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Phenotypic Variability of Genetic Diseases in Children
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Phenotypic Variability of Genetic Diseases in Children

A Special Issue of Genes (ISSN 2073-4425) belonging to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (15 January 2026) | Viewed by 7336

Editor

Dr. Ben Pode-Shakked

E-Mail Website
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

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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized 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

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

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Published Papers (4 papers)

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Research

10 pages, 862 KB  
Article
Further Support for Association of DAND5 with Autosomal Recessive Laterality Disorders
by Odelia Chorin, Yoav Bolkier, Uriel Katz, Yishay Salem, Yair Anikster, Nechama Shalva, Ortal Barel, Moshe Giladi, Rotem Semo-Oz, Dror Ben-Ruby, Shelly Lev-Hochberg, Hadas Ityel, Lior Greenbaum, Asaf Vivante, Annick Rein-Rothschild and Ben Pode-Shakked
Genes 2026, 17(8), 852; https://doi.org/10.3390/genes17080852 - 24 Jul 2026
Viewed by 508
Abstract
Background: Laterality defects are rare congenital malformations that encompass congenital heart defects (CHDs) together with abnormalities of visceral organ arrangement (situs inversus or situs ambiguous). These defects may be isolated or part of a syndromic presentation with multisystem involvement. While over 50 genes [...] Read more.
Background: Laterality defects are rare congenital malformations that encompass congenital heart defects (CHDs) together with abnormalities of visceral organ arrangement (situs inversus or situs ambiguous). These defects may be isolated or part of a syndromic presentation with multisystem involvement. While over 50 genes have been implicated in laterality disorders, across multiple modes of inheritance, many cases remain molecularly undiagnosed. We sought to elucidate the molecular basis of dextrocardia, CHDs and visceral heterotaxy in two unrelated individuals of Arab-Muslim descent. Methods: Detailed clinical phenotyping and exome sequencing (ES) were performed for each of the probands, followed by familial segregation analysis. Results: ES revealed a shared homozygous variant in the Dan Domain Family Member 5 (DAND5) gene (NM_152654.3): c.396_397dup, p.(Tyr133SerfsTer11). DAND5 encodes a member of the Cerberus-related DAN protein family, which is involved in the establishment of left body asymmetry. This frameshift variant introduces a premature stop codon within the final exon, which is predicted to escape nonsense-mediated decay (NMD), resulting in a truncated protein lacking the functional DAN domain. Conclusions: DAND5 has recently been suggested as a candidate gene in heterotaxy and CHDs. Our findings further support biallelic loss of function variants in DAND5 autosomal recessive laterality defects. Full article
(This article belongs to the Special Issue Phenotypic Variability of Genetic Diseases in Children)
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14 pages, 2442 KB  
Article
Broadening the Phenotypic Spectrum of MAFB-Related Disease: Renal, Auricular, Ocular, and Nervous System Involvement
by Aviva Eliyahu, Danit Atias-Varon, Ortal Barel, Yulia Khavkin, Elon Pras, Haike Reznik-Wolf, Odelia Chorin, Tomer Poleg, Ari Biller, Pazit Beckerman, Nabil Abu-Amer, Tamara Wygnanski-Jaffe, Lior Greenbaum, Asaf Vivante and Irit Krause
Genes 2026, 17(3), 342; https://doi.org/10.3390/genes17030342 - 19 Mar 2026
Viewed by 1008
Abstract
Background: Focal segmental glomerulosclerosis (FSGS) is a leading cause of renal disease presenting with steroid-resistant nephrotic syndrome (SNRS) and variable stages of chronic kidney disease (CKD). Monogenic etiologies for FSGS are increasingly recognized, particularly in pediatric and familial cases. Missense variants in the [...] Read more.
Background: Focal segmental glomerulosclerosis (FSGS) is a leading cause of renal disease presenting with steroid-resistant nephrotic syndrome (SNRS) and variable stages of chronic kidney disease (CKD). Monogenic etiologies for FSGS are increasingly recognized, particularly in pediatric and familial cases. Missense variants in the MAF BZIP Transcription Factor B (MAFB) gene cause a dominantly inherited condition with variable phenotype, ranging from isolated ocular or renal manifestations to syndromic FSGS. Methods: Detailed clinical and genetic investigations were conducted in an extended family presenting with a spectrum of renal and extra-renal manifestations. Results: Using Exome Sequencing (ES), a heterozygous variant, c.797T>C; p.(Leu266Pro) in the MAFB gene was identified in multiple affected family members. Variant segregation confirmed its presence in additional family members. The proband exhibited CKD accompanied by congenital auricular anomalies, hearing loss, and neurodevelopmental delay. An affected sibling presented with nephrotic-range proteinuria, Duane retraction syndrome (DRS) and neurodevelopmental involvement, while another family member had an isolated renal phenotype. Several of these features have not been previously associated with MAFB. Tools for structural modeling and stability predictions supported the functional impact of this variant. Conclusions: Our findings expand the phenotypic spectrum of MAFB-associated disease and further emphasize its variability. Full article
(This article belongs to the Special Issue Phenotypic Variability of Genetic Diseases in Children)
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14 pages, 877 KB  
Article
A Nationwide Analysis of the Phenotype/Genotype Landscape of Hemophagocytic Lymphohistiocytosis: UNC13D Associates with Poor Prognosis
by Dafna Brik Simon, Yarden Greental Ness, Orly Dgany, Sharon Noy-Lotan, Tanya Krasnov, Galit Berger, Tamar Feuerstein, Jerry Stein, Aviva Kraus, Asaf Yanir, Assaf Barg, Elad Jacoby, Noa Mandel-Shorer, Dan Harlev, Ehud Even-Or, Hannah Tamary, Oded Gilad, Orna Steinberg-Shemer and Joanne Yacobovich
Genes 2025, 16(11), 1315; https://doi.org/10.3390/genes16111315 - 2 Nov 2025
Cited by 2 | Viewed by 1435
Abstract
Background/objectives: Geographic and ethnic differences influence the genetic landscape of hemophagocytic lymphohistiocytosis (HLH) and the frequency of familial HLH (FHL); this in turn can affect outcomes. Methods: We collected data on 98 patients treated for HLH between 1 January 2001 and 31 July [...] Read more.
Background/objectives: Geographic and ethnic differences influence the genetic landscape of hemophagocytic lymphohistiocytosis (HLH) and the frequency of familial HLH (FHL); this in turn can affect outcomes. Methods: We collected data on 98 patients treated for HLH between 1 January 2001 and 31 July 2024 at four tertiary centers, characterizing the genotype/phenotype correlations. Results: Half of the patients, 51 (52%), were symptomatic by age 1 year and 43 (44%) were diagnosed by that age. Our varied population included 43% Sephardic/Ashkenazi/Ethiopian Jews, 50% Muslim Arabs, and 7% Druze. Molecular analysis was performed on 90.5% of patients and revealed an FHL-related variant in 72%. The genetic variation included biallelic variants in PRF1 (21), UNC13D (12), STXBP2 (15), and STX (1). Eight hemizygous variants were found in X-linked lymphoproliferative disorder-related genes. A RAB27A monoallelic variant in an infant with a severe phenotype was considered pathogenic. The recently described HLH-related gene, ZNFX1, was mutated with varying penetrance in three symptomatic siblings. Overall, of the 94/98 with follow-up, 77% are alive. Strikingly, 5/12 (41.6%) patients with UNC13D variants died while 14/15 (93.3%) patients with STXBP2 variants survived. Logistic regression found poor prognosis associated with young age at diagnosis (p < 0.001), any variant (p = 0.016), UNC13D variant (p < 0.001), poor initial treatment response (p = 0.009), and no BMT (p = 0.005). Conclusions: Our cohort included an extremely high rate of genetic testing and detection of FHL-related variants. UNC13D variations are associated with exceedingly poor outcomes. Response to initial treatment seems crucial for positive outcomes, as does access to hematopoietic stem cell transplantation. Overall, we report a high survival rate, possibly due to a high index of suspicion and prompt diagnosis. Full article
(This article belongs to the Special Issue Phenotypic Variability of Genetic Diseases in Children)
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14 pages, 777 KB  
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
Cited by 6 | Viewed by 3160
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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