Research

15 pages, 7236 KiB

Open AccessArticle

Seven Additional Patients with SOX17 Related Pulmonary Arterial Hypertension and Review of the Literature

by Natalia Gallego-Zazo, Lucía Miranda-Alcaraz, Alejandro Cruz-Utrilla, María Jesús del Cerro Marín, María Álvarez-Fuente, María del Mar Rodríguez Vázquez del Rey, Inmaculada Guillén Rodríguez, Victor Manuel Becerra-Munoz, Amparo Moya-Bonora, Nuria Ochoa Parra, Alejandro Parra, Patricia Pascual, Mario Cazalla, Cristina Silván, Pedro Arias, Diana Valverde, Vinicio de Jesús-Pérez, Pablo Lapunzina, Pilar Escribano-Subías and Jair Tenorio-Castano

Genes 2023, 14(10), 1965; https://doi.org/10.3390/genes14101965 - 20 Oct 2023

Viewed by 1419

Abstract

Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. [...] Read more.

Pulmonary arterial hypertension (PAH) is an infrequent disorder characterized by high blood pressure in the pulmonary arteries. It may lead to premature death or the requirement for lung and/or heart transplantation. Genetics plays an important and increasing role in the diagnosis of PAH. Here, we report seven additional patients with variants in SOX17 and a review of sixty previously described patients in the literature. Patients described in this study suffered with additional conditions including large septal defects, as described by other groups. Collectively, sixty-seven PAH patients have been reported so far with variants in SOX17, including missense and loss-of-function (LoF) variants. The majority of the loss-of-function variants found in SOX17 were detected in the last exon of the gene. Meanwhile, most missense variants were located within exon one, suggesting a probable tolerated change at the amino terminal part of the protein. In addition, we reported two idiopathic PAH patients presenting with the same variant previously detected in five patients by other studies, suggesting a possible hot spot. Research conducted on PAH associated with congenital heart disease (CHD) indicated that variants in SOX17 might be particularly prevalent in this subgroup, as two out of our seven additional patients presented with CHD. Further research is still necessary to clarify the precise association between the biological pathway of SOX17 and the development of PAH. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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16 pages, 2422 KiB

Open AccessArticle

Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders

by Saadia Maryam Saadi, Elisa Cali, Lubaba Bintee Khalid, Hammad Yousaf, Ghazala Zafar, Haq Nawaz Khan, Muhammad Sher, Barbara Vona, Uzma Abdullah, Naveed Altaf Malik, Joakim Klar, Stephanie Efthymiou, Niklas Dahl, Henry Houlden, Mathias Toft, Shahid Mahmood Baig, Ambrin Fatima and Zafar Iqbal

Genes 2023, 14(7), 1404; https://doi.org/10.3390/genes14071404 - 06 Jul 2023

Viewed by 2125

Abstract

Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the [...] Read more.

Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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12 pages, 865 KiB

Open AccessArticle

PTRH2 Gene Variants: Recent Review of the Phenotypic Features and Their Bioinformatics Analysis

by Rajech Sharkia, Sahil Jain, Muhammad Mahajnah, Clair Habib, Abdussalam Azem, Wasif Al-Shareef and Abdelnaser Zalan

Genes 2023, 14(5), 1031; https://doi.org/10.3390/genes14051031 - 30 Apr 2023

Cited by 1 | Viewed by 1804

Abstract

Peptidyl-tRNA hydrolase 2 (PTRH2) is an evolutionarily highly conserved mitochondrial protein. The biallelic mutations in the PTRH2 gene have been suggested to cause a rare autosomal recessive disorder characterized by an infantile-onset multisystem neurologic endocrine and pancreatic disease (IMNEPD). Patients with IMNEPD present [...] Read more.

Peptidyl-tRNA hydrolase 2 (PTRH2) is an evolutionarily highly conserved mitochondrial protein. The biallelic mutations in the PTRH2 gene have been suggested to cause a rare autosomal recessive disorder characterized by an infantile-onset multisystem neurologic endocrine and pancreatic disease (IMNEPD). Patients with IMNEPD present varying clinical manifestations, including global developmental delay associated with microcephaly, growth retardation, progressive ataxia, distal muscle weakness with ankle contractures, demyelinating sensorimotor neuropathy, sensorineural hearing loss, and abnormalities of thyroid, pancreas, and liver. In the current study, we conducted an extensive literature review with an emphasis on the variable clinical spectrum and genotypes in patients. Additionally, we reported on a new case with a previously documented mutation. A bioinformatics analysis of the various PTRH2 gene variants was also carried out from a structural perspective. It appears that the most common clinical characteristics among all patients include motor delay (92%), neuropathy (90%), distal weakness (86.4%), intellectual disability (84%), hearing impairment (80%), ataxia (79%), and deformity of head and face (~70%). The less common characteristics include hand deformity (64%), cerebellar atrophy/hypoplasia (47%), and pancreatic abnormality (35%), while the least common appear to be diabetes mellitus (~30%), liver abnormality (~22%), and hypothyroidism (16%). Three missense mutations were revealed in the PTRH2 gene, the most common one being Q85P, which was shared by four different Arab communities and was presented in our new case. Moreover, four different nonsense mutations in the PTRH2 gene were detected. It may be concluded that disease severity depends on the PTRH2 gene variant, as most of the clinical features are manifested by nonsense mutations, while only the common features are presented by missense mutations. A bioinformatics analysis of the various PTRH2 gene variants also suggested the mutations to be deleterious, as they seem to disrupt the structural confirmation of the enzyme, leading to loss of stability and functionality. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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13 pages, 2281 KiB

Open AccessArticle

Genetic Screening of Targeted Region on the Chromosome 22q11.2 in Patients with Microtia and Congenital Heart Defect

by Caiyun Zhu, Yang Yang, Bo Pan, Hui Wei, Jiahang Ju, Nuo Si and Qi Xu

Genes 2023, 14(4), 879; https://doi.org/10.3390/genes14040879 - 07 Apr 2023

Viewed by 1342

Abstract

Microtia is a congenital malformation characterized by a small, abnormally shaped auricle (pinna) ranging in severity. Congenital heart defect (CHD) is one of the comorbid anomalies with microtia. However, the genetic basis of the co-existence of microtia and CHD remains unclear. Copy number [...] Read more.

Microtia is a congenital malformation characterized by a small, abnormally shaped auricle (pinna) ranging in severity. Congenital heart defect (CHD) is one of the comorbid anomalies with microtia. However, the genetic basis of the co-existence of microtia and CHD remains unclear. Copy number variations (CNVs) of 22q11.2 contribute significantly to microtia and CHD, respectively, thus suggesting a possible shared genetic cause embedded in this genomic region. In this study, 19 sporadic patients with microtia and CHD, as well as a nuclear family, were enrolled for genetic screening of single nucleotide variations (SNVs) and CNVs in 22q11.2 by target capture sequencing. We detected a total of 105 potential deleterious variations, which were enriched in ear- or heart-development-related genes, including TBX1 and DGCR8. The gene burden analysis also suggested that these genes carry more deleterious mutations in the patients, as well as several other genes associated with cardiac development, such as CLTCL1. Additionally, a microduplication harboring SUSD2 was validated in an independent cohort. This study provides new insights into the underlying mechanisms for the comorbidity of microtia and CHD focusing on chromosome 22q11.2, and suggests that a combination of genetic variations, including SNVs and CNVs, may play a crucial role instead of single gene mutation. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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18 pages, 2360 KiB

Open AccessArticle

Reconstruction of a Comprehensive Interactome and Experimental Data Analysis of FRA10AC1 May Provide Insights into Its Biological Role in Health and Disease

by Theologia Sarafidou, Eleni Galliopoulou, Despina Apostolopoulou, Georgios A. Fragkiadakis and Nicholas K. Moschonas

Genes 2023, 14(3), 568; https://doi.org/10.3390/genes14030568 - 24 Feb 2023

Viewed by 1624

Abstract

FRA10AC1, the causative gene for the manifestation of the FRA10A fragile site, encodes a well-conserved nuclear protein characterized as a non-core spliceosomal component. Pre-mRNA splicing perturbations have been linked with neurodevelopmental diseases. FRA10AC1 variants have been, recently, causally linked with severe neuropathological [...] Read more.

FRA10AC1, the causative gene for the manifestation of the FRA10A fragile site, encodes a well-conserved nuclear protein characterized as a non-core spliceosomal component. Pre-mRNA splicing perturbations have been linked with neurodevelopmental diseases. FRA10AC1 variants have been, recently, causally linked with severe neuropathological and growth retardation phenotypes. To further elucidate the participation of FRA10AC1 in spliceosomal multiprotein complexes and its involvement in neurological phenotypes related to splicing, we exploited protein–protein interaction experimental data and explored network information and information deduced from transcriptomics. We confirmed the direct interaction of FRA10AC1with ESS2, a non-core spliceosomal protein, mapped their interacting domains, and documented their tissue co-localization and physical interaction at the level of intracellular protein stoichiometries. Although FRA10AC1 and SF3B2, a major core spliceosomal protein, were shown to interact under in vitro conditions, the endogenous proteins failed to co-immunoprecipitate. A reconstruction of a comprehensive, strictly binary, protein–protein interaction network of FRA10AC1 revealed dense interconnectivity with many disease-associated spliceosomal components and several non-spliceosomal regulatory proteins. The topological neighborhood of FRA10AC1 depicts an interactome associated with multiple severe monogenic and multifactorial neurodevelopmental diseases mainly referring to spliceosomopathies. Our results suggest that FRA10AC1 involvement in pre-mRNA processing might be strengthened by interconnecting splicing with transcription and mRNA export, and they propose the broader role(s) of FRA10AC1 in cell pathophysiology. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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34 pages, 7400 KiB

Open AccessArticle

Evolutionary Landscape of SOX Genes to Inform Genotype-to-Phenotype Relationships

by Adam Underwood, Daniel T Rasicci, David Hinds, Jackson T Mitchell, Jacob K Zieba, Joshua Mills, Nicholas E Arnold, Taylor W Cook, Mehdi Moustaqil, Yann Gambin, Emma Sierecki, Frank Fontaine, Sophie Vanderweele, Akansha S Das, William Cvammen, Olivia Sirpilla, Xavier Soehnlen, Kristen Bricker, Maram Alokaili, Morgan Green, Sadie Heeringa, Amy M Wilstermann, Thomas M. Freeland, Dinah Qutob, Amy Milsted, Ralf Jauch, Timothy J Triche, Jr., Connie M Krawczyk, Caleb P Bupp, Surender Rajasekaran, Mathias Francois and Jeremy W. Prokop Show full author list Hide full author list

Genes 2023, 14(1), 222; https://doi.org/10.3390/genes14010222 - 14 Jan 2023

Cited by 2 | Viewed by 3618

Abstract

The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype–phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 [...] Read more.

The SOX transcription factor family is pivotal in controlling aspects of development. To identify genotype–phenotype relationships of SOX proteins, we performed a non-biased study of SOX using 1890 open-reading frame and 6667 amino acid sequences in combination with structural dynamics to interpret 3999 gnomAD, 485 ClinVar, 1174 Geno2MP, and 4313 COSMIC human variants. We identified, within the HMG (High Mobility Group)- box, twenty-seven amino acids with changes in multiple SOX proteins annotated to clinical pathologies. These sites were screened through Geno2MP medical phenotypes, revealing novel SOX15 R104G associated with musculature abnormality and SOX8 R159G with intellectual disability. Within gnomAD, SOX18 E137K (rs201931544), found within the HMG box of ~0.8% of Latinx individuals, is associated with seizures and neurological complications, potentially through blood–brain barrier alterations. A total of 56 highly conserved variants were found at sites outside the HMG-box, including several within the SOX2 HMG-box-flanking region with neurological associations, several in the SOX9 dimerization region associated with Campomelic Dysplasia, SOX14 K88R (rs199932938) flanking the HMG box associated with cardiovascular complications within European populations, and SOX7 A379V (rs143587868) within an SOXF conserved far C-terminal domain heterozygous in 0.716% of African individuals with associated eye phenotypes. This SOX data compilation builds a robust genotype-to-phenotype association for a gene family through more robust ortholog data integration. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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10 pages, 854 KiB

Open AccessArticle

Reclassification of DMD Duplications as Benign: Recommendations for Cautious Interpretation of Variants Identified in Prenatal Screening

by Wenbin He, Guiquan Meng, Xiao Hu, Jing Dai, Jiyang Liu, Xiurong Li, Hao Hu, Yueqiu Tan, Qianjun Zhang, Guangxiu Lu, Ge Lin and Juan Du

Genes 2022, 13(11), 1972; https://doi.org/10.3390/genes13111972 - 28 Oct 2022

Cited by 4 | Viewed by 1595

Abstract

Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical [...] Read more.

Duplications are the main type of dystrophin gene (DMD) variants, which typically cause dystrophinopathies such as Duchenne muscular dystrophy and Becker muscular dystrophy. Maternally inherited exon duplication in DMD in fetuses is a relatively common finding of genetic screening in clinical practice. However, there is no standard strategy for interpretation of the pathogenicity of DMD duplications during prenatal screening, especially for male fetuses, in which maternally inherited pathogenic DMD variants more frequently cause dystrophinopathies. Here, we report three non-contiguous DMD duplications identified in a woman and her male fetus during prenatal screening. Multiplex ligation probe amplification and long-read sequencing were performed on the woman and her family members to verify the presence of DMD duplications. Structural rearrangements in the DMD gene were mapped by long-read sequencing, and the breakpoint junction sequences were validated using Sanger sequencing. The woman and her father carried three non-contiguous DMD duplications. Long-read and Sanger sequencing revealed that the woman’s father carried an intact DMD copy and a complex structural rearrangement of the DMD gene. Therefore, we reclassified these three non-contiguous DMD duplications, one of which is listed as pathogenic, as benign. We postulate that breakpoint analysis should be performed on identified DMD duplication variants, and the pathogenicity of the duplications found during prenatal screening should be interpreted cautiously for clinical prediction and genetic/reproductive counseling. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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12 pages, 2074 KiB

Open AccessArticle

A Novel De Novo NFKBIA Missense Mutation Associated to Ectodermal Dysplasia with Dysgammaglobulinemia

by Chai Teng Chear, Bader Abdul Kader El Farran, Marina Sham, Kavetha Ramalingam, Lokman Mohd Noh, Intan Hakimah Ismail, Mei Yee Chiow, Mohd Farid Baharin, Adiratna Mat Ripen and Saharuddin Bin Mohamad

Genes 2022, 13(10), 1900; https://doi.org/10.3390/genes13101900 - 19 Oct 2022

Cited by 3 | Viewed by 2219

Abstract

Background: Inborn errors of immunity (IEIs) are comprised of heterogeneous groups of genetic disorders affecting immune function. In this report, a 17-month-old Malay patient suspected of having Hyper IgM syndrome, a type of IEIs, was described. However, the diagnosis of Hyper IgM syndrome [...] Read more.

Background: Inborn errors of immunity (IEIs) are comprised of heterogeneous groups of genetic disorders affecting immune function. In this report, a 17-month-old Malay patient suspected of having Hyper IgM syndrome, a type of IEIs, was described. However, the diagnosis of Hyper IgM syndrome was excluded by the normal functional studies and the mild features of ectodermal dysplasia observed from a further clinical phenotype inspection. Methods: Whole-exome sequencing (WES) was performed to unravel the causative mutation in this patient. Results: The variant analysis demonstrated a novel missense mutation in NFKBIA (NM_020529:c.94A > T,NP_065390:p.Ser32Cys) and was predicted as damaging by in silico prediction tools. The NFKBIA gene encodes for IκBα, a member of nuclear factor kappa B (NF-κB) inhibitors, playing an important role in regulating NF-κB activity. The mutation occurred at the six degrons (Asp31-Ser36) in IκBα which were evolutionarily conserved across several species. Prediction analysis suggested that the substitution of Ser32Cys may cause a loss of the phosphorylation site at residue 32 and a gain of the sumoylation site at residue 38, resulting in the alteration of post-translational modifications of IκBα required for NF-κB activation. Conclusion: Our analysis hints that the post-translational modification in the NFKBIA Ser32Cys mutant would alter the signaling pathway of NF-κB. Our findings support the usefulness of WES in diagnosing IEIs and suggest the role of post-translational modification of IκBα. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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11 pages, 1415 KiB

Open AccessArticle

A Novel Intragenic Duplication in the HDAC8 Gene Underlying a Case of Cornelia de Lange Syndrome

by Cristina Lucia-Campos, Irene Valenzuela, Ana Latorre-Pellicer, David Ros-Pardo, Marta Gil-Salvador, María Arnedo, Beatriz Puisac, Neus Castells, Alberto Plaja, Anna Tenes, Ivon Cuscó, Laura Trujillano, Feliciano J. Ramos, Eduardo F. Tizzano, Paulino Gómez-Puertas and Juan Pié

Genes 2022, 13(8), 1413; https://doi.org/10.3390/genes13081413 - 08 Aug 2022

Cited by 1 | Viewed by 1974

Abstract

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the [...] Read more.

Cornelia de Lange syndrome (CdLS) is a multisystemic genetic disorder characterized by distinctive facial features, growth retardation, and intellectual disability, as well as various systemic conditions. It is caused by genetic variants in genes related to the cohesin complex. Single-nucleotide variations are the best-known genetic cause of CdLS; however, copy number variants (CNVs) clearly underlie a substantial proportion of cases of the syndrome. The NIPBL gene was thought to be the locus within which clinically relevant CNVs contributed to CdLS. However, in the last few years, pathogenic CNVs have been identified in other genes such as HDAC8, RAD21, and SMC1A. Here, we studied an affected girl presenting with a classic CdLS phenotype heterozygous for a de novo ~32 kbp intragenic duplication affecting exon 10 of HDAC8. Molecular analyses revealed an alteration in the physiological splicing that included a 96 bp insertion between exons 9 and 10 of the main transcript of HDAC8. The aberrant transcript was predicted to generate a truncated protein whose accessibility to the active center was restricted, showing reduced ease of substrate entry into the mutated enzyme. Lastly, we conclude that the duplication is responsible for the patient’s phenotype, highlighting the contribution of CNVs as a molecular cause underlying CdLS. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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Review

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14 pages, 321 KiB

Open AccessReview

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

by Kateryna Kalyta, Weronika Stelmaszczyk, Dominika Szczęśniak, Lidia Kotuła, Paula Dobosz and Magdalena Mroczek

Genes 2023, 14(8), 1562; https://doi.org/10.3390/genes14081562 - 31 Jul 2023

Viewed by 2047

Abstract

Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across [...] Read more.

Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur “later in life”. The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

16 pages, 1872 KiB

Open AccessReview

CRISPR-Cas: ‘The Multipurpose Molecular Tool’ for Gene Therapy and Diagnosis

by Stéphane Sauvagère and Christian Siatka

Genes 2023, 14(8), 1542; https://doi.org/10.3390/genes14081542 - 27 Jul 2023

Cited by 2 | Viewed by 2024

Abstract

Since the discovery of the CRISPR-Cas engineering system in 2012, several approaches for using this innovative molecular tool in therapeutic strategies and even diagnosis have been investigated. The use of this tool requires a global approach to DNA damage processes and repair systems [...] Read more.

Since the discovery of the CRISPR-Cas engineering system in 2012, several approaches for using this innovative molecular tool in therapeutic strategies and even diagnosis have been investigated. The use of this tool requires a global approach to DNA damage processes and repair systems in cells. The diversity in the functions of various Cas proteins allows for the use of this technology in clinical applications and trials. Wide variants of Cas12 and Cas13 are exploited using the collateral effect in many diagnostic applications. Even though this tool is well known, its use still raises real-world ethical and regulatory questions. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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10 pages, 1356 KiB

Open AccessReview

Biomarkers for Monitoring Renal Damage Due to Fabry Disease in Patients Treated with Migalastat: A Review for Nephrologists

by Sebastián Jaurretche, Hernan Conde, Ana Gonzalez Schain, Franco Ruiz, Maria Victoria Sgro and Graciela Venera

Genes 2022, 13(10), 1751; https://doi.org/10.3390/genes13101751 - 28 Sep 2022

Cited by 4 | Viewed by 1877

Abstract

Nephropathy is a major Fabry disease complication. Kidney biopsies reveal glomerulosclerosis even in pediatric patients. The main manifestations of Fabry nephropathy include reduced glomerular filtration rate and proteinuria. In 2016, an oral pharmacological Chaperone was approved to treat Fabry patients with “amenable” mutations. [...] Read more.

Nephropathy is a major Fabry disease complication. Kidney biopsies reveal glomerulosclerosis even in pediatric patients. The main manifestations of Fabry nephropathy include reduced glomerular filtration rate and proteinuria. In 2016, an oral pharmacological Chaperone was approved to treat Fabry patients with “amenable” mutations. Because (i) Fabry disease is a rare disorder that frequently causes kidney damage, and (ii) a new therapeutic is currently available, it is necessary to review wich biomarkers are useful for nephropathy follow-up among Fabry “amenable” patients receiving migalastat. The literature search was conducted in MEDLINE, EMBASE, SCOPUS, Cochrane, and Google academic. Prospective studies in which renal biomarkers were the dependent variable or criterion, with at least 6 months of follow-up, were included. Finally, we recorded relevant information in an ad hoc database and summarized the main results. To date, the main useful biomarker for nephropathy monitoring among Fabry “amenable” patients receiving migalastat is glomerular filtration rate estimated by equations that include serum creatinine. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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Other

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10 pages, 1779 KiB

Open AccessCase Report

New SLC22A12 (URAT1) Variant Associated with Renal Hypouricemia Identified by Whole-Exome Sequencing Analysis and Bioinformatics Predictions

by Ana Perdomo-Ramírez, Elena Ramos-Trujillo and Félix Claverie-Martín

Genes 2023, 14(9), 1823; https://doi.org/10.3390/genes14091823 - 20 Sep 2023

Viewed by 931

Abstract

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this [...] Read more.

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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12 pages, 3365 KiB

Open AccessCase Report

A Splicing Variant in RDH8 Is Associated with Autosomal Recessive Stargardt Macular Dystrophy

by Stefania Zampatti, Cristina Peconi, Giulia Calvino, Rosangela Ferese, Stefano Gambardella, Raffaella Cascella, Jacopo Sebastiani, Benedetto Falsini, Andrea Cusumano and Emiliano Giardina

Genes 2023, 14(8), 1659; https://doi.org/10.3390/genes14081659 - 21 Aug 2023

Cited by 1 | Viewed by 867

Abstract

Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic [...] Read more.

Stargardt macular dystrophy is a genetic disorder, but in many cases, the causative gene remains unrevealed. Through a combined approach (whole-exome sequencing and phenotype/family-driven filtering algorithm) and a multilevel validation (international database searching, prediction scores calculation, splicing analysis assay, segregation analyses), a biallelic mutation in the RDH8 gene was identified to be responsible for Stargardt macular dystrophy in a consanguineous Italian family. This paper is a report on the first family in which a biallelic deleterious mutation in RDH8 is detected. The disease phenotype is consistent with the expected phenotype hypothesized in previous studies on murine models. The application of the combined approach to genetic data and the multilevel validation allowed the identification of a splicing mutation in a gene that has never been reported before in human disorders. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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8 pages, 1700 KiB

Open AccessCase Report

Liver Involvement in Patients with Rare MBOAT7 Variants and Intellectual Disability: A Case Report and Literature Review

by Luisa Ronzoni, Matteo Mureddu, Francesco Malvestiti, Vittoria Moretti, Cristiana Bianco, Giulia Periti, Margherita Baldassarri, Francesca Ariani, Anna Carrer, Serena Pelusi, Alessandra Renieri, Daniele Prati and Luca Valenti

Genes 2023, 14(8), 1633; https://doi.org/10.3390/genes14081633 - 16 Aug 2023

Viewed by 1183

Abstract

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) protein is an acyltransferase catalyzing arachidonic acid incorporation into lysophosphatidylinositol. Patients with rare, biallelic loss-of-function variants of the MBOAT7 gene display intellectual disability with neurodevelopmental defects. The rs641738 inherited variant associated with reduced hepatic MBOAT7 expression has [...] Read more.

The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) protein is an acyltransferase catalyzing arachidonic acid incorporation into lysophosphatidylinositol. Patients with rare, biallelic loss-of-function variants of the MBOAT7 gene display intellectual disability with neurodevelopmental defects. The rs641738 inherited variant associated with reduced hepatic MBOAT7 expression has been linked to steatotic liver disease susceptibility. However, the impact of biallelic loss-of-function MBOAT7 variants on liver disease is not known. We report on a 2-year-old girl with MBOAT7-related intellectual disability and steatotic liver disease, confirming that MBOAT7 loss-of-function predisposes to liver disease. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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8 pages, 251 KiB

Open AccessCase Report

A Rare Case of Precocious Puberty in a Child with a Novel GATA-4 Gene Mutation: Implications for Disorders of Sex Development (DSD) and Review of the Literature

by Tommaso Aversa, Giovanni Luppino, Domenico Corica, Giorgia Pepe, Mariella Valenzise, Roberto Coco, Alessandra Li Pomi and Malgorzata Wasniewska

Genes 2023, 14(8), 1631; https://doi.org/10.3390/genes14081631 - 16 Aug 2023

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Abstract

Background: Disorders/Differences of sex development (DSD) are often due to disruptions of the genetic programs that regulate gonad development. The GATA-4 gene, located on chromosome 8p23.1, encodes GATA-binding protein 4 (GATA-4), a transcription factor that is essential for cardiac and gonadal development and [...] Read more.

Background: Disorders/Differences of sex development (DSD) are often due to disruptions of the genetic programs that regulate gonad development. The GATA-4 gene, located on chromosome 8p23.1, encodes GATA-binding protein 4 (GATA-4), a transcription factor that is essential for cardiac and gonadal development and sexual differentiation. Case Description: A child with a history of micropenis and cryptorchidism. At 8 years of age, he came under our observation for an increase in sexual pubic hair (pubarche). The laboratory parameters and the GnRH test suggested a central precocious puberty (CPP). Treatment with GnRH analogs was started, and we decided to perform genetic tests for DSD. The NGS genetic investigation showed a novel and heterozygous variant in the GATA-4 gene. Discussion: In the literature, 26 cases with 46,XY DSD due to the GATA4 gene were reported. Conclusion: The novel variant in the GATA-4 gene of our patient was not previously associated with DSD. This is the first case of a DSD due to a GATA-4 mutation that develops precocious puberty. Precocious puberty could be associated with DSD and considered a prelude to hypogonadism in some cases. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

10 pages, 534 KiB

Open AccessCase Report

Co-Inheritance of Pathogenic Variants in PKD1 and PKD2 Genes Determined by Parental Segregation and De Novo Origin: A Case Report

by Ludovico Graziani, Stefania Zampatti, Miriam Lucia Carriero, Chiara Minotti, Cristina Peconi, Mario Bengala, Emiliano Giardina and Giuseppe Novelli

Genes 2023, 14(8), 1589; https://doi.org/10.3390/genes14081589 - 06 Aug 2023

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Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern [...] Read more.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, and it is typically caused by PKD1 and PKD2 heterozygous variants. Nonetheless, the extensive phenotypic variability observed among affected individuals, even within the same family, suggests a more complex pattern of inheritance. We describe an ADPKD family in which the proband presented with an earlier and more severe renal phenotype (clinical diagnosis at the age of 14 and end-stage renal disease aged 24), compared to the other affected family members. Next-generation sequencing (NGS)-based analysis of polycystic kidney disease (PKD)-associated genes in the proband revealed the presence of a pathogenic PKD2 variant and a likely pathogenic variant in PKD1, according to the American College of Medical Genetics and Genomics (ACMG) criteria. The PKD2 nonsense p.Arg872Ter variant was segregated from the proband’s father, with a mild phenotype. A similar mild disease presentation was found in the proband’s aunts and uncle (the father’s siblings). The frameshift p.Asp3832ProfsTer128 novel variant within PKD1 carried by the proband in addition to the pathogenic PKD2 variant was not found in either parent. This report highlights that the co-inheritance of two or more PKD genes or alleles may explain the extensive phenotypic variability among affected family members, thus emphasizing the importance of NGS-based techniques in the definition of the prognostic course. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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13 pages, 3777 KiB

Open AccessCase Report

White Sponge Nevus Caused by Keratin 4 Gene Mutation: A Case Report

by Yahui Qiao, Binjie Liu, Ruiqi Bai, Jingwen Cai and Qian Peng

Genes 2022, 13(12), 2184; https://doi.org/10.3390/genes13122184 - 22 Nov 2022

Cited by 2 | Viewed by 4709

Abstract

White sponge nevus (WSN) is a rare autosomal dominant disease with a family history, often caused by mutations of the keratin 4 (K4) and keratin 13 (K13) genes in patients. It is characterized by frequently occurred white corrugated folds in the bilateral buccal [...] Read more.

White sponge nevus (WSN) is a rare autosomal dominant disease with a family history, often caused by mutations of the keratin 4 (K4) and keratin 13 (K13) genes in patients. It is characterized by frequently occurred white corrugated folds in the bilateral buccal mucosa with soft texture. On histopathological examination, hyperkeratosis of epithelial cells, edema, and vacuolar changes in the spinous cells are observed in the lesions, despite a normal layer of basal cells. WSN should be differentiated from other oral white spot diseases, mainly oral lichen planus, oral candidiasis, oral white edema, and Heck’s disease, to reduce misdiagnosis and unnecessary treatment. At present, there is no specific treatment method. The purpose of this study was to report the clinical data of four WSN patients of the same family with the K4 gene mutation. The occurrence of WSN in a pair of monozygotic twins with very similar clinical presentations was identified for the first time. The gene sequencing results showed that there was a heterozygous deletion (C. 438_440delCAA) in exon 1 of the K4 gene, resulting in an aspartic acid loss in both the proband and his father. Finally, the etiology, pathogenesis, pathological manifestations, clinical manifestations, diagnosis, differential diagnosis, and related treatment methods are discussed to provide a reference for clinical treatment of the disease. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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9 pages, 452 KiB

Open AccessCase Report

A Novel Nonsense Variant in GRM1 Causes Autosomal Recessive Spinocerebellar Ataxia 13 in a Consanguineous Pakistani Family

by Hammad Yousaf, Ambrin Fatima, Zafar Ali, Shahid M. Baig, Mathias Toft and Zafar Iqbal

Genes 2022, 13(9), 1667; https://doi.org/10.3390/genes13091667 - 17 Sep 2022

Cited by 5 | Viewed by 3804

Abstract

Background and objectives: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an ultra-rare disorder characterized by slowly progressive cerebellar ataxia, cognitive deficiencies, and skeletal and oculomotor abnormalities. The objective of this case report is to expand the clinical and molecular spectrum of SCAR13. Methods: We [...] Read more.

Background and objectives: Autosomal recessive spinocerebellar ataxia-13 (SCAR13) is an ultra-rare disorder characterized by slowly progressive cerebellar ataxia, cognitive deficiencies, and skeletal and oculomotor abnormalities. The objective of this case report is to expand the clinical and molecular spectrum of SCAR13. Methods: We investigated a consanguineous Pakistani family with four patients partially presenting with clinical features of SCAR13 using whole exome sequencing. Segregation analysis was performed by Sanger sequencing in all the available individuals of the family. Results: Patients presented with quadrupedal gait, delayed developmental milestones, non-progressive peripheral neuropathy, and cognitive impairment. Whole exome sequencing identified a novel pathogenic nonsense homozygous variant, Gly240*, in the gene GRM1 as a cause of SCAR13 that segregates with the recessive disease. Discussion: We report a novel homozygous nonsense variant in the GRM1 gene in four Pakistani patients presenting with clinical features that partially overlap with the already reported phenotype of SCAR13. In addition, the family presented quadrupedal gait and non-progressive symptoms, manifestations which have not been recognized previously. So far, only four variants in GRM1 have been reported, in families of Roma, Iranian, and Tunisian origins. The current study adds to the mutation spectrum of GRM1 and provides a rare presentation of SCAR13, the first from the Pakistani population. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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8 pages, 938 KiB

Open AccessCase Report

McCune-Albright Syndrome in Infant with Growth Hormone Excess

by Katarina Brzica, Marko Simunovic, Matea Ivancic, Darija Tudor, Ivna Skrabic and Veselin Skrabic

Genes 2022, 13(8), 1345; https://doi.org/10.3390/genes13081345 - 27 Jul 2022

Cited by 1 | Viewed by 2912

Abstract

Background: McCune-Albright is a rare syndrome, caused by mutation of the GNAS1 gene, and is characterized by an appearance of multiple endocrinopathies, most commonly premature puberty, polyostotic fibrous dysplasia and skin changes called cafe au lait macules. Case report: We present the case [...] Read more.

Background: McCune-Albright is a rare syndrome, caused by mutation of the GNAS1 gene, and is characterized by an appearance of multiple endocrinopathies, most commonly premature puberty, polyostotic fibrous dysplasia and skin changes called cafe au lait macules. Case report: We present the case of a patient who is, to the best of our knowledge and after extensive review of literature, the youngest McCune-Albright syndrome patient with growth hormone excess, diagnosed at 8.9 months of age. An extensive diagnostic procedure was done upon the diagnosis. Hormonal assessment was performed and all hormone levels were within reference range, and an additional oral glucose suppression that noted the presence of growth hormone excess. Magnetic resonance imaging of the pituitary gland did not detect a tumor process. The genetic analysis of the GNAS1 gene from skin punch biopsy came back negative. Octreotide was administered as therapy for growth hormone excess at 9.8 months. After the introduction of therapy, we noted a decrease in growth rate from 29.38 to 16.6 cm/year. Conclusion: This case report emphasizes the lack of available data on treatment of growth hormone excess and follow-up in pediatric population and the need for further research. Full article

(This article belongs to the Special Issue Genetics and Genomics of Rare Disorders)

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