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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 44161

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Special Issue Editor

Dr. José M. Millán

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Guest Editor

Health Research Institute La Fe, Valencia, Spain
Interests: genetics of rare diseases; inherited retinal dystrophies; hearing loss; neuromuscular disorders; gene editing; gene therapy

Special Issue Information

Dear Colleagues,

Rare diseases are defined by their low prevalence but, as a whole, they affect 8–10% of the population in Western countries. Six to seven thousand rare diseases have been reported in the literature, and the number is regularly increasing. There are many differences among them in terms of etiopathology, age of onset, affected organs and tissues, etc., but about 80% of them have a genetic cause.

Therefore, the genetic testing of rare diseases is a key point for confirming the clinical diagnosis, offering the correct genetic counseling to the patients and their relatives and, more recently, the possibility of receiving a treatment or engaging in a DNA-based clinical trial.

High-throughput sequencing has revolutionized the field of genetic testing. The previous screening methods based on gene-by-gene strategies have now been replaced by custom panels, clinical exomes, or even whole-exome sequencing. However, the best strategy for each disease or group of diseases depends on the genetic nature of that disease, the number of involved genes, or the type of mutation.

This Special Issue will be focused on clinical genetics, genetic counselling, rare metabolic diseases, sensorineural disorders, neuromuscular diseases, and bioinformatics, among other topics.

Dr. José Millán
Guest Editor

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Keywords

clinical genetics
bioinformatics
genetic counselling
sensorineural disorders
neurodevelopment
metabolic diseases
neurological diseases
rare pediatric diseases

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review, Other

4 pages, 209 KiB

Open AccessEditorial

Genetic Testing for Rare Diseases

by José M. Millán and Gema García-García

Diagnostics 2022, 12(4), 809; https://doi.org/10.3390/diagnostics12040809 - 25 Mar 2022

Cited by 1 | Viewed by 2197

Abstract

The term rare disease was coined in the 1970s to refer to diseases that have a low prevalence [...] Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

Research

Jump to: Editorial, Review, Other

16 pages, 2083 KiB

Open AccessArticle

Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia)

by Valeriia Yu. Danilchenko, Marina V. Zytsar, Ekaterina A. Maslova, Marita S. Bady-Khoo, Nikolay A. Barashkov, Igor V. Morozov, Alexander A. Bondar and Olga L. Posukh

Diagnostics 2021, 11(12), 2378; https://doi.org/10.3390/diagnostics11122378 - 17 Dec 2021

Cited by 12 | Viewed by 3271

Abstract

Hereditary hearing loss (HL) is known to be highly locus/allelic heterogeneous, and the prevalence of different HL forms significantly varies among populations worldwide. Investigation of region-specific landscapes of hereditary HL is important for local healthcare and medical genetic services. Mutations in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4) and Pendred syndrome are common genetic causes of hereditary HL, at least in some Asian populations. We present for the first time the results of a thorough analysis of the SLC26A4 gene by Sanger sequencing in the large cohorts of patients with HL of unknown etiology belonging to two neighboring indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians). A definite genetic diagnosis based on the presence of biallelic SLC26A4 mutations was established for 28.2% (62/220) of all enrolled Tuvinian patients vs. 4.3% (4/93) of Altaian patients. The rate of the SLC26A4-related HL in Tuvinian patients appeared to be one of the highest among populations worldwide. The SLC26A4 mutational spectrum was characterized by the presence of Asian-specific mutations c.919-2A>G and c.2027T>A (p.Leu676Gln), predominantly found in Tuvinian patients, and c.2168A>G (p.His723Arg), which was only detected in Altaian patients. In addition, a novel pathogenic variant c.1545T>G (p.Phe515Leu) was found with high frequency in Tuvinian patients. Overall, based on the findings of this study and our previous research, we were able to uncover the genetic causes of HL in 50.5% of Tuvinian patients and 34.5% of Altaian patients. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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11 pages, 583 KiB

Open AccessArticle

Correlation of Genotype and Perinatal Period, Time of Diagnosis and Anthropometric Data before Commencement of Recombinant Human Growth Hormone Treatment in Polish Patients with Prader–Willi Syndrome

by Agnieszka Lecka-Ambroziak, Marta Wysocka-Mincewicz, Katarzyna Doleżal-Ołtarzewska, Agata Zygmunt-Górska, Teresa Żak, Anna Noczyńska, Dorota Birkholz-Walerzak, Renata Stawerska, Maciej Hilczer, Monika Obara-Moszyńska, Barbara Rabska-Pietrzak, Elżbieta Gołębiowska, Adam Dudek, Elżbieta Petriczko, Mieczysław Szalecki and on behalf of the Polish Coordination Group for rhGH Treatment

Diagnostics 2021, 11(5), 798; https://doi.org/10.3390/diagnostics11050798 - 28 Apr 2021

Cited by 6 | Viewed by 2316

Abstract

Genotype–phenotype correlation in patients with Prader–Willi syndrome (PWS) has still not been fully described. We retrospectively analysed data of 147 patients and compared groups according to genetic diagnosis: paternal deletion of chromosome 15q11-q13 (DEL 15, n = 81), maternal uniparental disomy (UPD 15, n = 10), excluded DEL 15 (UPD 15 or imprinting centre defect, UPD/ID, n = 30). Group DEL 15 had an earlier genetic diagnosis and recombinant human growth hormone (rhGH) start (p = 0.00), with a higher insulin-like growth factor 1 (IGF1) level compared to group UPD/ID (p = 0.04). Among perinatal characteristics, there was only a tendency towards lower birth weight SDS in group UPD 15 (p = 0.06). We also compared data at rhGH start in relation to genetic diagnosis age—group 1: age ≤9 months, group 2: >9 months ≤ 2 years, group 3: > 2 years. Group 1 had the earliest rhGH start (p = 0.00), with lower body mass index (BMI) SDS (p = 0.00) and a tendency towards a higher IGF1 level compared to group 3 (p = 0.05). Genetic background in children with PWS is related to time of diagnosis and rhGH start, with a difference in IGF1 level before the therapy, but it seems to have little impact on perinatal data. Early genetic diagnosis leads to early rhGH treatment with favourable lower BMI SDS. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

10 pages, 1070 KiB

Open AccessArticle

Next-Generation Molecular Investigations in Lysosomal Diseases: Clinical Integration of a Comprehensive Targeted Panel

by Bénédicte Sudrié-Arnaud, Sarah Snanoudj, Ivana Dabaj, Hélène Dranguet, Lenaig Abily-Donval, Axel Lebas, Myriam Vezain, Bénédicte Héron, Isabelle Marie, Marc Duval-Arnould, Stéphane Marret, Abdellah Tebani and Soumeya Bekri

Diagnostics 2021, 11(2), 294; https://doi.org/10.3390/diagnostics11020294 - 12 Feb 2021

Cited by 5 | Viewed by 2700

Abstract

Diagnosis of lysosomal disorders (LDs) may be hampered by their clinical heterogeneity, phenotypic overlap, and variable age at onset. Conventional biological diagnostic procedures are based on a series of sequential investigations and require multiple sampling. Early diagnosis may allow for timely treatment and prevent clinical complications. In order to improve LDs diagnosis, we developed a capture-based next generation sequencing (NGS) panel allowing the detection of single nucleotide variants (SNVs), small insertions and deletions, and copy number variants (CNVs) in 51 genes related to LDs. The design of the LD panel covered at least coding regions, promoter region, and flanking intronic sequences for 51 genes. The validation of this panel consisted in testing 21 well-characterized samples and evaluating analytical and diagnostic performance metrics. Bioinformatics pipelines have been validated for SNVs, indels and CNVs. The clinical output of this panel was tested in five novel cases. This capture-based NGS panel provides an average coverage depth of 474× which allows the detection of SNVs and CNVs in one comprehensive assay. All the targeted regions were covered above the minimum required depth of 30×. To illustrate the clinical utility, five novel cases have been sequenced using this panel and the identified variants have been confirmed using Sanger sequencing or quantitative multiplex PCR of short fluorescent fragments (QMPSF). The application of NGS as first-line approach to analyze suspected LD cases may speed up the identification of alterations in LD-associated genes. NGS approaches combined with bioinformatics analyses, are a useful and cost-effective tool for identifying the causative variations in LDs. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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17 pages, 585 KiB

Open AccessArticle

Early Onset Ataxia with Comorbid Dystonia: Clinical, Anatomical and Biological Pathway Analysis Expose Shared Pathophysiology

by Deborah A. Sival, Martinica Garofalo, Rick Brandsma, Tom A. Bokkers, Marloes van den Berg, Tom J. de Koning, Marina A. J. Tijssen and Dineke S. Verbeek

Diagnostics 2020, 10(12), 997; https://doi.org/10.3390/diagnostics10120997 - 24 Nov 2020

Cited by 7 | Viewed by 6145

Abstract

In degenerative adult onset ataxia (AOA), dystonic comorbidity is attributed to one disease continuum. However, in early adult onset ataxia (EOA), the prevalence and pathogenesis of dystonic comorbidity (EOAD⁺), are still unclear. In 80 EOA-patients, we determined the EOAD⁺-prevalence in association with MRI-abnormalities. Subsequently, we explored underlying biological pathways by genetic network and functional enrichment analysis. We checked pathway-outcomes in specific EOAD⁺-genotypes by comparing results with non-specifically (in-silico-determined) shared genes in up-to-date EOA, AOA and dystonia gene panels (that could concurrently cause ataxia and dystonia). In the majority (65%) of EOA-patients, mild EOAD⁺-features concurred with extra-cerebellar MRI abnormalities (at pons and/or basal-ganglia and/or thalamus (p = 0.001)). Genetic network and functional enrichment analysis in EOAD⁺-genotypes indicated an association with organelle- and cellular-component organization (important for energy production and signal transduction). In non-specifically, in-silico-determined shared EOA, AOA and dystonia genes, pathways were enriched for Krebs-cycle and fatty acid/lipid-metabolic processes. In frequently occurring EOAD⁺-phenotypes, clinical, anatomical and biological pathway analyses reveal shared pathophysiology between ataxia and dystonia, associated with cellular energy metabolism and network signal transduction. Insight in the underlying pathophysiology of heterogeneous EOAD⁺-phenotype-genotype relationships supports the rationale for testing with complete, up-to-date movement disorder gene lists, instead of single EOA gene-panels. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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Review

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12 pages, 1135 KiB

Open AccessReview

Current Status of Genetic Counselling for Rare Diseases in Spain

by Sara Álvaro-Sánchez, Irene Abreu-Rodríguez, Anna Abulí, Clara Serra-Juhe and Maria del Carmen Garrido-Navas

Diagnostics 2021, 11(12), 2320; https://doi.org/10.3390/diagnostics11122320 - 9 Dec 2021

Cited by 4 | Viewed by 4977

Abstract

Genetic Counselling is essential for providing personalised information and support to patients with Rare Diseases (RD). Unlike most other developed countries, Spain does not recognize geneticists or genetic counsellors as healthcare professionals Thus, patients with RD face not only challenges associated with their own disease but also deal with lack of knowledge, uncertainty, and other psychosocial issues arising as a consequence of diagnostic delay. In this review, we highlight the importance of genetic counsellors in the field of RD as well as evaluate the current situation in which rare disease patients receive genetic services in Spain. We describe the main units and strategies at the national level assisting patients with RD and we conclude with a series of future perspectives and unmet needs that Spain should overcome to improve the management of patients with RD. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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18 pages, 8041 KiB

Open AccessReview

Facilitations and Hurdles of Genetic Testing in Neuromuscular Disorders

by Andrea Barp, Lorena Mosca and Valeria Ada Sansone

Diagnostics 2021, 11(4), 701; https://doi.org/10.3390/diagnostics11040701 - 14 Apr 2021

Cited by 13 | Viewed by 3948

Abstract

Neuromuscular disorders (NMDs) comprise a heterogeneous group of disorders that affect about one in every thousand individuals worldwide. The vast majority of NMDs has a genetic cause, with about 600 genes already identified. Application of genetic testing in NMDs can be useful for several reasons: correct diagnostic definition of a proband, extensive familial counselling to identify subjects at risk, and prenatal diagnosis to prevent the recurrence of the disease; furthermore, identification of specific genetic mutations still remains mandatory in some cases for clinical trial enrollment where new gene therapies are now approaching. Even though genetic analysis is catching on in the neuromuscular field, pitfalls and hurdles still remain and they should be taken into account by clinicians, as for example the use of next generation sequencing (NGS) where many single nucleotide variants of “unknown significance” can emerge, complicating the correct interpretation of genotype-phenotype relationship. Finally, when all efforts in terms of molecular analysis have been carried on, a portion of patients affected by NMDs still remain “not genetically defined”. In the present review we analyze the evolution of genetic techniques, from Sanger sequencing to NGS, and we discuss “facilitations and hurdles” of genetic testing which must always be balanced by clinicians, in order to ensure a correct diagnostic definition, but taking always into account the benefit that the patient could obtain especially in terms of “therapeutic offer”. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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17 pages, 815 KiB

Open AccessReview

Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

by Yasmin Tatour and Tamar Ben-Yosef

Diagnostics 2020, 10(10), 779; https://doi.org/10.3390/diagnostics10100779 - 2 Oct 2020

Cited by 54 | Viewed by 6329

Abstract

Inherited retinal diseases (IRDs), which are among the most common genetic diseases in humans, define a clinically and genetically heterogeneous group of disorders. Over 80 forms of syndromic IRDs have been described. Approximately 200 genes are associated with these syndromes. The majority of syndromic IRDs are recessively inherited and rare. Many, although not all, syndromic IRDs can be classified into one of two major disease groups: inborn errors of metabolism and ciliopathies. Besides the retina, the systems and organs most commonly involved in syndromic IRDs are the central nervous system, ophthalmic extra-retinal tissues, ear, skeleton, kidney and the cardiovascular system. Due to the high degree of phenotypic variability and phenotypic overlap found in syndromic IRDs, correct diagnosis based on phenotypic features alone may be challenging and sometimes misleading. Therefore, genetic testing has become the benchmark for the diagnosis and management of patients with these conditions, as it complements the clinical findings and facilitates an accurate clinical diagnosis and treatment. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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Other

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8 pages, 2661 KiB

Open AccessCase Report

Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss

by Luke Mansard, Christel Vaché, Julie Bianchi, Corinne Baudoin, Isabelle Perthus, Bertrand Isidor, Catherine Blanchet, David Baux, Michel Koenig, Vasiliki Kalatzis and Anne-Françoise Roux

Diagnostics 2022, 12(1), 207; https://doi.org/10.3390/diagnostics12010207 - 15 Jan 2022

Cited by 8 | Viewed by 2122

Abstract

GSDME, also known as DFNA5, is a gene implicated in autosomal dominant nonsyndromic hearing loss (ADNSHL), affecting, at first, the high frequencies with a subsequent progression over all frequencies. To date, all the GSDME pathogenic variants associated with deafness lead to skipping of exon 8. In two families with apparent ADNSHL, massively parallel sequencing (MPS) integrating a coverage-based method for detection of copy number variations (CNVs) was applied, and it identified the first two causal GSDME structural variants affecting exon 8. The deleterious impact of the c.991-60_1095del variant, which includes the acceptor splice site sequence of exon 8, was confirmed by the study of the proband’s transcripts. The second mutational event is a complex rearrangement that deletes almost all of the exon 8 sequence. This study increases the mutational spectrum of the GSDME gene and highlights the crucial importance of MPS data for the detection of GSDME exon 8 deletions, even though the identification of a causal single-exon CNV by MPS analysis is still challenging. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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7 pages, 1874 KiB

Open AccessCase Report

When Familial Hearing Loss Means Genetic Heterogeneity: A Model Case Report

by Camille Cenni, Luke Mansard, Catherine Blanchet, David Baux, Christel Vaché, Corinne Baudoin, Mélodie Moclyn, Valérie Faugère, Michel Mondain, Eric Jeziorski, Anne-Françoise Roux and Marjolaine Willems

Diagnostics 2021, 11(9), 1636; https://doi.org/10.3390/diagnostics11091636 - 7 Sep 2021

Cited by 3 | Viewed by 1948

Abstract

We describe a family with both hearing loss (HL) and thrombocytopenia, caused by pathogenic variants in three genes. The proband was a child with neonatal thrombocytopenia, childhood-onset HL, hyper-laxity and severe myopia. The child’s mother (and some of her relatives) presented with moderate thrombocytopenia and adulthood-onset HL. The child’s father (and some of his relatives) presented with adult-onset HL. An HL panel analysis, completed by whole exome sequencing, was performed in this complex family. We identified three pathogenic variants in three different genes: MYH9, MYO7A and ACTG1. The thrombocytopenia in the child and her mother is explained by the MYH9 variant. The post-lingual HL in the paternal branch is explained by the MYO7A variant, absent in the proband, while the congenital HL of the child is explained by a de novo ACTG1 variant. This family, in which HL segregates, illustrates that multiple genetic conditions coexist in individuals and make patient care more complex than expected. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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6 pages, 9044 KiB

Open AccessCase Report

An Atypical Case of Head Tremor and Extensive White Matter in an Adult Female Caused by 3-Hydroxy-3-methylglutaryl-CoA Lyase Deficiency

by Nassim Boutouchent, Julie Bourilhon, Bénédicte Sudrié-Arnaud, Antoine Bonnevalle, Lucie Guyant-Maréchal, Cécile Acquaviva, Loréna Dujardin-Ippolito, Soumeya Bekri, Ivana Dabaj and Abdellah Tebani

Diagnostics 2021, 11(9), 1561; https://doi.org/10.3390/diagnostics11091561 - 28 Aug 2021

Cited by 3 | Viewed by 2301

Abstract

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) Lyase deficiency (HMGLD) (OMIM 246450) is an autosomal recessive genetic disorder caused by homozygous or compound heterozygous variants in the HMGCL gene located on 1p36.11. Clinically, this disorder is characterized by a life-threatening metabolic intoxication with a presentation including severe hypoglycemia without ketosis, metabolic acidosis, hyper-ammoniemia, hepatomegaly and a coma. HMGLD clinical onset is within the first few months of life after a symptomatic free period. In nonacute periods, the treatment is based on a protein- and fat-restricted diet. L-carnitine supplementation is recommended. A late onset presentation has been described in very few cases, and only two adult cases have been reported. The present work aims to describe an incidental discovery of an HMGLD case in a 54-year-old patient and reports a comprehensive review of clinical and biological features in adult patients to raise awareness about the late-onset presentation of this disease. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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8 pages, 1132 KiB

Open AccessCase Report

Coexistence of Growth Hormone Deficiency and Pituitary Microadenoma in a Child with Unique Mosaic Turner Syndrome: A Case Report and Literature Review

by Eu Gene Park, Eun-Jung Kim, Eun-Jee Kim, Hyun-Young Kim, Sun-Hee Kim and Aram Yang

Diagnostics 2020, 10(10), 783; https://doi.org/10.3390/diagnostics10100783 - 4 Oct 2020

Cited by 4 | Viewed by 3459

Abstract

Turner syndrome (TS) is a genetic disorder with phenotypic heterogeneity caused by the monosomy or structural abnormalities of the X chromosome, and it has a prevalence of about 1/2500 females live birth. The variable clinical features of TS include short stature, gonadal failure, and skeletal dysplasia. The association with growth hormone (GH) deficiency or other hypopituitarism in TS is extremely rare, with only a few case reports published in the literature. Here, we report the first case of a patient with mosaic TS with complete GH deficiency and pituitary microadenoma, and we include the literature review. During the work-up of the patient for severe short stature, three GH provocation tests revealed peak GH levels of less than 5 ng/mL, which was compatible with complete GH deficiency. Sella magnetic resonance imaging showed an 8 mm non-enhancing pituitary adenoma with mild superior displacement of the optic chiasm. Karyotyping revealed the presence of ring chromosome X and monosomy X (46,X,r(X)/45,X/46,X,psu dic r(X;X)), which indicated a mosaic TS. It is important to consider not only chromosome analyses in females with short stature, but also the possibility of the coexistence of complete GH deficiency accompanying pituitary lesions in TS. In conclusion, the present study reports the first case of GH deficiency and pituitary adenoma in a patient with rare mosaic TS, which extends the genotype–phenotype spectrum for TS. Full article

(This article belongs to the Special Issue Genetic Testing for Rare Diseases)

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