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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 (20 June 2021) | Viewed by 31411

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Special Issue Editors

Prof. Dr. Domenico Coviello

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Guest Editor

Director of Laboratory of Human Genetics IRCCS Istituto Giannina Gaslini Research Institute and Children Hospital Via Gerolamo Gaslini 5, 16147 Genova, Italy
Interests: human genetic testing in mendelian disease; in vitro model of genetic diseases for the development of innovative gene therapy; haploinsufficiency syndromes (Sotos Syndrome) in which microRNA could stimulate the normal allele; gene expression and WGS to clarify pathogenesis in undiagnosed complex patients

Prof. Dr. Pablo Lapunzina

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1. INGEMM—Institute of Medical and Molecular Genetics Hospital Universitario La Paz – IdiPAZ, 261-28046 Madrid, Spain
2. CIBERER—Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, 261-28046 Madrid, Spain
3. ITHACA—European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability, 1049 Brussels, Belgium
Interests: genomic medicine; gain of function and loss of function mutations; overgrowth syndromes; imprinting disorders; novel genes associated to intellectual disabilities; Sotos syndrome; Becwith–Wiedemann syndrome; Simpson–Golabi–Behmel syndrome; WGS and WES in genetic diseases
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Zilfalil Alwi

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Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
Interests: thalassaemia; population genomics; medical genetic testing

Prof. Dr. Ghada El Kamah

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Guest Editor

Coordinator of the Hereditary Blood Disorders (HBD) and Genodermatoses Clinics and Research Team, Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, El Buhouth St., Dokki 12611, Cairo, Egypt
Interests: human genetics testing; counseling and genotype–phenotype correlation in rare and common diseases, particularly HBD and genodermatoses; research on genetic therapeutic approaches; in vitro gene editing; gene expression studies and microRNAs both as biomarkers and their therapeutic values

Special Issue Information

Dear Colleagues,

Genetics testing is currently one of the most pressing needs in all disciplines in the medical field, from the beginning of life—i.e., reproductive medicine—to the late stages of our lives—i.e., cancer/chronic conditions treatment. The population in the US and Europe is getting older with two main consequences: (a) couples are looking for children at older ages with more genetic problems arising that need to be investigated; (b) genetics has moved to genomics, which also involves more common conditions, and therefore we have moved from single gene analysis to NGS revolution with large gene panels sequenced and also with increasing requests of WGS and WGS analysis. The accumulation of high-throughput sequencing data is revealing, every day, new variants that need to be interpreted to understand if they are connected with the pathogenesis of medical conditions.

This Special Issue invites research articles, reviews, and short communications including but not limited to: current approaches in genetic testing both in classical genetic conditions, in rare cases of complex syndrome, more common medical conditions with a genetic predisposition where the phenotype cannot be fully explained by the classical genomic approaches but need needs high-throughput data with new lines of analysis to reveal which genes work together to express a given trait.

Prof. Dr. Domenico Coviello
Prof. Dr. Pablo Lapunzina
Prof. Dr. Zilfalil Alwi
Prof. Dr. Ghada El Kamah
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Genetic testing
nGS
Genotype–phenotype correlation
WES
WGS
Gene expression analysis
Genetic counselling
Genome education
Complex disease
Genodermatoses
Genomic medicine

Published Papers (10 papers)

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Research

24 pages, 9408 KiB

Open AccessArticle

Confirmation of a Phenotypic Entity for TSPEAR Variants in Egyptian Ectodermal Dysplasia Patients and Role of Ethnicity

by Eman A. Rabie, Inas S. M. Sayed, Khalda Amr, Hoda A. Ahmed, Mostafa I. Mostafa, Nehal F. Hassib, Heba El-Sayed, Suher K. Zada and Ghada El-Kamah

Genes 2022, 13(6), 1056; https://doi.org/10.3390/genes13061056 - 13 Jun 2022

Viewed by 2445

Abstract

Ectodermal dysplasia (ED) are hereditary disorders characterized by the disturbance of the ectodermal development of at least two of four ectodermal tissues: teeth, hair, nails and sweat glands. Clinical classification of ED is challenged by overlapping features, variable expressivity, and low number of patients, hindering full phenotypic spectrum identification. Disease-causing variants in elements of major developmental pathways, e.g., Ectodysplasin/NFκB, Wnt, and Tp63 pathways, have been identified in fewer than half of ED phenotypes. Whole-exome sequencing (WES) was performed for ten Egyptian ED patients presenting with tooth agenesis, normal sweating, scalp hypotrichosis, and sharing characteristic facial features. WES was followed by in silico analysis of the effects of novel detected genetic variants on mRNA and protein structure. The study identified four novel rare pathogenic and likely pathogenic TSPEAR variants, a gene which was recently found to be involved in ectodermal organogenesis. A novel in-frame deletion recurred in eight patients from six unrelated families. Comparing our cohort to previously reported TSPEAR cohorts highlighted the influence of ethnicity on TSPEAR phenotypic affection. Our study expands the clinical and mutational spectrum of the growing TSPEAR associated phenotypes, and pinpoints the influence of WES and in silico tools on identification of rare disease-causing variants. Full article

(This article belongs to the Special Issue Genetic Tests)

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6 pages, 1351 KiB

Open AccessArticle

PanelDesign: Integrating Epidemiological Information into the Design of Diagnostic NGS Gene Panels

by Jörg Schmidtke, Peter Philipp, Kathrin Rommel, Ralf Glaubitz, Jörg T. Epplen and Michael Krawczak

Genes 2022, 13(4), 684; https://doi.org/10.3390/genes13040684 - 13 Apr 2022

Cited by 1 | Viewed by 1400

Abstract

We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given NGS panel to be ranked according to the frequency of the associated diseases, thereby highlighting potential core genes as defined by the Eurogenetest/ESHG guidelines for diagnostic next generation DNA sequencing. In addition, PanelDesign can be used to evaluate the contribution of different genes to a given disease following ACMG (American College of Medical Genetics) technical standards. Full article

(This article belongs to the Special Issue Genetic Tests)

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10 pages, 1595 KiB

Open AccessArticle

Hemoglobin A₂ and Heterogeneous Diagnostic Relevance Observed in Eight New Variants of the Delta Globin Gene

by Noraesah Mahmud, Massimo Maffei, Massimo Mogni, Gian Luca Forni, Valeria Maria Pinto, Giuseppina Barberio, Silvana Ungari, Antonella Maffè, Cristina Curcio, Francesco Zanolli, Raffaella Paventa, Mariarosa Carta, Alberta Caleffi, Mariella Mercadanti, Sauro Maoggi, Giovanni Ivaldi and Domenico Coviello

Genes 2021, 12(11), 1821; https://doi.org/10.3390/genes12111821 - 19 Nov 2021

Cited by 1 | Viewed by 1771

Abstract

Background: Hemoglobin A (Hb A) (α₂β₂) in the normal adult subject constitutes 96–98% of hemoglobin, and Hb F is normally less than 1%, while for hemoglobin A₂ (Hb A₂) (α₂δ₂), the normal reference values are between 2.0 and 3.3%. It is important to evaluate the presence of possible delta gene mutations in a population at high risk for globin gene defects in order to correctly diagnose the β-thalassemia carrier. Methods: The most used methods for the quantification of Hb A₂ are based on automated high performance liquid chromatography (HPLC) or capillary electrophoresis (CE). In particular Hb analyses were performed by HPLC on three dedicated devices. DNA analyses were performed according to local standard protocols. Results: Here, we described eight new δ-globin gene variants discovered and characterized in some laboratories in Northern Italy in recent years. These new variants were added to the many already known Hb A₂ variants that were found with an estimated frequency of about 1–2% during the screening tests in our laboratories. Conclusions: The knowledge recognition of the delta variant on Hb analysis and accurate molecular characterization is crucial to provide an accurate definitive thalassemia diagnosis, particularly in young subjects who would like to ask for a prenatal diagnosis or preimplantation genetic diagnosis. Full article

(This article belongs to the Special Issue Genetic Tests)

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23 pages, 1361 KiB

Open AccessArticle

Spectrum of Genetic Diseases in Tunisia: Current Situation and Main Milestones Achieved

by Nessrine Mezzi, Olfa Messaoud, Rahma Mkaouar, Nadia Zitouna, Safa Romdhane, Ghaith Abdessalem, Cherine Charfeddine, Faouzi Maazoul, Ines Ouerteni, Yosr Hamdi, Anissa Zaouak, Ridha Mrad, Sonia Abdelhak and Lilia Romdhane

Genes 2021, 12(11), 1820; https://doi.org/10.3390/genes12111820 - 19 Nov 2021

Cited by 3 | Viewed by 2355

Abstract

Genetic diseases in Tunisia are a real public health problem given their chronicity and the lack of knowledge concerning their prevalence and etiology, and the high rates of consanguinity. Hence, we performed systematic reviews of the literature in order to provide a more recent spectrum of these disorders and to expose the challenges that still exist to tackle these kinds of diseases. A manual textual data mining was conducted using MeSH and PubMed databases. Collected data were classified according to the CIM-10 classification and the transmission mode. The spectrum of these diseases is estimated to be 589 entities. This suggests remarkable progress through the development of biomedical health research activities and building capacities. Sixty percent of the reported disorders are autosomal recessive, which could be explained by the high prevalence of endogamous mating. Congenital malformations (29.54%) are the major disease group, followed by metabolic diseases (22%). Sixty percent of the genetic diseases have a known molecular etiology. We also reported additional cases of comorbidity that seem to be a common phenomenon in our population. We also noticed that epidemiological data are scarce. Newborn and carrier screening was only limited to pilot projects for a few genetic diseases. Collected data are being integrated into a database under construction that will be a valuable decision-making tool. This study provides the current situation of genetic diseases in Tunisia and highlights their particularities. Early detection of the disease is important to initiate critical intervention and to reduce morbidity and mortality. Full article

(This article belongs to the Special Issue Genetic Tests)

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13 pages, 2270 KiB

Open AccessArticle

Genetic and Molecular Evaluation: Reporting Three Novel Mutations and Creating Awareness of Pycnodysostosis Disease

by Khalda Sayed Amr, Hala T. El-Bassyouni, Sawsan Abdel Hady, Mostafa I. Mostafa, Mennat I. Mehrez, Domenico Coviello and Ghada Y. El-Kamah

Genes 2021, 12(10), 1552; https://doi.org/10.3390/genes12101552 - 29 Sep 2021

Cited by 5 | Viewed by 1867

Abstract

Pycnodysostosis is a rare autosomal recessive disorder with characteristic diagnostic manifestations. This study aims to phenotype and provide molecular characterization of Egyptian patients, with emphasis on identifying unusual phenotypes and raising awareness about pycnodysostosis with different presentations to avoid a mis- or under-diagnosis and consequent mismanagement. We report on 22 Egyptian pycnodysostosis patients, including 9 new participants, all descending from consanguineous families and their ages ranging from 6 to 15 years. In addition, prenatal diagnosis was performed in one family with affected siblings. They all presented with short stature, except for one patient who presented with pancytopenia as her primary complaint. Moreover, 41.2% of patients had sleep apnea, 14% presented with craniosynostosis, and 44.4% had failure of tooth development. Molecular analysis via direct exome sequencing of the cathepsin K gene revealed three novel mutations ((NM_000396.3) c.761_763delCCT, c.864_865delAA, and c.509G>T) as well as two previously reported mutations among nine new cases. The following is our conclusion: This study expands the molecular spectrum of pycnodysostosis by identifying three novel mutations and adds to the clinical and orodental aspects of the disease. The link between the CTSK gene mutations and the failure of tooth development has not been established, and further studies could help to improve our understanding of the molecular pathology. Full article

(This article belongs to the Special Issue Genetic Tests)

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13 pages, 311 KiB

Open AccessArticle

Whole-Genome Profiles of Malay Colorectal Cancer Patients with Intact MMR Proteins

by Wan Khairunnisa Wan Juhari, Khairul Bariah Ahmad Amin Noordin, Andee Dzulkarnaen Zakaria, Wan Faiziah Wan Abdul Rahman, Wan Muhamad Mokhzani Wan Muhamad Mokhter, Muhammad Radzi Abu Hassan, Ahmad Shanwani Mohammed Sidek and Bin Alwi Zilfalil

Genes 2021, 12(9), 1448; https://doi.org/10.3390/genes12091448 - 20 Sep 2021

Cited by 5 | Viewed by 3047

Abstract

Background: This study aimed to identify new genes associated with CRC in patients with normal mismatch repair (MMR) protein expression. Method: Whole-genome sequencing (WGS) was performed in seven early-age-onset Malay CRC patients. Potential germline genetic variants, including single-nucleotide variations and insertions and deletions (indels), were prioritized using functional and predictive algorithms. Results: An average of 3.2 million single-nucleotide variations (SNVs) and over 800 indels were identified. Three potential candidate variants in three genes—IFNE, PTCH2 and SEMA3D—which were predicted to affect protein function, were identified in three Malay CRC patients. In addition, 19 candidate genes—ANKDD1B, CENPM, CLDN5, MAGEB16, MAP3K14, MOB3C, MS4A12, MUC19, OR2L8, OR51Q1, OR51AR1, PDE4DIP, PKD1L3, PRIM2, PRM3, SEC22B, TPTE, USP29 and ZNF117—harbouring nonsense variants were prioritised. These genes are suggested to play a role in cancer predisposition and to be associated with cancer risk. Pathway enrichment analysis indicated significant enrichment in the olfactory signalling pathway. Conclusion: This study provides a new spectrum of insights into the potential genes, variants and pathways associated with CRC in Malay patients. Full article

(This article belongs to the Special Issue Genetic Tests)

16 pages, 6382 KiB

Open AccessArticle

Gene Mutations of the Three Ectodysplasin Pathway Key Players (EDA, EDAR, and EDARADD) Account for More than 60% of Egyptian Ectodermal Dysplasia: A Report of Seven Novel Mutations

by Hoda A. Ahmed, Ghada Y. El-Kamah, Eman Rabie, Mostafa I. Mostafa, Maha R. Abouzaid, Nehal F. Hassib, Mennat I. Mehrez, Mohamed A. Abdel-Kader, Yasmine H. Mohsen, Suher K. Zada, Khalda S. Amr and Inas S. M. Sayed

Genes 2021, 12(9), 1389; https://doi.org/10.3390/genes12091389 - 08 Sep 2021

Cited by 9 | Viewed by 2756

Abstract

Ectodermal dysplasia (ED) is a diverse group of genetic disorders caused by congenital defects of two or more ectodermal-derived body structures, namely, hair, teeth, nails, and some glands, e.g., sweat glands. Molecular pathogenesis of ED involves mutations of genes encoding key proteins of major developmental pathways, including ectodysplasin (EDA) and wingless-type (WNT) pathways. The most common ED phenotype is hypohidrotic/anhidrotic ectodermal dysplasia (HED) featuring hypotrichosis, hypohidrosis/anhidrosis, and hypodontia. Molecular diagnosis is fundamental for disease management and emerging treatments. We used targeted next generation sequencing to study EDA, EDAR, EDARADD, and WNT10A genes in 45 Egyptian ED patients with or without hypohidrosis. We present genotype and phenotype data of 28 molecularly-characterized patients demonstrating genetic heterogeneity, variable expressivity, and intrafamilial phenotypic variability. Thirteen mutations were reported, including four novel EDA mutations, two novel EDARADD, and one novel EDAR mutations. Identified mutations congregated in exons encoding key functional domains. EDA is the most common gene contributing to 85% of the identified Egyptian ED genetic spectrum, followed by EDARADD (10%) and EDAR (5%). Our cohort represents the first and largest cohort from North Africa where more than 60% of ED patients were identified emphasizing the need for exome sequencing to explore unidentified cases. Full article

(This article belongs to the Special Issue Genetic Tests)

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13 pages, 626 KiB

Open AccessArticle

Framing Effects on Decision-Making for Diagnostic Genetic Testing: Results from a Randomized Trial

by Andrew A. Dwyer, Hongjie Shen, Ziwei Zeng, Matt Gregas and Min Zhao

Genes 2021, 12(6), 941; https://doi.org/10.3390/genes12060941 - 20 Jun 2021

Cited by 3 | Viewed by 3237

Abstract

Genetic testing is increasingly part of routine clinical care. However, testing decisions may be characterized by regret as findings also implicate blood relatives. It is not known if genetic testing decisions are affected by the way information is presented (i.e., framing effects). We employed a randomized factorial design to examine framing effects on hypothetical genetic testing scenarios (common, life-threatening disease and rare, life-altering disease). Participants (n = 1012) received one of six decision frames: choice, default (n = 2; opt-in, opt-out), or enhanced choice (n = 3, based on the Theory of Planned Behavior). We compared testing decision, satisfaction, regret, and decision cognitions across decision frames and between scenarios. Participants randomized to ‘choice’ were least likely to opt for genetic testing compared with default and enhanced choice frames (78% vs. 83–91%, p < 0.05). Neither satisfaction nor regret differed across frames. Perceived autonomy (behavioral control) predicted satisfaction (B = 0.085, p < 0.001) while lack of control predicted regret (B = 0.346, p < 0.001). Opting for genetic testing did not differ between disease scenarios (p = 0.23). Results suggest framing can nudge individuals towards opting for genetic testing. These findings have important implications for individual self-determination in the genomic era. Similarities between scenarios with disparate disease trajectories point to possible modular approaches for web-based decisional support. Full article

(This article belongs to the Special Issue Genetic Tests)

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9 pages, 583 KiB

Open AccessArticle

Schuurs–Hoeijmakers Syndrome (PACS1 Neurodevelopmental Disorder): Seven Novel Patients and a Review

by Jair Tenorio-Castaño, Beatriz Morte, Julián Nevado, Víctor Martinez-Glez, Fernando Santos-Simarro, Sixto García-Miñaúr, María Palomares-Bralo, Marta Pacio-Míguez, Beatriz Gómez, Pedro Arias, Alba Alcochea, Juan Carrión, Patricia Arias, Berta Almoguera, Fermina López-Grondona, Isabel Lorda-Sanchez, Enrique Galán-Gómez, Irene Valenzuela, María Pilar Méndez Perez, Ivón Cuscó, Francisco Barros, Juan Pié, Sergio Ramos, Feliciano J. Ramos, Alma Kuechler, Eduardo Tizzano, Carmen Ayuso, Frank J. Kaiser, Luis A. Pérez-Jurado, Ángel Carracedo, The ENoD-CIBERER Consortium, The SIDE Consortium and Pablo Lapunzina Show full author list Hide full author list

Genes 2021, 12(5), 738; https://doi.org/10.3390/genes12050738 - 13 May 2021

Cited by 13 | Viewed by 9025

Abstract

Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%). Full article

(This article belongs to the Special Issue Genetic Tests)

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10 pages, 258 KiB

Open AccessArticle

Expanding the Phenotypic Spectrum of PAX6 Mutations: From Congenital Cataracts to Nystagmus

by Maria Nieves-Moreno, Susana Noval, Jesus Peralta, María Palomares-Bralo, Angela del Pozo, Sixto Garcia-Miñaur, Fernando Santos-Simarro and Elena Vallespin

Genes 2021, 12(5), 707; https://doi.org/10.3390/genes12050707 - 09 May 2021

Cited by 8 | Viewed by 2036

Abstract

Background: Congenital aniridia is a complex ocular disorder, usually associated with severe visual impairment, generally caused by mutations on the PAX6 gene. The clinical phenotype of PAX6 mutations is highly variable, making the genotype–phenotype correlations difficult to establish. Methods: we describe the phenotype of eight patients from seven unrelated families with confirmed mutations in PAX6, and very different clinical manifestations. Results: Only two patients had the classical aniridia phenotype while the other two presented with aniridia-related manifestations, such as aniridia-related keratopathy or partial aniridia. Congenital cataracts were the main manifestation in three of the patients in this series. All the patients had nystagmus and low visual acuity. Conclusions: The diagnosis of mild forms of aniridia is challenging, but these patients have a potentially blinding hereditary disease that might present with a more severe phenotype in future generations. Clinicians should be aware of the mild aniridia phenotype and request genetic testing to perform an accurate diagnosis. Full article

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