Molecular Syndromology[JOURNAL]
Sun
200 papers
Syndromic Alobar Holoprosencephaly Associated with a de novo 2p21p16.2 Contiguous Gene Deletion: A Neonatal Case Report.
Keçeci R, Keçeci HN, Büyükeren M … +2 more , Yılmaz FH, Özcan B
Mol Syndromol · 2026 Mar · PMID 42125343 · Full text
BACKGROUND: Chromosome 2p21 harbors , a major driver gene for holoprosencephaly (HPE). Large copy number variants (CNVs) overlapping 2p21p16.2 are rare and may present with pleiotropic congenital anomalies. CASE PRESENTA...
BACKGROUND: Chromosome 2p21 harbors , a major driver gene for holoprosencephaly (HPE). Large copy number variants (CNVs) overlapping 2p21p16.2 are rare and may present with pleiotropic congenital anomalies. CASE PRESENTATION: A female neonate born at 27 weeks (1,000 g) after placental abruption was diagnosed with distinguishable craniofacial features, alobar HPE, agenesis of the corpus collosum (ACC), and a 6-mm atrial septal defect. Chromosomal microarray analysis revealed a heterozygous 11.3 Mb interstitial deletion at arr[GRCh38] 2p21p16.2(43075433_54379379)x1, containing entire , , and a cluster of mismatch repair (MMR) genes such as . The parents do not have dysmorphic features, their karyotype analysis was normal, and based on the available data, the CNV was considered de novo. CONCLUSION: The patient's phenotype is consistent with haploinsufficiency leading to severe forebrain division insufficiency; the adjacent MMR deletion defines the Lynch susceptibility locus. We emphasize the need to consider the risk of cancer in later life, in addition to the currently available findings.
Investigation of the Expression Levels of Exosomal miRNAs in the Patients: Myocardial Infarction with Nonobstructive Coronary Arteries.
Yalcintepe S, Altay S, Demir M … +8 more , Sezginer Guler H, Zhuri D, Sut N, Demir S, Atli E, Ikbal Atli E, Eker D, Gurkan H
Mol Syndromol · 2026 Mar · PMID 42111225 · Full text
INTRODUCTION: Myocardial infarction with nonobstructive coronary artery disease (MINOCA) poses a challenge for diagnosis and treatment because of its heterogeneous etiology. The mechanisms underlying MINOCA are diverse a...
INTRODUCTION: Myocardial infarction with nonobstructive coronary artery disease (MINOCA) poses a challenge for diagnosis and treatment because of its heterogeneous etiology. The mechanisms underlying MINOCA are diverse and include plaque disruption, coronary spasm, microvascular dysfunction, and thromboembolism. However, the specific molecular pathways involved are not fully understood. MicroRNAs (miRNAs) are known as potential biomarkers and regulators of various cardiovascular diseases. In our study, we aimed to investigate the relationship between MINOCA and exosomal miRNA expression and to determine the potential of these exosomal miRNAs as biomarkers for prognosis, diagnosis, and treatment. METHODS: Three groups were included in the study: (1) the MINOCA group, (2) the myocardial infarction with obstructive coronary artery disease group, and (3) the healthy control group. Exosomal miRNA isolation was performed from all participants, and the expression levels of hsa-miR-16-5p, hsa-miR-92a-3p, hsa-miR-487a-5p, and hsa-miR-490-3p were analyzed by quantitative real-time PCR (polymerase chain reaction). ΔΔCt values were determined, and statistical analyses were performed after these values were obtained. RESULTS: Statistical analysis of hsa-miR-16-5p, hsa-miR-92a-3p, hsa-miR-487a-5p, and hsa-miR-490-3p revealed that the expression levels of hsa-miR-490-3p were significantly different between the groups in the MINOCA group ( = 0.022). hsa-miR-16-5p was found to be closely related to the statistical significance level ( = 0.078). hsa-miR-92a-3p and hsa-miR-487a-5p were not significantly different between the groups. CONCLUSION: Our study revealed that miR-490-3p, which was detected at a statistically significant level in the MINOCA group, is an effective biomarker in MINOCA patients. This miRNA has been reported in only a few studies on myocardial infarction, and our study is the first to report it in relation to MINOCA. The fact that hsa-miR-16-5p is close to statistical significance, whereas statistical significance was not detected for hsa-miR-92a-3p and hsa-miR-487a-5p, indicates that studies with a larger number of individuals are needed.
Gillespie Syndrome: Greek Patient with Novel Mutation and Atypical Presentation - Expansion of the Phenotype and Literature Review.
Lithoxopoulou M, Alvanou M, Pavlidou E … +11 more , Tziola T, Babatseva E, Drogouti E, Tramma D, Sterpi M, Papadopoulou A, Seliniotaki AK, Diamanti E, Tsakalidis C, Mataftsi A, Ververi A
Mol Syndromol · 2026 Mar · PMID 42111224 · Full text
INTRODUCTION: Gillespie syndrome is characterized by bilateral aniridia, cerebellar hypoplasia leading to ataxia, congenital hypotonia, and variable degrees of intellectual disability. The condition is attributed to path...
INTRODUCTION: Gillespie syndrome is characterized by bilateral aniridia, cerebellar hypoplasia leading to ataxia, congenital hypotonia, and variable degrees of intellectual disability. The condition is attributed to pathogenic variants in , either in a biallelic manner or as heterozygous dominant-negative mutations. CASE PRESENTATION: Herein, we report the case of a male neonate with generalized hypotonia, and bilateral aniridia, identified during routine newborn eye screening. His abdominal ultrasound revealed a left dysplastic pleiocystic kidney, and his brain magnetic resonance imaging showed mega cisterna magna. In the second month of life, he presented with intestinal malrotation requiring surgical repair. Whole exome sequencing revealed a homozygous deletion of exons 3 and 4 in the gene, confirmed by molecular karyotype (array CGH). The patient was diagnosed with Gillespie syndrome, consistent with his ophthalmological and neurological findings. CONCLUSION: Urinary and gastrointestinal issues such as a pleiocystic kidney and malrotation have not previously been associated with Gillespie syndrome. While these findings may be coincidental, they could represent new phenotypic features of the condition.
Cytomolecular Analysis of a Ring X Chromosome in a Patient with Turner Syndrome: A Case Report.
Cruz da Silva EK, Rocha RB, de Sousa Passos P … +5 more , Correa de Oliveira EH, Liehr T, Serrão das Neves DB, Benzaquem DC, Fantin C
Mol Syndromol · 2026 Mar · PMID 42100471 · Full text
INTRODUCTION: Turner syndrome (TS) is a genetic disorder caused by the complete or partial absence of one of the X chromosomes. Its clinical features include short stature, gonadal dysgenesis, primary amenorrhea, and inf...
INTRODUCTION: Turner syndrome (TS) is a genetic disorder caused by the complete or partial absence of one of the X chromosomes. Its clinical features include short stature, gonadal dysgenesis, primary amenorrhea, and infertility. The condition presents significant phenotypic variability, especially in cases involving chromosomal mosaicism and structural abnormalities. CASE PRESENTATION: A 21-year-old female patient from Tapauá, Amazonas, Brazil, was evaluated due to irregular bleeding followed by secondary amenorrhea. Cytogenetic analysis of peripheral blood lymphocytes was performed using conventional G-banding, followed by fluorescence in situ hybridization (FISH) for molecular characterization. Cytogenetic analysis revealed 2 cell lines: one with monosomy X (45,X) and another with 46 chromosomes including a ring X chromosome. The final karyotype was mos45,X[170]/46,X,r(X)(p11.22q13.23)[30]. The presence of a ring X chromosome was confirmed by FISH. CONCLUSION: This case illustrates the relevance of combining classical and molecular cytogenetic techniques to identify structural X chromosome abnormalities. Such analysis is essential for accurate diagnosis, understanding genotype-phenotype correlations, and guiding clinical management and genetic counseling in patients with TS.
Genetic Skeletal Disorders with Defects in Glycosaminoglycan Biosynthesis.
Tsujioka Y, Simsek Kiper PO, Unger S … +6 more , Handa A, Kono T, Jinzaki M, Rossi A, Superti-Furga A, Nishimura G
Mol Syndromol · 2026 Feb · PMID 42094029 · Full text
BACKGROUND: Proteoglycans are a major component of the connective tissue matrix, which consists of a core protein and covalently attached glycosaminoglycan (GAG) chains, which are highly sulfated polysaccharides with a t...
BACKGROUND: Proteoglycans are a major component of the connective tissue matrix, which consists of a core protein and covalently attached glycosaminoglycan (GAG) chains, which are highly sulfated polysaccharides with a tetrasaccharide linker for the core protein attachment. Impaired synthesis or degradation of GAG causes genetic disorders. In the 1950s, deficient lysosomal GAG degradation was discovered in mucopolysaccharidoses. In the 1990s, a defective enzyme for GAG synthesis was implicated in a variant of Ehlers-Danlos syndrome and an impaired GAG sulfation in diastrophic dysplasia. Newer studies have uncovered that abnormal GAG synthesis causes a large group of genetic skeletal disorders with joint and skin abnormalities. SUMMARY: The prototype of this group includes diastrophic dysplasia and Desbuquois dysplasia. The former is attributed to abnormal GAG sulfation, while the latter to impaired GAG chain elongation. Defective linker formation causes distinctive phenotypes termed linkeropathy. Moreover, there remain many disorders with defective GAG synthesis, in which the phenotypes are poorly documented and thus the clinical suspicion and even interpretation of molecular findings are challenging. Here, we attempt to review the skeletal manifestations of abnormal GAG synthesis disorders, based on our own experiences and previous reports. Each disorder has distinct clinical and radiological features, but they share some common skeletal manifestations, such as distal humeral hypoplasia, misshapen proximal femora, accelerated carpal ossification, and malsegmentation of the short tubular bones. KEY MESSAGE: Awareness of the phenotypic similarities and differences among this group of disorders facilitates our clinical and genetic practices for affected individuals.
A Systematic Bioinformatic Analysis of the miRNA Pathway in Inborn Errors of Amino Acid Metabolism Disorders.
Bayrak H, Sharafi P, Kılıç M
Mol Syndromol · 2026 Mar · PMID 42038754 · Full text
INTRODUCTION: Inborn errors of amino acid metabolism (IEAAM) are genetic defects that lead to the toxic accumulation of metabolites. While the genetic basis of these intoxication-type disorders is well-established, the r...
INTRODUCTION: Inborn errors of amino acid metabolism (IEAAM) are genetic defects that lead to the toxic accumulation of metabolites. While the genetic basis of these intoxication-type disorders is well-established, the regulatory role of microRNAs in their pathogenesis remains poorly synthesized. This systematic bioinformatic analysis aims to identify and validate specific miRNA-gene interactions that modulate key metabolic pathways in IEAAM. METHODS: A systematic literature search was conducted across PubMed and Scopus databases. We integrated identified miRNAs with metabolic genes using prediction tools (e.g., miRWalk, miRDB) and validated these interactions through functional pathway analysis using KEGG, DisGeNET, and PubChem database integration. RESULTS: Our analysis identified a consistent network of miRNAs associated with amino acid metabolism. Specifically, six miRNAs (mmu-miR-409-5p, hsa-miR-3944-3p, rno-miR-125b-5p, hsa-miR-145-5p, hsa-miR-5195-3p, and hsa-miR-1202) were bioinformatically validated to target key genes such as , , , , and . These miRNAs are significantly enriched in metabolic pathways (KEGG) and associated with clinical phenotypes including epilepsy and intoxication-related metabolic crises. CONCLUSION: This computational study provides the first systematic evidence of a conserved miRNA-gene regulatory network in aminoacidopathies. By identifying these six key regulatory miRNAs, our findings offer novel insights into the epigenetic modulation of metabolic blocks and highlight potential targets for future miRNA-based therapeutic interventions in IEAAM.
Evaluation of Cytogenetic and Molecular Genetic Tests in Patients with Short Stature.
Arslan G, Turan B, Çinleti T … +10 more , Yalçın HY, Kaya ÖÖ, Onguner S, Vural G, Nasırlı M, Birinci H, Arslan E, Eroğlu Filibeli B, Er E, Dündar BN
Mol Syndromol · 2026 Feb · PMID 42038753 · Full text
INTRODUCTION: Short stature is among the most common endocrinological diseases in childhood. The investigation of syndromic or non-syndromic genetic causes provides important data for etiology. This study aimed to presen...
INTRODUCTION: Short stature is among the most common endocrinological diseases in childhood. The investigation of syndromic or non-syndromic genetic causes provides important data for etiology. This study aimed to present the frequency of genetic variant detection in cases in which genetic studies were performed for short stature in our clinic and the clinical characteristics of patients in whom clinically significant variants were detected. METHODS: Two hundred forty-six patients who applied to our center with complaints of short stature and underwent genetic testing during a 1.5-year period were included. Anthropometric measurements, history and physical examination findings, and tests for the etiology of short stature were recorded retrospectively for all patients with pathological results. RESULTS: Genetic tests were performed for a total of 228 children with short stature, of whom 39 (17.2%) were male and 189 (82.8%) were female. Pathogenic variants were identified in 56 (24.5%) of 228 patients. The mean height standard deviation score (SDS) of all patients was -2.63 ± 1.42. The height SDS of the patients with the gene variant was -2.73 ± 1.32. Pathological results were detected in 26 of 113 patients (23%) who underwent karyotype analysis, while clinically significant pathogenic results were obtained in 2 of 67 patients (2.9%) who underwent microarray analysis, 9 of 76 patients (30.8%) who underwent short stature panel analysis, 5 of 18 patients (27.7%) who underwent RASopathy panel testing, 7 of 37 patients (15%) who underwent SHOX MLPA, and 7 of 17 patients (6.9%) who underwent skeletal dysplasia panel analysis. CONCLUSION: Different genetic causes and pathophysiological processes underlie isolated and/or syndromic short stature. With the development in genetics, it is becoming easier and more important to elucidate the etiology of short stature, as in other diseases. Our study supports the significance of genetic diagnosis in patients with short stature, as it can enable diagnosis even in the absence of specific clinical findings other than short stature, and guide the necessity, efficacy, and appropriate dosing of growth hormone therapy.
Expandingthe Phenotypic Spectrum of Deficiency: A Case Demonstrating a Stable, Nonprogressive Leukoencephalopathy Pattern.
Aygün H, Şahin İ, Taşkın A … +3 more , Ceylan AC, Karaali K, Köken ÖY
Mol Syndromol · 2026 Feb · PMID 41971559 · Full text
BACKGROUND: encodes a transfer RNA (tRNA) pseudouridine synthase essential for translational fidelity. Biallelic pathogenic variants cause a rare autosomal recessive neurodevelopmental disorder characterized by intellec...
BACKGROUND: encodes a transfer RNA (tRNA) pseudouridine synthase essential for translational fidelity. Biallelic pathogenic variants cause a rare autosomal recessive neurodevelopmental disorder characterized by intellectual disability, microcephaly, hypotonia, and gray sclera. Fewer than thirty individuals have been reported, including only five carrying the recurrent c.212A>G (p.Tyr71Cys) variant. CASE PRESENTATION: We describe a 17-year-old girl born to second-degree consanguineous parents presenting with lifelong global developmental delay, microcephaly, gray sclera, dysmorphic features, and intellectual disability. Neurological examination revealed hyporeflexia without seizures. Brain MRI demonstrated stable, nonprogressive, linear-nodular T2 hyperintense lesions confined to the subcortical white matter with a normal corpus callosum, an imaging pattern rarely associated with deficiency. Whole-exome sequencing identified a homozygous c.212A>G (p.Tyr71Cys) variant, classified as likely pathogenic based on ACMG criteria (PM2, PM3, PP3, PP5). CONCLUSION: This first reported -deficient patient from Turkey - and the fifth globally with p.Tyr71Cys - demonstrates a nonprogressive, radiologically silent white matter phenotype in the absence of epilepsy or callosal abnormalities. Her stable neurological course into late adolescence broadens the phenotypic spectrum of deficiency and underscores the need for long-term clinical monitoring in disorders of tRNA modification.
, , and Alterations versus Cardiac Malformations Related to 22q11.2 Deletion Syndrome.
Diniz BL, Deconte D, Böttcher AK … +5 more , Mergener R, Guaraná BB, Malgarezi de Moraes N, Machado Rosa RF, Gazzola Zen PR
Mol Syndromol · 2026 Apr · PMID 41940406 · Full text
INTRODUCTION: Congenital heart disease (CHD) comprises a wide spectrum of structural defects. However, the etiology of a large proportion of CHDs remains undefined. Among the genetic causes, 22q11.2 deletion syndrome is...
INTRODUCTION: Congenital heart disease (CHD) comprises a wide spectrum of structural defects. However, the etiology of a large proportion of CHDs remains undefined. Among the genetic causes, 22q11.2 deletion syndrome is the condition which most stands out. This association is related to many cardiac embryonic development genes being in the chromosome 22 region, as well as being a region with a high probability of errors in gene recombination, influencing normal levels of gene expression and affecting a gene's copy number. OBJECTIVE: This study aimed to compare molecular findings using multiplex ligation-dependent probe amplification assay in patients presenting CHD with a previous fluorescence in situ hybridization (FISH) diagnosis of 22q11.2DS versus patients without known genetic disorder. RESULTS: All patients had CHD and facial dysmorphia. Patients who had been previously diagnosed by FISH were found to have the exact same deletion size, low-copy-number repeat sequences and genes involved. when deleted or duplicated in different exons (1 and 6) showed distinct congenital heart defect phenotypes. Patients who did not have their diagnosis defined by FISH showed different molecular results, ranging from normal findings to alterations in the and genes. CONCLUSION: Molecular diversity in cardiac malformations is a reality and a great challenge since genotype-phenotype correlation is hindered. Therefore, new insights on that matter should be considered: 22q11.2 deletion syndrome should only be linked to the chromosome 22 region or is there a phenotype variability to be looked at that involves a broader genomic environment?
Targeted Clinical Analysis of PTPN11, SOS1, and NRAS Mutations and Associated Cardiac, Auditory, and Ophthalmologic Findings in Noonan Syndrome Patients.
Celik VD, Halici T, Alomari O
Mol Syndromol · 2026 Apr · PMID 41940405 · Full text
BACKGROUND: Noonan syndrome (NS) is a genetic disorder inherited as an autosomal dominant or sporadic trait, characterized by distinctive facial features, congenital heart defects, short stature, mental retardation, and...
BACKGROUND: Noonan syndrome (NS) is a genetic disorder inherited as an autosomal dominant or sporadic trait, characterized by distinctive facial features, congenital heart defects, short stature, mental retardation, and sensory impairments. The aim was to investigate the clinical correlations of selected variants in the PTPN11, SOS1, and NRAS genes with ophthalmologic, audiologic, and psychometric findings in patients clinically diagnosed with NS. METHODS: Thirty-two patients (8 females and 24 males) clinically diagnosed with NS and aged between 6 months and 18 years were included. Genetic testing was performed for PTPN11, SOS1, and NRAS genes. Patients underwent standardized examinations by the same ophthalmologist, audiologist, and psychologist. A comprehensive database of findings was created, and statistical analyses were performed using SPSS 17. RESULTS: Molecular analysis revealed variants in gene in 37.5% (12/32), related variants in 9.4% (3/32), and -related variant in 3.1% (1/32). Ophthalmologic assessments indicated astigmatism in 8 patients and myopia in 5. Hearing loss was identified in 21.9% (7/32) of the cohort, with two and one mutation-positive patients affected. Psychometric evaluations showed mental retardation in 40.6% (13/32), with a significant proportion of mutation-positive patients affected. CONCLUSION: The study found no significant relationships between genetic mutations and ophthalmologic, audiologic, or psychometric outcomes. Further investigations with larger sample sizes are necessary to elucidate the genotype-phenotype correlations in NS.
Identification of the Genetic Causes of Inherited Diseases in a North African Biobank: Implications for Genetic Diagnosis.
Charif M, Lhousni S, Ghanam A … +22 more , Rkain M, Benajiba N, Amrani R, Babakhouya A, Messaoudi S, Elouali A, Ayyad A, Najib A, El Mahi O, Benzirar A, Moutaouekkil M, Allaoui S, Benahmed M, Elidrissi Errahhali M, Elidrissi Errahhali M, Bouzidi A, Ouarzane M, Vincent AT, Sellam A, Lenaers G, Boulouiz R, Bellaoui M
Mol Syndromol · 2026 Apr · PMID 41940404 · Full text
INTRODUCTION: In North Africa, genetic diseases are widespread but under-studied due to limited research resources. This study used exome sequencing to identify disease-causing variants in a large series of Moroccan pati...
INTRODUCTION: In North Africa, genetic diseases are widespread but under-studied due to limited research resources. This study used exome sequencing to identify disease-causing variants in a large series of Moroccan patients with suspected genetic diseases. METHODS: A cohort of 30 patients with genetic diseases from the BRO Biobank underwent exome sequencing. Candidate variants were evaluated by segregation analysis and molecular modeling. RESULTS: Thirty-one variants were identified in 27 known genes. Interestingly, 54.8% of these variants were novel and therefore could be specific to the Moroccan population. Pathogenic or likely pathogenic disease-causing variants were identified in 22 of 30 patients, leading to a genetic testing yield of 73.3%. Moreover, the identified variants, classified as of uncertain significance, likely benign or benign, were predicted to alter protein structure using in silico modeling of 3D protein structure. The diagnosis was changed in 23% of patients with suspected genetic syndromes, and the etiology was determined in all patients with unrecognizable genetic disorder. CONCLUSION: This study represents the largest biobank-based study of inherited diseases in a North African country. It illustrates the genetic variability of the Moroccan population and improves our understanding of genotype-phenotype correlations. Furthermore, the relatively high yield of genetic testing obtained in this study justifies the need to implement exome sequencing in the clinical setting in Morocco for better genetic diagnosis.
Late Diagnosis of a 3p26.3p25.2 Microduplication in a Young Adult with Mild Neurodevelopmental Features: A Case Report and Literature Review.
Rangel-Méndez JA, Rubi-Castellanos R, Contreras-Capetillo S … +2 more , González-Herrera L, Pinto-Escalante D
Mol Syndromol · 2026 Feb · PMID 41937886 · Full text
INTRODUCTION: Intellectual disability with mild dysmorphic features may be attributed to perinatal complications such as neonatal hypoxia. However, chromosomal abnormalities may underlie these phenotypes. We report a cas...
INTRODUCTION: Intellectual disability with mild dysmorphic features may be attributed to perinatal complications such as neonatal hypoxia. However, chromosomal abnormalities may underlie these phenotypes. We report a case with rare copy number variants that are likely to have neurodevelopmental relevance. CASE PRESENTATION: A 21-year-old female presented with mild dysmorphic features and intellectual disability that was initially attributed to neonatal hypoxia (i.e., fetal distress). Array-CGH analysis revealed a pathogenic microduplication at 3p26.3p25.2 and a microduplication of uncertain significance at 2q11.2. The duplicated regions encompass several genes with known neurodevelopmental relevance, including and This case is the first clinical report of an adult with this specific chromosomal duplication. CONCLUSION: This case provides valuable insights into the long-term natural history and clinical evolution of these duplications. It underscores the importance of genetic evaluation in individuals with intellectual disability and subtle clinical features, when the morbidities are not definitively attributable to postnatal or perinatal events.
Clinical and Molecular Features of 11 Patients with Different Subtypes of Ehlers-Danlos Syndrome.
Doğan Arı AB, Arı H, Sezer A … +4 more , Ağırbaşlı D, Kurnaz E, Savaş Erdeve Ş, Kılıç E
Mol Syndromol · 2026 Feb · PMID 41937885 · Full text
INTRODUCTION: Ehlers-Danlos syndrome (EDS) comprises a group of clinically and genetically heterogeneous connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and increased tissue fra...
INTRODUCTION: Ehlers-Danlos syndrome (EDS) comprises a group of clinically and genetically heterogeneous connective tissue disorders characterized by joint hypermobility, skin hyperextensibility, and increased tissue fragility. As collagen is present in every organ system, EDS affects multiple body systems, and although its subtypes share overlapping features, each also exhibits distinctive clinical characteristics. METHODS: We report 11 EDS patients from eight unrelated families. Whole-exome sequencing, clinical exome sequencing, and Sanger sequencing were performed for genetic diagnosis. RESULTS: Six EDS subtypes were identified: cardiac valvular EDS, dermatosparaxis EDS, musculocontractural EDS type 1, combined osteogenesis imperfecta/EDS type 2, brittle cornea syndrome type 2, and kyphoscoliotic EDS types 1 and 2. All patients exhibited joint hypermobility and skin hyperextensibility. Eight different variants were detected, including two novel variants; five were classified as pathogenic, two as likely pathogenic, and one as a variant of uncertain significance. Molecular diagnoses influenced clinical management by enabling subtype-specific surveillance, such as cardiologic monitoring in cardiac valvular EDS, early ophthalmologic intervention in brittle cornea syndrome, avoidance of invasive procedures in dermatosparaxis EDS, implementation of fracture-preventive measures in patients with combined osteogenesis imperfecta/EDS, and improved surgical risk management across all EDS subtypes. CONCLUSION: This study expands the clinical and molecular spectrum of EDS by identifying two novel pathogenic variants and revealing previously unreported clinical findings. The results emphasize intrafamilial variability and the need to consider possible dual diagnoses, particularly in consanguineous families. Detailed phenotyping combined with comprehensive molecular testing improves subtype delineation and guides patient-specific surveillance and management strategies.
Encephalopathy: Cannabidiol as a Treatment Option and Expansion of the Genotype-Phenotype Spectrum - Case Reports.
Ngoh A, Wei H, Yeo TH … +4 more , Krishnappa J, Ling S, Tan EC, Chan DWS
Mol Syndromol · 2026 Feb · PMID 41909762 · Full text
INTRODUCTION: encodes syntaxin-binding protein 1, a protein with a role in trafficking of syntaxin-1 to the synapse and synaptic neurotransmitter release. Mutations in are associated with a wide range of neurodevelopme...
INTRODUCTION: encodes syntaxin-binding protein 1, a protein with a role in trafficking of syntaxin-1 to the synapse and synaptic neurotransmitter release. Mutations in are associated with a wide range of neurodevelopmental phenotypes, including epilepsy, intellectual disability, and movement disorders. CASE SERIES: We report 4 individuals with pathogenic variants in , including 2 previously unreported variants, presenting with a range of severity. One severely affected child with refractory seizures and distressing dystonia responded well to treatment with cannabidiol (CBD), with both seizure cessation and improvement in tone. CONCLUSION: variants are associated with significant phenotypic pleiotropy and a wide spectrum of severity. CBD may be beneficial for severely affected individuals with seizures and movement disorders that are refractory to conventional treatments.
Unraveling the Clinical and Genetic Landscape of Talipes Equinovarus (Clubfoot).
Almohrij S
Mol Syndromol · 2026 Feb · PMID 41884749 · Full text
BACKGROUND: Talipes equinovarus (TEV), commonly known as clubfoot, is a congenital skeletal deformity characterized by abnormal three-dimensional positioning of the foot, ankle, and lower limb. This condition arises from...
BACKGROUND: Talipes equinovarus (TEV), commonly known as clubfoot, is a congenital skeletal deformity characterized by abnormal three-dimensional positioning of the foot, ankle, and lower limb. This condition arises from developmental anomalies affecting multiple tissues in the lower limb, leading to disrupted alignment of foot and ankle joints. Without timely and appropriate intervention, TEV can result in persistent pain, structural deformities, and long-term functional impairments. SUMMARY: TEV is a congenital skeletal (musculoskeletal) disorder with unresolved molecular etiology. However, human genetic studies have identified rare variants and structural alterations in critical lower-limb patterning regulators such as the - transcriptional axis and posterior genes; however, these findings explain only a fraction of cases. The limited explanatory power of currently known genes points to substantial genetic heterogeneity and involvement of regulatory noncoding variants, polygenic risk, and genetic-environment interactions. In this review, we critically integrate existing human genetic and developmental evidence and identify key gaps in genotype-phenotype correlation that must be addressed to understand the underlying pathophysiological of TEV. The etiology of TEV involves a multifactorial interplay between genetic susceptibility and environmental influences. Familial aggregation and phenotypic variability within and between affected individuals support a heritable component in TEV pathogenesis. Genetic studies have implicated variants in genes encoding skeletal muscle contractile proteins and key developmental regulators, including , , and clusters (, , ), as well as . However, no singular high-penetrance gene has been definitively linked to TEV. The molecular pathways by which these genetic variants confer risk, and their genomic and proteomic interactions, require further elucidation. KEY MESSAGE: Enhancing our understanding of the genetic architecture and signaling pathways involved in TEV is essential to reveal the complex pathophysiology of this condition and may inform improved diagnostic and therapeutic strategies.
Whole Genome Sequence Identifies the Second Allele: An Intronic Variant in RYR1 Contributes to Early-Onset Fetal Akinesia Deformation Sequence.
Wang M, Hong J, Han S … +4 more , Jin P, Xu C, Qian Y, Dong M
Mol Syndromol · 2026 Feb · PMID 41878156 · Full text
INTRODUCTION: Fetal akinesia deformation sequence (FADS), a severe prenatal phenotype associated with congenital myopathies (CMs), is linked to mutations in the gene. Although whole exome sequencing (WES) is a standard...
INTRODUCTION: Fetal akinesia deformation sequence (FADS), a severe prenatal phenotype associated with congenital myopathies (CMs), is linked to mutations in the gene. Although whole exome sequencing (WES) is a standard diagnostic approach, certain pathogenic variants may remain undetected. In this study, we utilized whole genome sequencing (WGS) to investigate a recurrent case of FADS with negative WES results. METHODS: A couple who experienced four consecutive pregnancy losses, including two fetuses affected by FADS, underwent trio-WGS following negative WES findings. Variants were annotated using public databases and filtered according to ACMG guidelines. Functional validation of an intronic variant was conducted using RT-PCR, TA cloning, and Sanger sequencing. RESULTS: WGS identified two novel compound heterozygous variants in the affected fetus: a paternally inherited in-frame mutation (c.13659+655_14172 +588delinsCTGGCGCCCCATCTCAT) located the C-terminal hotspot and a maternally inherited deep intronic variant (c.4934+25G>A). Both of them were initially classified as variant of uncertain significance. RNA studies demonstrated that this intronic variant caused a 26-bp intron retention and frameshift, leading to its reclassification as pathogenic. And according to this PM3 evidence, the in-frame mutation was reclassified as likely pathogenic. Both variants were absent from population databases and exhibited segregation with the phenotype. CONCLUSION: This study highlights the utility of WGS in diagnosing fetal anomalies with negative WES results by identifying noncoding and structural variants. The identification of novel mutations broadens the genetic spectrum of recessive CMs and emphasizes the necessity for functional assays to accurately interpret intronic variants. WGS is recommended for cases of recurrent fetal anomalies when WES is inconclusive, although careful interpretation of variants is advised.
Diets-Jongmans Syndrome due to a Novel KDM3B Variant: The First Molecularly Confirmed Case from Turkey.
Deligozoglu D, Genc A, Kýlýc E … +2 more , Tepe D, Kocaay P
Mol Syndromol · 2026 Feb · PMID 41878155 · Full text
INTRODUCTION: Diets-Jongmans syndrome (DIJOS) is a rare neurodevelopmental disorder associated with heterozygous variants in . The phenotypic spectrum continues to expand as additional individuals are identified. CASE PR...
INTRODUCTION: Diets-Jongmans syndrome (DIJOS) is a rare neurodevelopmental disorder associated with heterozygous variants in . The phenotypic spectrum continues to expand as additional individuals are identified. CASE PRESENTATION: We report an 8-year-old girl who presented with short stature, micrognathia, a pointed chin, and mild developmental delay. Exome sequencing revealed a novel likely pathogenic heterozygous nonsense variant, (NM_016604.4)c.5068C>T p.(Gln1690Ter), which was also detected in her mother. Biochemical evaluation revealed growth hormone deficiency, which was confirmed by two stimulation tests. Short stature without intellectual disability was noted in the mother, indicating intrafamilial phenotypic variability. CONCLUSION: This case represents the first molecularly confirmed DIJOS patient from Turkey and adds further clinical observations regarding growth hormone deficiency in a patient with DIJOS.
Erratum.
Mol Syndromol · 2026 Jun · PMID 41859494 · Full text
[This corrects the article DOI: 10.1159/000547016.].
[This corrects the article DOI: 10.1159/000547016.].
Different Diagnoses, Common Ancestry: 22q11.2 Deletion Syndrome and Wiskott-Aldrich Syndrome in the Same Family.
Bobreshova A, Efimova I, Mukhina A … +20 more , Bogdanova D, Ogneva A, Yukhacheva D, Markova Z, Pershin D, Rodina Y, Balinova N, Raykina E, Zhavoronok D, Seitova G, Orlov D, Drozdov G, Sermyagina I, Zinchenko R, Shilova N, Polyakov A, Voronin S, Shcherbina A, Kutsev S, Marakhonov A
Mol Syndromol · 2026 Jan · PMID 41768875 · Full text
INTRODUCTION: Newborn screening program enable pre-symptomatic detection patients with severe forms of T and B cell immunodeficiency. Despite the high prevalence of 22q11.2 deletion syndrome, only 1 in 10 patients develo...
INTRODUCTION: Newborn screening program enable pre-symptomatic detection patients with severe forms of T and B cell immunodeficiency. Despite the high prevalence of 22q11.2 deletion syndrome, only 1 in 10 patients develop lymphopenia that can be detected by newborn screening program. This report presents a unique familial case of 22q11.2 deletion syndrome and Wiskott-Aldrich syndrome, highlighting the importance genetic counseling and a detailed analysis of the family history. CASE PRESENTATION: The article presents a case of the two rare genetic diseases in patients from the same family: 22q11.2 deletion syndrome in one and Wiskott-Aldrich syndrome in the other. Both diseases belong to the group of combined immunodeficiencies with syndromic features and are potentially life-threatening conditions requiring follow-up by a wide range of specialists: immunologists, geneticists, cardiologists, endocrinologists, and medical psychologists. CONCLUSION: Our work aimed to describe the clinical manifestations, genetic characteristics, and diagnosis of these disorders. It is worth emphasizing that the timely diagnosis of not only 22q11.2 deletion syndrome but also other primary immunodeficiencies in the Russian Federation became possible due to the introduction of extended neonatal screening into widespread practice. For such patients, comprehensive early interventional treatment and follow-up by a wide range of specialists is important to improve prognosis and quality of life.
Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and Related Disorders.
Corso BM, Simões LO, de Oliveira KMK … +15 more , Dos Santos AM, Angeloni LL, de Oliveira Sobrinho RP, Gil-da-Silva-Lopes VL, Marques-de-Faria AP, Maciel Guerra AT, Guerra-Junior G, Jorge AAL, Quedas EPS, Silveira HG, Toccoli G, Melaragno MI, Rare Genomes Project Consortium, Guaragna MS, Steiner CE
Mol Syndromol · 2026 Feb · PMID 41675685 · Full text
INTRODUCTION: RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac...
INTRODUCTION: RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk. METHODS: This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques. RESULTS: Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in , two in , and one each in , , and , besides one with variants in both and ), two with Noonan syndrome with multiple lentigines (both with variants in ), two with Neurofibromatosis-Noonan (), two with cardiofaciocutaneous syndrome (), and one each with Noonan syndrome-like with loose anagen hair (), Noonan syndrome-like (), and Costello syndrome (); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes. CONCLUSION: Three pairs of unrelated patients presented recurrent variants in the gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the gene and c.1A>G in the gene are variants for the first time associated with features of Noonan syndrome.
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