Submit to Genes Review for Genes Propose a Special Issue

Journal Menu

Journal Browser

Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

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 (10 November 2023) | Viewed by 24626

Share This Special Issue

Special Issue Editors

Dr. Miles D. Thompson

E-Mail
Guest Editor

1. Department of Pediatrics, University of California, San Diego, CA 92093, USA
2. Neurology Department, Krembil Neuroscience Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
Interests: laboratory medicine; genetics and genomics; molecular biology; developmental disability; pharmacogenomics; animal models; clinical trials; hyperphosphatasia with neurologic deficit (Mabry syndrome; MIM: 239300); genetic counseling

Prof. Dr. Arnold Munnich

E-Mail Website
Guest Editor

Institut national de la santé et de la recherche médicale (Inserm), 76031 Rouen, France
Interests: pediatrics; genetics; disease gene discovery; developmental disability; neurological disorders; metabolic disorders; mitochondrial disorders; malformations; sensory disability; clinical trials

Special Issue Information

Dear Colleagues,

Since the advent of next-generation sequencing (NGS), both whole exome sequencing (WES) and whole genome sequencing (WGS), we have seen rapid progress in gene discovery and diagnostics for developmental disabilities (DDs) as a whole, and rare DDs in particular. As a result, rare diseases have become more amenable to diagnosis and treatment innovation and are, as a result, considerably less ‘orphaned’. For example, bi-allelic mutations in approximately 16 of the 27 genes encoding portions of the glycosylphosphatidylinositol (GPI) biosynthesis pathway result in inherited GPI biosynthesis defects (GPIBDs), that, taken together, make up 0.15% of all DDs.

In this ‘Special Issue’, we present articles outlining innovation in the molecular genetics, biochemistry, and treatment of DDs in general. In addition to contributing to the literature on gene discovery and molecular biology, we hope our efforts will facilitate: 1) awareness of rare or undertreated developmental disabilities; 2) discussion of how improved diagnostics leads to improved treatment options for patients and their families in the context of genetic counseling; and 3) discussion of the use of animal and cell models of DDs in order to better understand disease processes, facilitate drug development, and establish clinical trials.

Dr. Miles D. Thompson
Prof. Dr. Arnold Munnich
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

Developmental disability
Orphan disease
Gene discovery
Next-generation sequencing (NGS)
While exome/genome sequencing
Molecular biology
Animal modeling
Laboratory diagnosis
Pharmacology/drug development
Natural history of disease

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review, Other

14 pages, 1346 KiB

Open AccessArticle

Effects of Remimazolam on Intracellular Calcium Dynamics in Myotubes Derived from Patients with Malignant Hyperthermia and Functional Analysis of Type 1 Ryanodine Receptor Gene Variants

by Hirotsugu Miyoshi, Sachiko Otsuki, Keiko Mukaida, Kenshiro Kido, Ayako Sumii, Tsuyoshi Ikeda, Yuko Noda, Toshimichi Yasuda, Soshi Narasaki, Takahiro Kato, Satoshi Kamiya, Yousuke T. Horikawa and Yasuo M. Tsutsumi

Genes 2023, 14(11), 2009; https://doi.org/10.3390/genes14112009 - 27 Oct 2023

Viewed by 901

Abstract

Remimazolam is a novel general anesthetic and its safety in patients with malignant hyperthermia (MH) is unknown. We used myotubes derived from the skeletal muscle of patients with MH to examine the response to ryanodine receptor 1 (RYR1) agonist and remimazolam in MH-susceptible patients. Patients underwent muscle biopsy for the Ca²⁺-induced Ca²⁺ release (CICR) rate test, a diagnostic tool for MH in Japan. Ten patients had myotubes obtained from skeletal muscle cultures, and the genes associated with malignant hyperthermia in these patients were analyzed. The EC₅₀ of caffeine, cresol, and remimazolam to induce intracellular calcium concentration change were compared between myotubes from CICR-negative genetic test patients and myotubes from other patients. Eight of the ten were CICR-positive, five of whom had RYR1 causative gene mutations or variants. Two patients had CICR-negative genetic tests, and as expected had the highest EC₅₀ (the concentration of a drug that gives a half-maximal response) in response to caffeine, 4CmC and remimazolam. Three patients had a positive CICR but no known variants in RYR1 or CACNA1S (voltage-gated calcium channel subunit alpha1S). Myotubes in these patients had significantly lower EC50s for all agents than myotubes in CICR-negative patients. When myotubes from a patient who was CICR-negative and had no gene variant were used as a control, myotubes from CICR-positive patients were more hyper-responsive than controls to all stimulants used. The EC₅₀ for remimazolam was lowest for myotubes from CICR-positive, RYR1-mutant patients, at 206 µM (corresponding to 123 µg/mL). The concentration was more than 80-times higher than the clinical concentration. RYR1 gene variants in R4645Q and W5020G were shown to be causative gene mutations for MH. Intracellular calcium in myotubes from MH patients are elevated at high concentrations of remimazolam but not at clinically used concentrations of remimazolam. Remimazolam appears to be safe to use in patients with MH. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

11 pages, 1102 KiB

Open AccessArticle

Rare Disease Education Outside of the Classroom and Clinic: Evaluation of the RARE Compassion Program for Undergraduate Medical Students

by Ari Morgenthau, Colton Margus, Michael P. Mackley and Ashley P. Miller

Genes 2022, 13(10), 1707; https://doi.org/10.3390/genes13101707 - 23 Sep 2022

Cited by 1 | Viewed by 2038

Abstract

Launched in 2014, the RARE Compassion Program is the first international educational program to pair medical students with rare disease patients in order to enhance exposure to and comfort with rare diseases. As part of ongoing quality improvement, this study retrospectively reviewed four years of participant registration data to conduct a program evaluation of the RARE Compassion Program between 2014–2018. During the study period, there were 334 student participants, representing 67.3% of Association of American Medical Colleges (AAMC) member medical schools, and 5389 rare disease volunteers. Despite not requiring in-person interaction, 90.64% of student–volunteer interactions were in-person, while only 5.89% and 3.46% were by video messaging or email correspondence, respectively (p = 0.0002). In a limited post participation survey, 91.7% of students, who matched to 19 out of 27 residency specialities, indicated they would recommend the program to their peers. These findings suggest that the RARE Compassion Program, designed to increase medical student engagement with rare disease patients, has broad appeal. It serves as a novel case study of how extracurricular initiatives supported by non-profit organizations can augment the medical training experience and improve understanding of important and often neglected perspectives. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

17 pages, 777 KiB

Open AccessArticle

The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge

by Luciana Musante, Paola Costa, Caterina Zanus, Flavio Faletra, Flora M. Murru, Anna M. Bianco, Martina La Bianca, Giulia Ragusa, Emmanouil Athanasakis, Adamo P. d’Adamo, Marco Carrozzi and Paolo Gasparini

Genes 2022, 13(3), 500; https://doi.org/10.3390/genes13030500 - 12 Mar 2022

Cited by 7 | Viewed by 2380

Abstract

Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

8 pages, 253 KiB

Open AccessArticle

Study of the Interaction between Executive Function and Adaptive Behavior at School in Girls with Fragile X Syndrome

by Lorena Joga-Elvira, Jennifer Martinez-Olmo, María-Luisa Joga, Carlos Jacas, Ana Roche-Martínez and Carme Brun-Gasca

Genes 2021, 12(8), 1108; https://doi.org/10.3390/genes12081108 - 21 Jul 2021

Viewed by 1573

Abstract

The aim of this research is to analyze the relationship between executive functions and adaptive behavior in girls with Fragile X syndrome (FXS) in the school setting. This study is part of a larger investigation conducted at the Hospital Parc Tauli in Sabadell. The sample consists of a total of 40 girls (26 with FXS and 14 control) aged 7–16 years, who were administered different neuropsychological tests (WISC-V, NEPSY-II, WCST, TOL) and questionnaires answered by teachers (ABAS-II, BRIEF 2, ADHD Rating Scale). The results show that there is a greater interaction between some areas of executive function (cognitive flexibility, auditory attention, and visual abstraction capacity) and certain areas of adaptive behavior (conceptual, practical, social, and total domains) in the FXS group than in the control group. These results suggest that an alteration in the executive functions was affecting the daily functioning of the girls with FXS to a greater extent. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

Review

Jump to: Research, Other

21 pages, 1897 KiB

Open AccessReview

FMR1 and Autism, an Intriguing Connection Revisited

by William Fyke and Milen Velinov

Genes 2021, 12(8), 1218; https://doi.org/10.3390/genes12081218 - 06 Aug 2021

Cited by 13 | Viewed by 6296

Abstract

Autism Spectrum Disorder (ASD) represents a distinct phenotype of behavioral dysfunction that includes deficiencies in communication and stereotypic behaviors. ASD affects about 2% of the US population. It is a highly heritable spectrum of conditions with substantial genetic heterogeneity. To date, mutations in over 100 genes have been reported in association with ASD phenotypes. Fragile X syndrome (FXS) is the most common single-gene disorder associated with ASD. The gene associated with FXS, FMR1 is located on chromosome X. Accordingly, the condition has more severe manifestations in males. FXS results from the loss of function of FMR1 due to the expansion of an unstable CGG repeat located in the 5′′ untranslated region of the gene. About 50% of the FXS males and 20% of the FXS females meet the Diagnostic Statistical Manual 5 (DSM-5) criteria for ASD. Among the individuals with ASD, about 3% test positive for FXS. FMRP, the protein product of FMR1, is a major gene regulator in the central nervous system. Multiple pathways regulated by FMRP are found to be dysfunctional in ASD patients who do not have FXS. Thus, FXS presents the opportunity to study cellular phenomena that may have wider applications in the management of ASD and to develop new strategies for ASD therapy. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

Other

Jump to: Research, Review

10 pages, 2639 KiB

Open AccessCase Report

Novel Homozygous FA2H Variant Causing the Full Spectrum of Fatty Acid Hydroxylase-Associated Neurodegeneration (SPG35)

by Alexander German, Jelena Jukic, Andreas Laner, Philipp Arnold, Eileen Socher, Angelika Mennecke, Manuel A. Schmidt, Jürgen Winkler, Angela Abicht and Martin Regensburger

Genes 2024, 15(1), 14; https://doi.org/10.3390/genes15010014 - 20 Dec 2023

Viewed by 943

Abstract

Fatty acid hydroxylase-associated neurodegeneration (FAHN/SPG35) is caused by pathogenic variants in FA2H and has been linked to a continuum of specific motor and non-motor neurological symptoms, leading to progressive disability. As an ultra-rare disease, its mutational spectrum has not been fully elucidated. Here, we present the prototypical workup of a novel FA2H variant, including clinical and in silico validation. An 18-year-old male patient presented with a history of childhood-onset progressive cognitive impairment, as well as progressive gait disturbance and lower extremity muscle cramps from the age of 15. Additional symptoms included exotropia, dystonia, and limb ataxia. Trio exome sequencing revealed a novel homozygous c.75C>G (p.Cys25Trp) missense variant in the FA2H gene, which was located in the cytochrome b5 heme-binding domain. Evolutionary conservation, prediction models, and structural protein modeling indicated a pathogenic loss of function. Brain imaging showed characteristic features, thus fulfilling the complete multisystem neurodegenerative phenotype of FAHN/SPG35. In summary, we here present a novel FA2H variant and provide prototypical clinical findings and structural analyses underpinning its pathogenicity. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

10 pages, 2178 KiB

Open AccessCase Report

A Rare Case of Concurrent 2q34q36 Duplication and 2q37 Deletion in a Neonate with Syndromic Features

by Francesco Nicola Riviello, Alessia Daponte, Emanuela Ponzi, Romina Ficarella, Paola Orsini, Roberta Bucci, Mario Ventura, Francesca Antonacci, Claudia Rita Catacchio and Mattia Gentile

Genes 2023, 14(12), 2194; https://doi.org/10.3390/genes14122194 - 10 Dec 2023

Viewed by 830

Abstract

Large-scale genomic structural variations can have significant clinical implications, depending on the specific altered genomic region. Briefly, 2q37 microdeletion syndrome is a prevalent subtelomeric deletion disorder characterized by variable-sized deletions. Affected patients exhibit a wide range of clinical manifestations, including short stature, facial dysmorphism, and features of autism spectrum disorder, among others. Conversely, isolated duplications of proximal chromosome 2q are rare and lack a distinct phenotype. In this report, we provide an extensive molecular analysis of a 15-day-old newborn referred for syndromic features. Our analysis reveals an 8.5 Mb microdeletion at 2q37.1, which extends to the telomere, in conjunction with an 8.6 Mb interstitial microduplication at 2q34q36.1. Our findings underscore the prominence of 2q37 terminal deletions as commonly reported genomic anomalies. We compare our patient’s phenotype with previously reported cases in the literature to contribute to a more refined classification of 2q37 microdeletion syndrome and assess the potential impact of 2q34q36.1 microduplication. We also investigate multiple hypotheses to clarify the genetic mechanisms responsible for the observed genomic rearrangement. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

9 pages, 1592 KiB

Open AccessCase Report

Excluding Digenic Inheritance of PGAP2 and PGAP3 Variants in Mabry Syndrome (OMIM 239300) Patient: Phenotypic Spectrum Associated with PGAP2 Gene Variants in Hyperphosphatasia with Mental Retardation Syndrome-3 (HPMRS3)

by Miles D. Thompson, Xueying Li, Michele Spencer-Manzon, Danielle M. Andrade, Yoshiko Murakami, Taroh Kinoshita and Thomas O. Carpenter

Genes 2023, 14(2), 359; https://doi.org/10.3390/genes14020359 - 30 Jan 2023

Cited by 2 | Viewed by 1381

Abstract

We present a case report of a child with features of hyperphosphatasia with neurologic deficit (HPMRS) or Mabry syndrome (MIM 239300) with variants of unknown significance in two post-GPI attachments to proteins genes, PGAP2 and PGAP3, that underlie HPMRS 3 and 4. Background: In addition to HPMRS 3 and 4, disruption of four phosphatidylinositol glycan (PIG) biosynthesis genes, PIGV, PIGO, PIGW and PIGY, result in HPMRS 1, 2, 5 and 6, respectively. Methods: Targeted exome panel sequencing identified homozygous variants of unknown significance (VUS) in PGAP2 c:284A>G and PGAP3 c:259G>A. To assay the pathogenicity of these variants, we conducted a rescue assay in PGAP2 and PGAP3 deficient CHO cell lines. Results: Using a strong (pME) promoter, the PGAP2 variant did not rescue activity in CHO cells and the protein was not detected. Flow cytometric analysis showed that CD59 and CD55 expression on the PGAP2 deficient cell line was not restored by variant PGAP2. By contrast, activity of the PGAP3 variant was similar to wild-type. Conclusions: For this patient with Mabry syndrome, the phenotype is likely to be predominantly HPMRS3: resulting from autosomal recessive inheritance of NM_001256240.2 PGAP2 c:284A>G, p.Tyr95Cys. We discuss strategies for establishing evidence for putative digenic inheritance in GPI deficiency disorders. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Graphical abstract

10 pages, 4097 KiB

Open AccessCase Report

Cytogenetic and Array-CGH Characterization of a Simple Case of Reciprocal t(3;10) Translocation Reveals a Hidden Deletion at 5q12

by Angelo Cellamare, Nicoletta Coccaro, Maria Cristina Nuzzi, Paola Casieri, Marilina Tampoia, Flavia Angela Maria Maggiolini, Mattia Gentile, Romina Ficarella, Emanuela Ponzi, Maria Rosa Conserva, Laura Cardarelli, Annunziata Panarese, Francesca Antonacci and Antonia Gesario

Genes 2021, 12(6), 877; https://doi.org/10.3390/genes12060877 - 07 Jun 2021

Viewed by 2318

Abstract

Chromosome deletions, including band 5q12, have rarely been reported and have been associated with a wide range of clinical manifestations, such as postnatal growth retardation, intellectual disability, hyperactivity, nonspecific ocular defects, facial dysmorphism, and epilepsy. In this study, we describe for the first time a child with growth retardation in which we identified a balanced t(3;10) translocation by conventional cytogenetic analysis in addition to an 8.6 Mb 5q12 deletion through array-CGH. Our results show that the phenotypic abnormalities of a case that had been interpreted as “balanced” by conventional cytogenetics are mainly due to a cryptic deletion, highlighting the need for molecular investigation in subjects with an abnormal phenotype before assuming the cause is an apparently simple cytogenetic rearrangement. Finally, we identify PDE4D and PIK3R1 genes as the two major candidates responsible for the clinical features expressed in our patient. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Figure 1

10 pages, 1543 KiB

Open AccessCase Report

Two Cases of Recessive Intellectual Disability Caused by NDST1 and METTL23 Variants

by Amjad Khan, Zhichao Miao, Muhammad Umair, Amir Ullah, Mohammad A. Alshabeeb, Muhammad Bilal, Farooq Ahmad, Gudrun A. Rappold, Muhammad Ansar and Raphael Carapito

Genes 2020, 11(9), 1021; https://doi.org/10.3390/genes11091021 - 31 Aug 2020

Cited by 9 | Viewed by 4215

Abstract

Intellectual disability (ID) is a highly heterogeneous genetic condition with more than a thousand genes described so far. By exome sequencing of two consanguineous families presenting hallmark features of ID, we identified two homozygous variants in two genes previously associated with autosomal recessive ID: NDST1 (c.1966G>A; p.Asp656Asn) and METTL23 (c.310T>C; p.Phe104Leu). The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the secondary structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic NDST1 and METTL23 variants in two cases of autosomal recessive ID further highlight the importance of these genes in proper brain function and development. Full article

(This article belongs to the Special Issue Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling)

► Show Figures

Journal Menu

Journal Browser

Human Developmental Disability, Neurogenetics and Rare Diseases: From Basic Science to Genetic Counseling

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (10 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI