart, skeleton, eyes, kidneys, and face and caused by pathogenic variants in the JAG1 or NOTCH2 gene. The variable expressivity of the clinical phenotype and the lack of genotype–phenotype correlations lead to significant diagnostic difficulties. Here we present an analysis of 18 patients with cholestasis who were diagnosed with ALGS. We used an NGS panel targeting coding exons of 52 genes, including the JAG1 and NOTCH2 genes. Sanger sequencing was used to verify the mutation in the affected individuals and family members. The specific facial phenotype was seen in 16/18 (88.9%). Heart defects were seen in 8/18 (44.4%) patients (pulmonary stenosis in 7/8). Butterfly vertebrae were seen in 5/14 (35.7%) patients. Renal involvement was detected in 2/18 (11.1%) cases—one patient had renal cysts, and one had obstructive hydronephrosis. An ophthalmology examination was performed on 12 children, and only one had posterior embryotoxon (8.3%). A percutaneous liver biopsy was performed in nine cases. Bile duct paucity was detected in six/nine cases (66.7%). Two patients required liver transplantation because of cirrhosis. We identified nine novel variants in the JAG1 gene—eight frameshift variants (c.1619_1622dupGCTA (p.Tyr541X), c.1160delG (p.Gly387fs), c.964dupT (p.C322fs), c.120delG (p.L40fs), c.1984dupG (p.Ala662Glyfs), c.3168_3169delAG (p.R1056Sfs*51), c.2688delG (p.896CysfsTer49), c.164dupG (p.Cys55fs)) and one missense variant, c.2806T > G (p.Cys936Gly). None of the patients presented with NOTCH2 variants. In accordance with the classical criteria, only six patients could meet the diagnostic criteria in our cohort without genetic analysis. Genetic testing is important in the diagnosis of ALGS and can help differentiate it from other types of cholestasis. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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9 pages, 967 KiB

Open AccessCommunication

Evaluation of Pathogenicity and Causativity of Variants in the MPZ and SH3TC2 Genes in a Family Case of Hereditary Peripheral Neuropathy

by Olga Shchagina, Mariya Orlova, Aisylu Murtazina, Alexandra Filatova, Mikhail Skoblov and Elena Dadali

Int. J. Mol. Sci. 2023, 24(12), 9786; https://doi.org/10.3390/ijms24129786 - 6 Jun 2023

Viewed by 1614

Abstract

The implementation of NGS methods into clinical practice allowed researchers effectively to establish the molecular cause of a disorder in cases of a genetically heterogeneous pathology. In cases of several potentially causative variants, we need additional analysis that can help in choosing a proper causative variant. In the current study, we described a family case of hereditary motor and sensory neuropathy (HMSN) type 1 (Charcot–Marie–Tooth disease). DNA analysis revealed two variants in the SH3TC2 gene (c.279G>A and c.1177+5G>A), as well as a previously described variant c.449−9C>T in the MPZ gene, in a heterozygous state. This family segregation study was incomplete because of the proband’s father's unavailability. To evaluate the variants’ pathogenicity, minigene splicing assay was carried out. This study showed no effect of the MPZ variant on splicing, but the c.1177+5G>A variant in the SH3TC2 gene leads to the retention of 122 nucleotides from intron 10 in the RNA sequence, causing a frameshift and an occurrence of a premature stop codon (NP_078853.2:p.Ala393GlyfsTer2). Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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12 pages, 2250 KiB

Open AccessArticle

Clinical and Genetic Characteristics of Calvarial Doughnut Lesions with Bone Fragility in Three Families with a Reccurent SGMS2 Gene Variant

by Elena Merkuryeva, Tatiana Markova, Anton Tyurin, Diana Valeeva, Vladimir Kenis, Maria Sumina, Igor Sorokin, Olga Shchagina, Mikhail Skoblov, Maria Nefedova, Rita Khusainova, Ekaterina Zakharova, Elena Dadali and Sergey Kutsev

Int. J. Mol. Sci. 2023, 24(9), 8021; https://doi.org/10.3390/ijms24098021 - 28 Apr 2023

Cited by 2 | Viewed by 1568

Abstract

Calvarial doughnut lesions (CDL) with bone fragility with or without spondylometaphyseal dysplasia (MIM: #126550) is a rare autosomal dominant skeletal disorder characterized by low bone mineral density, spinal and peripheral fractures, and specific sclerotic lesions of the cranial bones. In the current classification of skeletal disorders, the disease is included in the group of bone fragility disorders along with osteogenesis imperfecta. The disease is caused by pathogenic variants in the SGMS2 gene, the protein product of which is sphingomyelin synthase 2, which primarily contributes to sphingomyelin (SM) synthesis—the main lipid component of the plasma membrane essential for bone mineralization. To date, 15 patients from eight families with CDL with bone fragility have been described in the literature, and a recurrent variant c.148C>T (p.Arg50Ter) in the SGMS2 gene has been identified, which was found in patients from six families. We diagnosed the disease in 11 more patients from three unrelated families, caused by the same heterozygous nonsense variant c.148C>T (p.Arg50Ter) in the SGMS2 gene. Our results show wide interfamilial and intrafamilial phenotypic variability in patients with a detected recurrent variant in the SGMS2 gene, the presence of which must be taken into consideration in the diagnosis of the disease. The primary analysis of this variant will contribute to optimal molecular genetic diagnostics, which can reduce diagnostic costs and time. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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10 pages, 254 KiB

Open AccessArticle

The CFTR Gene Germline Heterozygous Pathogenic Variants in Russian Patients with Malignant Neoplasms and Healthy Carriers: 11,800 WGS Results

by Maria Makarova, Marina Nemtsova, Anastasiia Danishevich, Denis Chernevskiy, Maxim Belenikin, Anastasiia Krinitsina, Elena Baranova, Olesya Sagaydak, Maria Vorontsova, Igor Khatkov, Lyudmila Zhukova, Natalia Bodunova, Sergey Nikolaev, Mariya Byakhova, Anna Semenova, Vsevolod Galkin and Saida Gadzhieva

Int. J. Mol. Sci. 2023, 24(9), 7940; https://doi.org/10.3390/ijms24097940 - 27 Apr 2023

Cited by 2 | Viewed by 2764

Abstract

More than 275 million people in the world are carriers of a heterozygous mutation of the CFTR gene, associated with cystic fibrosis, the most common autosomal recessive disease among Caucasians. Some recent studies assessed the association between carriers of CFTR variants and some pathologies, including cancer risk. The aim of this study is to analyze the landscape of germline pathogenic heterozygous CFTR variants in patients with diagnosed malignant neoplasms. For the first time in Russia, we evaluated the frequency of CFTR pathogenic variants by whole-genome sequencing in 1800 patients with cancer and compared this with frequencies of CFTR variants in the control group (1825 people) adjusted for age and 10,000 healthy individuals. In the issue, 47 out of 1800 patients (2.6%) were carriers of CFTR pathogenic genetic variants: 0.028 (42/1525) (2.8%) among breast cancer patients, 0.017 (3/181) (1.7%) among colorectal cancer patients and 0.021 (2/94) (2.1%) among ovarian cancer patients. Pathogenic CFTR variants were found in 52/1825 cases (2.85%) in the control group and 221 (2.21%) in 10,000 healthy individuals. Based on the results of the comparison, there was no significant difference in the frequency and distribution of pathogenic variants of the CFTR gene, which is probably due to the study limitations. Obviously, additional studies are needed to assess the clinical significance of the heterozygous carriage of CFTR pathogenic variants in the development of various pathologies in the future, particularly cancer. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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8 pages, 603 KiB

Open AccessCase Report

PGT-M, a Useful Tool to Manage the Lynch Syndrome Transmission

by Ilaria Listorti, Roberta Manzo, Cristiana Arrivi, Cecilia Mencacci, Anil Biricik, Ermanno Greco and Pierfrancesco Greco

Int. J. Mol. Sci. 2023, 24(22), 16114; https://doi.org/10.3390/ijms242216114 - 9 Nov 2023

Cited by 1 | Viewed by 1057

Abstract

Lynch syndrome is one of the most common hereditary cancer sensitivity syndromes and is caused by autosomal-dominant germline mutations in DNA mismatch repair genes. In patients affected by this syndrome, pre-implantation genetic testing for monogenic disorders (PGT-M) could be the elective technique used to prevent the transmission of this hereditary syndrome to offspring. Notably, despite the severity of the condition, some authors have observed a markedly lower demand for PGT-M in these patients compared to those with other hereditary conditions. A 34-year-old woman with a medical history of Lynch syndrome associated with endometrial cancer came to the Villa Mafalda fertility center in Rome in order to conceive a healthy baby. In a pre-implantation genetic testing for aneuploidy (PGT-A) + PGT-M cycle, eight blastocysts were formed. Six out of eight blastocysts were affected by the same mother syndrome. One of the other two was aneuploid and the other one was a mosaic embryo, which resulted in a healthy pregnancy. The aim of this report is to emphasize the importance of a multidisciplinary approach to managing patients with this condition. In vitro fertilization (IVF), specifically PGT-M, is a tool that allow patients to conceive biological children with lower risk of inheriting the disease. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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10 pages, 1346 KiB

Open AccessCase Report

Unusual Trisomy X Phenotype Associated with a Concurrent Heterozygous 16p11.2 Deletion: Importance of an Integral Approach for Proper Diagnosis

by Ariadna González-del Angel, Miguel Angel Alcántara-Ortigoza, Sandra Ramos, Carolina Algara-Ramírez, Marco Antonio Hernández-Hernández and Lorenza Saenger-Rivas

Int. J. Mol. Sci. 2023, 24(19), 14643; https://doi.org/10.3390/ijms241914643 - 27 Sep 2023

Cited by 1 | Viewed by 1181

Abstract

Trisomy X is the most frequent sex chromosome anomaly in women, but it is often underdiagnosed postnatally because most patients do not show any clinical manifestation. It is estimated that only 10% of patients with trisomy X are diagnosed by clinical findings. Thus, it has been proposed that the clinical spectrum is not yet fully delimited, and additional uncommon or atypical clinical manifestations could be related to this entity. The present report describes a female carrying trisomy X but presenting atypical manifestations, including severe intellectual disability, short stature, thymus hypoplasia, and congenital hypothyroidism (CH). These clinical findings were initially attributed to trisomy X. However, chromosome microarray analysis (CMA) subsequently revealed that the patient also bears a heterozygous 304-kb deletion at 16p11.2. This pathogenic copy-number variant (CNV) encompasses 13 genes, including TUFM. Some authors recommend that when a phenotype differs from that described for an identified microdeletion, the presence of pathogenic variants in the non-deleted allele should be considered to assess for an autosomal recessive disorder; thus, we used a panel of 697 genes to rule out a pathogenic variant in the non-deleted TUFM allele. We discuss the possible phenotypic modifications that might be related to an additional CNV in individuals with sex chromosome aneuploidy (SCA), as seen in our patient. The presence of karyotype-demonstrated trisomy X and CMA-identified 16p11.2 deletion highlights the importance of always correlating a patient’s clinical phenotype with the results of genetic studies. When the phenotype includes unusual manifestations and/or exhibits discrepancies with that described in the literature, as exemplified by our patient, a more extensive analysis should be undertaken to enable a correct diagnosis that will support proper management, genetic counseling, and medical follow-up. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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7 pages, 679 KiB

Open AccessCase Report

Clinical Presentation of a Patient with a Congenital Disorder of Glycosylation, Type IIs (ATP6AP1), and Liver Transplantation

by Natalia Semenova, Olga Shatokhina, Olga Shchagina, Elena Kamenec, Andrey Marakhonov, Anna Degtyareva, Natalia Taran and Tatiana Strokova

Int. J. Mol. Sci. 2023, 24(8), 7449; https://doi.org/10.3390/ijms24087449 - 18 Apr 2023

Cited by 2 | Viewed by 1345

Abstract

The congenital disorder of glycosylation type IIs (ATP6AP1-CDG; OMIM# 300972) is a rare X-linked recessive complex syndrome characterized by liver dysfunction, recurrent bacterial infections, hypogammaglobulinemia, and defective glycosylation of serum proteins. Here, we examine the case of a 1-year-old male patient of Buryat origin, who presented with liver dysfunction. At the age of 3 months, he was hospitalized with jaundice and hepatosplenomegaly. Whole-exome sequencing identified the ATP6AP1 gene missense variant NM_001183.6:c.938A>G (p.Tyr313Cys) in the hemizygous state, which was previously reported in a patient with immunodeficiency type 47. At the age of 10 months, the patient successfully underwent orthotopic liver transplantation. After the transplantation, the use of Tacrolimus entailed severe adverse effect (colitis with perforation). Replacing Tacrolimus with Everolimus led to improvement. Previously reported patients demonstrated abnormal N- and O-glycosylation, but these data were collected without any specific treatment. In contrast, in our patient, isoelectric focusing (IEF) of serum transferrin was performed only after the liver transplant and showed a normal IEF pattern. Thus, liver transplantation could be a curative option for patients with ATP6AP1-CDG. Full article

(This article belongs to the Special Issue Advances in Human Hereditary Diseases: Genetics and Genomics Research)

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