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Application of Next-Generation Sequencing in Genetic Diseases Diagnosis
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Application of Next-Generation Sequencing in Genetic Diseases Diagnosis

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 April 2025) | Viewed by 9055

Special Issue Editor

Dr. Laia Pedrola

E-Mail Website
Guest Editor
Genetics Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
Interests: genomics; next generation sequencing; genetic diagnosis; inherited diseases

Special Issue Information

Dear Colleagues,

High-throughput sequencing has represented a significant revolution in the field of genetic medicine and the diagnosis of inherited diseases. Currently, we can find highly efficient technical solutions but with great challenges in the clinical interpretation of genetic results, especially since the implementation of whole exome and genome sequencing into routine clinical practice. This great challenge is accompanied by the difficulty of incidental findings interpretation and counseling and also the use of complex samples such as circulating tumor DNA, maternal plasma, and cell-free DNA fetal samples.

This Special Issue on Application of Next-Generation Sequencing in Genetic Diseases Diagnosis will provide novel insights and an updated overview of these technology applications and how they can interfere in the pathophysiology, diagnosis, and treatment of inherited disorders. Given the complexity and broadness of these topics, contributions from experts in the field through research papers and reviews are welcome.

Dr. Laia Pedrola
Guest Editor

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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

  • genomics
  • next-generation sequencing
  • genetic diagnosis
  • inherited diseases
  • diagnosis

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Published Papers (6 papers)

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Research

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11 pages, 1365 KiB  
Article
Intrafamilial Phenotypic Variability of the FGFR1 p.Cys277Tyr Variant: A Case Report and Review of the Literature
by Anna Szoszkiewicz, Anna Sowińska-Seidler, Karolina Gruca-Stryjak and Aleksander Jamsheer
Genes 2025, 16(5), 495; https://doi.org/10.3390/genes16050495 - 26 Apr 2025
Viewed by 289
Abstract
Background: Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known [...] Read more.
Background: Split-hand/foot malformation (SHFM) is a rare congenital limb anomaly defined by the absence or hypoplasia of the central rays of the autopod. SHFM occurs as an isolated entity or part of genetic syndromes with several causative copy-number variations or monogenic alterations known to be involved in the disease pathomechanism. On the other hand, cleft lip/palate (CL/P) usually results from polygenic and environmental factors, with the complex interplay of both leading to this malformation. Pathogenic variants in FGFR1 have been linked to phenotypically distinct disorders, including Hartsfield syndrome, Kallmann syndrome, Jackson–Weiss syndrome, osteoglophonic dysplasia, and Pfeiffer syndrome. Although pathogenic variants in FGFR1 can contribute to syndromic SHFM or CL/P, their role in isolated SHFM or CL remains poorly described in the literature. Methods: We conducted targeted next-generation sequencing (NGS) in the proband with SHFM, followed by segregation analysis in the family members. Results: In this study, we report an index patient presenting with isolated SHFM and his brother with CL and facial dysmorphism, as well as their father with isolated hyposmia. Targeted next-generation sequencing revealed a previously reported heterozygous missense pathogenic variant in FGFR1 (c.830G>A; p.Cys277Tyr) in both affected siblings and their hyposmic father. Conclusions: This study expands the phenotypic spectrum associated with FGFR1 pathogenic variants, emphasizing their involvement in non-syndromic SHFM and CL or isolated hyposmia. Our findings highlight the importance of considering FGFR1 in the molecular diagnosis of isolated SHFM or orofacial clefting, point to the high intrafamilial variability of FGFR1 pathogenic variants, and demonstrate the diagnostic value of targeted NGS in rare congenital malformations. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Genetic Diseases Diagnosis)
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14 pages, 1809 KiB  
Article
Metachromatic Leukodystrophy in Morocco: Identification of Causative Variants by Next-Generation Sequencing (NGS)
by Miloud Hammoud, María Domínguez-Ruiz, Imane Assiri, Daniel Rodrigues, Nisrine Aboussair, Val F. Lanza, Jesús Villarrubia, Cristóbal Colón, Naima Fdil and Francisco J. del Castillo
Genes 2024, 15(12), 1515; https://doi.org/10.3390/genes15121515 - 26 Nov 2024
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Abstract
(1) Background: Most rare disease patients endure long delays in obtaining a correct diagnosis, the so-called “diagnostic odyssey”, due to a combination of the rarity of their disorder and the lack of awareness of rare diseases among both primary care professionals and specialists. [...] Read more.
(1) Background: Most rare disease patients endure long delays in obtaining a correct diagnosis, the so-called “diagnostic odyssey”, due to a combination of the rarity of their disorder and the lack of awareness of rare diseases among both primary care professionals and specialists. Next-generation sequencing (NGS) techniques that target genes underlying diverse phenotypic traits or groups of diseases are helping reduce these delays; (2) Methods: We used a combination of biochemical (thin-layer chromatography and high-performance liquid chromatography-tandem mass spectrometry), NGS (resequencing gene panels) and splicing assays to achieve a complete diagnosis of three patients with suspected metachromatic leukodystrophy, a neurologic lysosomal disorder; (3) Results: Affected individuals in each family were homozygotes for harmful variants in the ARSA gene, one of them novel (c.854+1dup, in family 1) and the other already described (c.640G>A, p.(Ala214Thr), in family 2). In addition, both affected individuals in family 2 were carriers of a known pathogenic variant in an additionallysosomal disease gene, GNPTAB (for mucolipidosis III). This additional variant may modify the clinical presentation by increasing lysosomal dysfunction. (4) Conclusions: We demonstrated the deleterious effect of the novel variant c.854+1dup on the splicing of ARSA transcripts. We also confirmed the involvement of variant c.640G>A in metachromatic leukodystrophy. Our results show the power of diagnostic approaches that combine deep phenotyping, NGS, and biochemical and functional techniques. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Genetic Diseases Diagnosis)
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11 pages, 240 KiB  
Article
Noonan Syndrome: Relation of Genotype to Cardiovascular Phenotype—A Multi-Center Retrospective Study
by Nikola Ilic, Stasa Krasic, Nina Maric, Vladimir Gasic, Jovana Krstic, Dimitrije Cvetkovic, Vesna Miljkovic, Boris Zec, Ales Maver, Vladislav Vukomanovic and Adrijan Sarajlija
Genes 2024, 15(11), 1463; https://doi.org/10.3390/genes15111463 - 13 Nov 2024
Cited by 1 | Viewed by 1937
Abstract
Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of [...] Read more.
Background: Noonan syndrome (NS) is a congenital genetic disorder with a prevalence of 1 in 1000 to 2500 live births, and is characterized by distinctive facial features, short stature, chest deformities, and congenital heart disease. This study aims to evaluate the prevalence of specific genetic mutations and their impact on cardiovascular and other outcomes in NS. Methods: We conducted a retrospective clinical study of 25 pediatric patients diagnosed with NS at two institutions: The Mother and Child Health Care Institute of Serbia and the Clinic for Children Diseases, University Clinical Center of the Republic of Srpska. Patients underwent whole-exome sequencing (WES) to identify genetic mutations. Clinical data, including cardiovascular manifestations, psychomotor development, and stature, were analyzed in relation to mutation types. Results: The cohort comprised 60% male and 40% female patients, with a median age at diagnosis of 7.2 years. Cardiovascular abnormalities were present in 88% of patients. Mutations in PTPN11 were most commonly associated with pulmonary valve stenosis (PVS), while RAF1 mutations were prevalent in patients with hypertrophic cardiomyopathy (HCM). No significant association was found between cardiac disease and delayed psychomotor development (p = 0.755), even though the likelihood ratio showed significance in that regard (p = 0.018). Short stature was observed in 48% of patients but was not significantly correlated with genetic type of disease, presence of cardiac disease, or developmental delay. Conclusions: The study confirms the high prevalence of cardiovascular manifestations in NS and highlights genotype–phenotype correlations. While cardiac abnormalities are common, their impact on psychomotor development and stature is less clear. Further research is needed to explore genetic interactions influencing these outcomes and refine clinical management strategies. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Genetic Diseases Diagnosis)
9 pages, 1196 KiB  
Article
Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 Caused by a Novel PIGA Variant Not Associated with a Skewed X-Inactivation Pattern
by Alba Gabaldon-Albero, Lourdes Cordon, Amparo Sempere, Laia Pedrola, Carla Martin-Grau, Silvestre Oltra, Sandra Monfort, Alfonso Caro-Llopis, Marta Dominguez-Martinez, Sara Hernandez-Muela, Monica Rosello, Carmen Orellana and Francisco Martinez
Genes 2024, 15(6), 802; https://doi.org/10.3390/genes15060802 - 18 Jun 2024
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Abstract
Germline variants in the phosphatidylinositol glycan class A (PIGA) gene, which is involved in glycosylphosphatidylinositol (GPI) biosynthesis, cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) with X-linked recessive inheritance. The available literature has described a pattern of almost 100% X-chromosome inactivation in [...] Read more.
Germline variants in the phosphatidylinositol glycan class A (PIGA) gene, which is involved in glycosylphosphatidylinositol (GPI) biosynthesis, cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) with X-linked recessive inheritance. The available literature has described a pattern of almost 100% X-chromosome inactivation in mothers carrying PIGA variants. Here, we report a male infant with MCAHS2 caused by a novel PIGA variant inherited from his mother, who has a non-skewed pattern of X inactivation. Phenotypic evidence supporting the pathogenicity of the variant was obtained by flow-cytometry tests. We propose that the assessment in neutrophils of the expression of GPI-anchored proteins (GPI-APs), especially CD16, should be considered in cases with variants of unknown significance with random X-inactivation in carrier mothers in order to clarify the pathogenic role of PIGA or other gene variants linked to the synthesis of GPI-APs. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Genetic Diseases Diagnosis)
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13 pages, 241 KiB  
Article
Reverse Phenotyping after Whole-Exome Sequencing in Children with Developmental Delay/Intellectual Disability—An Exception or a Necessity?
by Nikola Ilic, Nina Maric, Ales Maver, Lluis Armengol, Ruzica Kravljanac, Jana Cirkovic, Jovana Krstic, Danijela Radivojevic, Sanja Cirkovic, Slavica Ostojic, Stasa Krasic, Aleksandra Paripovic, Vladislav Vukomanovic, Borut Peterlin, Gorica Maric and Adrijan Sarajlija
Genes 2024, 15(6), 789; https://doi.org/10.3390/genes15060789 - 15 Jun 2024
Viewed by 1837
Abstract
This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis [...] Read more.
This study delves into the diagnostic yield of whole-exome sequencing (WES) in pediatric patients presenting with developmental delay/intellectual disability (DD/ID), while also exploring the utility of Reverse Phenotyping (RP) in refining diagnoses. A cohort of 100 pediatric patients underwent WES, yielding a diagnosis in 66% of cases. Notably, RP played a significant role in cases with negative prior genetic testing, underscoring its significance in complex diagnostic scenarios. The study revealed a spectrum of genetic conditions contributing to DD/ID, illustrating the heterogeneity of etiological factors. Despite challenges, WES demonstrated effectiveness, particularly in cases with metabolic abnormalities. Reverse phenotyping was indicated in half of the patients with positive WES findings. Neural network models exhibited moderate-to-exceptional predictive abilities for aiding in patient selection for WES and RP. These findings emphasize the importance of employing comprehensive genetic approaches and RP in unraveling the genetic underpinnings of DD/ID, thereby facilitating personalized management and genetic counseling for affected individuals and families. This research contributes insights into the genetic landscape of DD/ID, enhancing our understanding and guiding clinical practice in this particular field of clinical genetics. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Genetic Diseases Diagnosis)

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7 pages, 731 KiB  
Brief Report
Novel Variant in ANO5 Muscular Dystrophy: Identification by Whole Genome Sequencing and Quad Analysis
by Mario Ćuk, Busra Unal, Luka Lovrenčić, McKenzie Walker, Connor P. Hayes, Feruza Abraamyan, Maja Prutki, Goran Krakar, Lidija Srkoč-Majčica and Arezou A. Ghazani
Genes 2024, 15(10), 1300; https://doi.org/10.3390/genes15101300 - 6 Oct 2024
Viewed by 1831
Abstract
Background: The phenotypic spectrum of ANO5 muscle disease ranges widely from elevated creatine kinase (CK) levels in the serum of asymptomatic individuals to progressive muscular dystrophy. Due to overlapping clinical features among muscular dystrophies, the diagnosis of ANO5 muscle disease is established by [...] Read more.
Background: The phenotypic spectrum of ANO5 muscle disease ranges widely from elevated creatine kinase (CK) levels in the serum of asymptomatic individuals to progressive muscular dystrophy. Due to overlapping clinical features among muscular dystrophies, the diagnosis of ANO5 muscle disease is established by molecular genetic tests. Early diagnosis is crucial for the clinical management of symptoms and to mitigate cardiac and musculoskeletal complications. Methods: Quad-joint analysis was performed on whole genome sequencing (WGS) data obtained from an 18-year-old female with mild myalgia and elevated CK and her unaffected parents and sister. The phenotype-driven analysis was performed to prioritize genomic alterations related to the phenotype. The zygosity-based analysis investigated compound heterozygous and de novo status for all variants. Results: The quad-joint WGS analysis revealed a novel pathogenic heterozygous variant, ANO5:c.1770_1773del (p.Phe593Metfs*15), that was paternally inherited. A second and known pathogenic heterozygous variant, ANO5:c.148C>T (p.Arg50*), was also present that was maternally inherited. The genome finding led to the diagnosis of autosomal recessive ANO5 muscle disease and an early personalized clinical management for the patient regarding her cardiac and musculoskeletal health. Conclusions: This is the first report of the ANO5:c.1770_1773del variant in the literature. This report highlights the spectrum of ANO5 muscle disease and describes the role of quad-joint WGS in the early diagnosis and preventive clinical management of ANO5 muscle disease. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Genetic Diseases Diagnosis)
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