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Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing...
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Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing Approach

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 (25 November 2022) | Viewed by 10568

Special Issue Editors

Dr. Manuela Priolo

E-Mail Website
Guest Editor
SSD Genetica Medica, Grande Ospedale Metropolitano “Bianchi- Melacrino- Morelli”, 89128 Reggio Calabria, Italy
Interests: dysmorphology/syndromology; overgrowth syndromes; genetics; genotype-phenotype correlation; whole genome sequencing; mutation; genetic counselling; recurrence risk; rare disease; oncogenetics; familial cancer genetics; personalised medicine; target therapy
Dr. Marco Tartaglia

E-Mail Website
Guest Editor
Genetics and Rare Diseases Research Division, Bambino Gesù, Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy
Interests: noonan syndrome; RASopathies; rare diseases; genomics; functional genomics; disease gene discovery

Special Issue Information

Dear Colleagues,

We would like to invite you to participate in this Special Issue, “Multiple molecular diagnoses in Rare Diseases through massive parallel sequencing approach”.

More than 6000 rare diseases have been described so far. On the whole,  80% of rare diseases are of genetic origin and are often chronic and life-threatening. Among genetic rare diseases, almost 70% start in childhood. Rare diseases are characterised by a wide diversity of symptoms and signs not only among different conditions but also between patients suffering from the same disease. Due to the low prevalence of each disorder, medical expertise is rare, knowledge is scarce, care opportunities are inadequate, and research is limited. Whole exome sequencing (trio-WES) analysis has substantially improved the chance of obtaining a genetic diagnosis in rare and ultra-rare diseases. Moreover, in approximately 5% of cases, WES allows the dissection of complex phenotypes as the result of concomitant pathogenic variants involving two or multiple genes (dual molecular diagnoses) as proven by the massive use of WES in selected cohorts of “partially solved” patients (i.e., presentations that only in part are explained by one single identified genetic variant), which has provided evidence that at least one third of cases reported as ‘phenotypic expansion’ actually represent blended phenotypes due to concomitant co-occurring pathogenic variants (multilocus pathogenetic variants).

The purpose of this Special Issue is to host particularly interesting complex case reports solved by WES with final multiple molecular diagnoses, as well as research and review papers on rare diseases and complex phenotypes in order to assess the real effectiveness of WES in solving complex diagnoses and to eventually stress pitfalls in this approach solved by alternative strategies (WGS, mDNA signature). Great attention will be given to accurate genotype–phenotype correlation in multiple molecular diagnoses in solving complex phenotypes.

Dr. Manuela Priolo
Dr. Marco Tartaglia
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

  • dual molecular diagnosis
  • whole exome sequencing
  • distinct vs. overlapping phenotypes
  • orphan diseases
  • complex phenotypes
  • whole genome sequencing
  • blended phenotypes
  • multilocus pathogenetic variants

Published Papers (5 papers)

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15 pages, 1844 KiB  
Article
Challenging Occam’s Razor: Dual Molecular Diagnoses Explain Entangled Clinical Pictures
by Beatrice Spedicati, Anna Morgan, Giulia Pianigiani, Luciana Musante, Elisa Rubinato, Aurora Santin, Giuseppe Giovanni Nardone, Flavio Faletra and Giorgia Girotto
Genes 2022, 13(11), 2023; https://doi.org/10.3390/genes13112023 - 3 Nov 2022
Viewed by 1435
Abstract
Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report the identification of double genetic disorders in a series of patients with complex clinical [...] Read more.
Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report the identification of double genetic disorders in a series of patients with complex clinical features. In the last 24 months, 342 syndromic patients have been recruited and clinically characterised. Whole Exome Sequencing analysis has been performed on the proband and on both parents and identified seven patients affected by a dual molecular diagnosis. Upon a detailed evaluation of both their clinical and molecular features, subjects are able to be divided into two groups: (A) five patients who present distinct phenotypes, due to each of the two different underlying genetic diseases; (B) two patients with overlapping clinical features that may be underpinned by both the identified genetic variations. Notably, only in one case a multilocus genomic variation was already suspected during the clinical evaluation. Overall, our findings highlight how dual molecular diagnoses represent a challenging model of complex inheritance that should always be considered whenever a patient shows atypical clinical features. Indeed, an accurate genetic characterisation is of the utmost importance to provide patients with a personalised and safe clinical management. Full article
(This article belongs to the Special Issue Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing Approach)
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12 pages, 671 KiB  
Article
Phenotypic Variation in Two Siblings Affected with Shwachman-Diamond Syndrome: The Use of Expert Variant Interpreter (eVai) Suggests Clinical Relevance of a Variant in the KMT2A Gene
by Ibrahim Taha, Federica De Paoli, Selena Foroni, Susanna Zucca, Ivan Limongelli, Marco Cipolli, Cesare Danesino, Ugo Ramenghi and Antonella Minelli
Genes 2022, 13(8), 1314; https://doi.org/10.3390/genes13081314 - 23 Jul 2022
Cited by 2 | Viewed by 2477
Abstract
Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in [...] Read more.
Introduction. Shwachman-Diamond Syndrome (SDS) is an autosomal-recessive disorder characterized by neutropenia, pancreatic exocrine insufficiency, skeletal dysplasia, and an increased risk for leukemic transformation. Biallelic mutations in the SBDS gene have been found in about 90% of patients. The clinical spectrum of SDS in patients is wide, and variability has been noticed between different patients, siblings, and even within the same patient over time. Herein, we present two SDS siblings (UPN42 and UPN43) carrying the same SBDS mutations and showing relevant differences in their phenotypic presentation. Study aim. We attempted to understand whether other germline variants, in addition to SBDS, could explain some of the clinical variability noticed between the siblings. Methods. Whole-exome sequencing (WES) was performed. Human Phenotype Ontology (HPO) terms were defined for each patient, and the WES data were analyzed using the eVai and DIVAs platforms. Results. In UPN43, we found and confirmed, using Sanger sequencing, a novel de novo variant (c.10663G > A, p.Gly3555Ser) in the KMT2A gene that is associated with autosomal-dominant Wiedemann–Steiner Syndrome. The variant is classified as pathogenic according to different in silico prediction tools. Interestingly, it was found to be related to some of the HPO terms that describe UPN43. Conclusions. We postulate that the KMT2A variant found in UPN43 has a concomitant and co-occurring clinical effect, in addition to SBDS mutation. This dual molecular effect, supported by in silico prediction, could help to understand some of the clinical variations found among the siblings. In the future, these new data are likely to be useful for personalized medicine and therapy for selected cases. Full article
(This article belongs to the Special Issue Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing Approach)
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11 pages, 251 KiB  
Article
Atypical, Composite, or Blended Phenotypes: How Different Molecular Mechanisms Could Associate in Double-Diagnosed Patients
by Erica Rosina, Lidia Pezzani, Laura Pezzoli, Daniela Marchetti, Matteo Bellini, Alba Pilotta, Olga Calabrese, Emanuele Nicastro, Francesco Cirillo, Anna Cereda, Agnese Scatigno, Donatella Milani and Maria Iascone
Genes 2022, 13(7), 1275; https://doi.org/10.3390/genes13071275 - 19 Jul 2022
Cited by 10 | Viewed by 1451
Abstract
In the last few years, trio-Whole Exome Sequencing (WES) analysis has revolutionized the diagnostic process for patients with rare genetic syndromes, demonstrating its potential even in non-specific clinical pictures and in atypical presentations of known diseases. Multiple disorders in a single patient have [...] Read more.
In the last few years, trio-Whole Exome Sequencing (WES) analysis has revolutionized the diagnostic process for patients with rare genetic syndromes, demonstrating its potential even in non-specific clinical pictures and in atypical presentations of known diseases. Multiple disorders in a single patient have been estimated to occur in approximately 2–7.5% of diagnosed cases, with higher frequency in consanguineous families. Here, we report the clinical and molecular characterisation of eight illustrative patients for whom trio-WES allowed for identifing more than one genetic condition. Double homozygosity represented the causal mechanism in only half of them, whereas the other half showed peculiar multilocus combinations. The paper takes into consideration difficulties and learned lessons from our experience and therefore supports the powerful role of wide analyses for ascertaining multiple genetic diseases in complex patients, especially when a clinical suspicion could account for the majority of clinical signs. It finally makes clear how a patient’s “deep phenotyping” might not be sufficient to suggest the presence of multiple genetic diagnoses but remains essential to validate an unexpected multilocus result from genetic tests. Full article
(This article belongs to the Special Issue Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing Approach)
10 pages, 700 KiB  
Article
Complex Presentation of Hao-Fountain Syndrome Solved by Exome Sequencing Highlighting Co-Occurring Genomic Variants
by Manuela Priolo, Cecilia Mancini, Simone Pizzi, Luigi Chiriatti, Francesca Clementina Radio, Viviana Cordeddu, Letizia Pintomalli, Corrado Mammì, Bruno Dallapiccola and Marco Tartaglia
Genes 2022, 13(5), 889; https://doi.org/10.3390/genes13050889 - 16 May 2022
Cited by 6 | Viewed by 2721
Abstract
Objective: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation. Patients and Methods: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, [...] Read more.
Objective: The co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation. Patients and Methods: A 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition. Results: Four co-occurring genomic events fully explaining the proband’s clinical features were identified. A de novo truncating USP7 variant was disclosed as the cause of Hao–Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in CFTR explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating PKD2 variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis. Conclusions: The co-occurring variants in USP7 and CFTR variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the CFTR-related disorder symptoms and monitor renal function and other complications associated with PKD2 haploinsufficiency, addressing proper care and surveillance. Full article
(This article belongs to the Special Issue Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing Approach)
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11 pages, 1084 KiB  
Case Report
Dual Molecular Diagnoses of Recessive Disorders in a Child from Consanguineous Parents: Case Report and Literature Review
by Gabriela Roldão Correia-Costa, Ana Mondadori dos Santos, Nicole de Leeuw, Sumara Zuanazi Pinto Rigatto, Vera Maria Santoro Belangero, Carlos Eduardo Steiner, Vera Lúcia Gil-da-Silva-Lopes and Társis Paiva Vieira
Genes 2022, 13(12), 2377; https://doi.org/10.3390/genes13122377 - 16 Dec 2022
Cited by 3 | Viewed by 1619
Abstract
The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a [...] Read more.
The widespread use of whole exome sequencing (WES) resulted in the discovery of multilocus pathogenic variations (MPV), defined as two or more distinct or overlapping Mendelian disorders occurring in a patient, leading to a blended phenotype. In this study, we report on a child with autosomal recessive primary microcephaly-5 (MCPH5) and nephropathic cystinosis. The proband is the first child of consanguineous parents, presenting a complex phenotype including neurodevelopmental delay, microcephaly, growth restriction, significant delay of bone maturation, lissencephaly, and abnormality of neuronal migration, photophobia, and renal tubular acidosis. WES revealed two pathogenic and homozygous variants: a c.4174C>T variant in the ASPM gene and a c.382C>T variant in the CTNS gene, explaining the complex phenotype. The literature review showed that most of the patients harboring two variants in recessive disease genes are born to consanguineous parents. To the best of our knowledge, the patient herein described is the first one harboring pathogenic variants in both the ASPM and CTNS genes. These findings highlight the importance of searching for MPV in patients with complex phenotypes investigated by genome-wide testing methods, especially for those patients born to consanguineous parents. Full article
(This article belongs to the Special Issue Multiple Molecular Diagnoses in Rare Disease through Massive Parallel Sequencing Approach)
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