Phenotypic Variability of Genetic Diseases in Children

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 25 August 2025 | Viewed by 1030

Special Issue Editor


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Guest Editor
1. The Institute for Rare Diseases, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel-Aviv, Israel
2. Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel
Interests: neurodevelopmental disorders; craniofacial anomalies; genetic disorders; rare diseases; pediatrics

Special Issue Information

Dear Colleagues,

The past few decades has seen significant advancements in Next-Generation Sequencing (NGS) technology. The growing accessibility of whole-exome and -genome sequencing (WES and WGS, respectively) has revolutionized the clinical practice of numerous fields in pediatrics. Furthermore, this has shed new light on current knowledge regarding the phenotypic variability of rare genetic disorders affecting infants and children, as individuals less severely affected, or those presenting with atypical or previously unrecognized phenotypic features, are now more likely to achieve a molecular diagnosis.

The aim of this Special Issue is to provide updated and novel insights into the phenotypic spectrum of rare genetic disorders affecting children. Furthermore, we aim to showcase new discoveries into the associations between genes and human phenotypes. Colleagues are encouraged to submit original articles or reviews on this topic.

Dr. Ben Pode-Shakked
Guest Editor

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Keywords

  • phenotypic variability
  • genetic disorders
  • rare diseases
  • neurodevelopmental disorders
  • craniofacial anomalies
  • next-generation sequencing

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Published Papers (1 paper)

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Research

14 pages, 777 KiB  
Article
Increased Prevalence of Psychiatric Disorders in Children with RASopathies: Comparing NF1, Noonan Syndrome Spectrum Disorder, and the General Population
by Yaffa Serur, Odeya Russo, Chloe Alexa McGhee and Tamar Green
Genes 2025, 16(7), 843; https://doi.org/10.3390/genes16070843 - 19 Jul 2025
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Abstract
Background/Objectives: Neurofibromatosis type 1 (NF1) and Noonan syndrome spectrum disorders (NSSD) are the most common RASopathies, resulting from germline mutations that affect the RAS-MAPK signaling pathway. Both are associated with increased risk for neurodevelopmental and psychiatric conditions, yet few studies have used [...] Read more.
Background/Objectives: Neurofibromatosis type 1 (NF1) and Noonan syndrome spectrum disorders (NSSD) are the most common RASopathies, resulting from germline mutations that affect the RAS-MAPK signaling pathway. Both are associated with increased risk for neurodevelopmental and psychiatric conditions, yet few studies have used structured diagnostic interviews to compare their psychiatric comorbidities. Methods: We conducted clinician-administered DSM-5 diagnostic assessments (KSADS) in 123 children with RASopathies (NF1 = 29, NSSD = 94; ages 5–15). Diagnosis prevalence was compared within each group and to population-based estimates. Results: Psychiatric diagnoses were highly prevalent, at 79.3% in NF1 and 76.6% in NSSD, with ADHD (NF1 = 72.4%, NSSD = 51.1%) and anxiety disorders (NF1 = 37.9% and NSSD = 43.6%) being the most common, rates substantially higher than those reported in general population estimates. Behavioral and sleep disorders were identified in approximately 25% of both groups. Notably, social anxiety disorder was identified in 14.9% of NSSD but not in NF1. Full-scale IQ did not significantly differ by diagnosis status. Specific anxiety disorders, elimination disorders, obsessive–compulsive disorder, and post-traumatic stress disorder were characterized, expanding the known psychiatric phenotype of RASopathies. Conclusions: Children with NF1 and NSSD demonstrate similarly high rates of ADHD, anxiety, and behavioral disorders compared to the general population; in addition, we report sleep disorders in NSSD and characterize psychiatric disorders not previously described in RASopathies. The shared psychiatric profiles may reflect the common effect of RAS-MAPK pathway dysregulation on psychiatric outcomes. These findings highlight the need for early, syndrome-informed mental health screening and intervention in the clinical care of individuals with RASopathies. Full article
(This article belongs to the Special Issue Phenotypic Variability of Genetic Diseases in Children)
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