Molecular Syndromology[JOURNAL]
Sun
200 papers
5-Oxoprolinase Deficiency and Epilepsy: A Report of Four Cases with New Clinical Findings and Clinical Diversity Even in the Same Family.
Koseci B, Kara E, Burgac E … +5 more , Kaplan I, Kor D, Bulut FD, Ozcan N, Onenli Mungan N
Mol Syndromol · 2026 Feb · PMID 41675684 · Full text
INTRODUCTION: 5-Oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione metabolism: the glutathione synthetase and the 5-oxoprolinase. 5-Oxoprolina...
INTRODUCTION: 5-Oxoprolinuria is primarily suggestive of genetic defects in two enzymes belonging to the gamma-glutamyl cycle in the glutathione metabolism: the glutathione synthetase and the 5-oxoprolinase. 5-Oxoprolinase deficiency is a sporadic autosomal recessive disorder of the gamma-glutamyl cycle, primarily caused by pathogenic variants in the gene. Low levels of 5-oxoproline can normally be detected in urine, although high levels are a clue for diagnosing 5-oxoprolinase deficiency. The clinical picture is not well defined due to the limited number of cases. Some authors questioned whether it is a real inherited metabolic disorder or only a nonspecific biochemical finding. Nephrolithiasis, enterocolitis, PMR, and microcytic anemia are the well-known clinical symptoms and signs of 5-oxoprolinuria (pyroglutamic aciduria). METHODS: We present 4 patients who were diagnosed with 5-oxoprolinuria that had different clinical symptoms and 3 out of 4 patients were siblings. RESULTS: In this study, 2 female and 2 male patients with 5-oxoprolinase deficiency were included. There were different clinical findings in the same family. Patients had unreported clinical symptoms such as growth retardation and drug-resistant epilepsy. CONCLUSION: OPLAH gene mutations have been observed to cause different clinical findings in the same family. A correlation was found between urine 5-oxoproline levels and the severity of clinical findings.
Clinical and Genetic Spectrum of -Related Disease.
Sarıkaya Uzan G, Özyılmaz B, Doğan G … +5 more , Baydan F, Güzin Y, Gençpınar P, Gazeteci Tekin H, Olgaç Dündar N
Mol Syndromol · 2026 Feb · PMID 41675683 · Full text
INTRODUCTION: In this study, we examined the genotype-phenotype characteristics of the cases with pathogenic/possibly pathogenic variants in the gene that we follow in our clinic. METHODS: Data of patients who applied t...
INTRODUCTION: In this study, we examined the genotype-phenotype characteristics of the cases with pathogenic/possibly pathogenic variants in the gene that we follow in our clinic. METHODS: Data of patients who applied to our clinic and had pathogenic/possibly pathogenic/variant of unknown significance variants in the gene were evaluated retrospectively. Patients were examined in terms of demographic, clinical, and individual genetic data, age of symptom-onset, sex, clinical features, clinical types, variants, cardiac involvement, muscle biopsy results, serum creatinine kinase (CK) levels, family history, and consanguinity. RESULTS: The variants were detected in 19 patients from 18 different families. The most common ( = 5, 38.4%) variant was the c.7880T>G (p.Val2627Gly) heterozygous change. 63.1% of our patients were male ( = 12) and 37.9% were female. Admission complaints included a floppy baby, developmental delay, or hyperCKemia. The most common clinical spectrum was malignant hyperthermia (MH) sensitivity ( = 8, 44.4%). We also identified four novel variants in our cohort. CONCLUSION: is known to be the gene most associated with MH. It is very important to manage and take precautions against possible comorbidities and anesthesia complications. For this reason, we think that analyses should be given priority in the diagnostic algorithm.
Dominant Dystrophic Epidermolysis Bullosa with Variant Confirmed by Whole-Exome Sequencing in a Chinese Family and Genotype-Phenotype Correlation Analysis.
Feng X, Liu C, Niu W … +11 more , Hu Y, Zhen Q, Chen W, Wang Y, Li Z, Du J, Guo X, Lv M, Zhang Y, Han Y, Sun L
Mol Syndromol · 2026 Feb · PMID 41675682 · Full text
INTRODUCTION: Epidermolysis bullosa (EB) comprises a diverse group of rare, incurable genetic disorders characterized by blistering of the skin. These conditions have variable clinical presentations and poorly understood...
INTRODUCTION: Epidermolysis bullosa (EB) comprises a diverse group of rare, incurable genetic disorders characterized by blistering of the skin. These conditions have variable clinical presentations and poorly understood genotypes and phenotypes. This study aimed to confirm the diagnosis of dystrophic epidermolysis bullosa (DEB) in a family and analyze gene-phenotype correlations. METHODS: The study involved 3 patients, two controls, and one member with an unknown phenotype. We performed whole exome sequencing (WES) on family members to identify EB-associated genes, with Sanger sequencing for validation. RESULTS: (1) WES revealed missense variants in the ([c.4274T>C.L1425P] and [c.3602G>A.R1201H]) genes in the family; although recorded in the dbSNP database, they have not been reported in previous articles and classified as of uncertain significance by InterVar. These findings were confirmed by Sanger sequencing. (2) Statistical analysis indicated a significant association between DEB and epidermolysis bullosa simplex with junctional epidermolysis bullosa ( = 0.031) in dominant and recessive inheritance patterns, respectively. However, no significant correlation was found between the clinical phenotype of DEB and variant types (nonsense and missense), inheritance patterns (dominant and recessive), or between familial and sporadic cases. CONCLUSION: This study identified variants in the gene within Chinese families, expanding the variant spectrum of DEB. These findings lay the groundwork for improved genetic diagnosis and counseling.
Expanding the Clinical Spectrum of RERE-Related Disorders: A Case Report of Neurodevelopmental Disorder with Brain Malformations Including Chiari Type I.
Pachajoa H, Gutierrez-Obando AM, Leal AF
Mol Syndromol · 2025 Dec · PMID 41669386 · Full text
INTRODUCTION: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) is a rare genetic condition caused by heterozygous pathogenic variants in the gene, which encodes a transcriptiona...
INTRODUCTION: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) is a rare genetic condition caused by heterozygous pathogenic variants in the gene, which encodes a transcriptional co-repressor essential for embryonic development. Most reported cases result from de novo variants and show a broad spectrum of neurodevelopmental and structural abnormalities. This report expands the phenotypic spectrum of NEDBEH by describing the first association with a Chiari type I malformation. CASE PRESENTATION: We report a 26-year-old Colombian male presenting with global developmental delay, progressive spasticity, mild dysmorphic features and a Chiari type I malformation, a finding not previously linked to variants. Whole-exome sequencing identified a heterozygous de novo missense variant in (NM_001042681.3:c.815A>G; p.Tyr272Cys), initially classified as a variant of uncertain significance but supported as likely pathogenic according to ACMG criteria (PP3, PM2). The gene functions as a retinoic acid-dependent transcriptional cofactor, a pathway critical for hindbrain segmentation and morphogenesis, providing a plausible mechanism for the cerebellar anomaly observed. CONCLUSION: This case broadens the clinical spectrum of -related NEDBEH, suggesting potential cerebellar involvement secondary to disrupted retinoic acid signaling. It emphasizes the importance of genomic testing for patients with neurodevelopmental delay and structural brain malformations, enabling accurate diagnosis, genetic counseling, and deeper understanding of rare developmental disorders.
Clinical Exome Sequencing as a Key Diagnostic Tool: A Rare de novo Variant in Dizygotic Twins.
Bouchahta H, Sahli M, Amllal N … +3 more , Ouhenach M, Sbabou L, Sefiani A
Mol Syndromol · 2026 Jan · PMID 41657762 · Full text
INTRODUCTION: -associated neurodevelopmental disorders are rare genetic conditions caused by pathogenic variants in the gene, which plays a crucial role in neuronal development. Mutations in the gene are increasingly a...
INTRODUCTION: -associated neurodevelopmental disorders are rare genetic conditions caused by pathogenic variants in the gene, which plays a crucial role in neuronal development. Mutations in the gene are increasingly associated with autosomal dominant inheritance. However, de novo occurrences in dizygotic twins remain rare and poorly understood. CASE PRESENTATION: In this work, clinical exome sequencing (CES) was performed on dizygotic twin sisters who presented with neurodevelopmental delay, intellectual disability, behavioral issues, and microcephaly. Segregation analysis using conventional Sanger sequencing was conducted on the parents to assess the inheritance pattern. A pathogenic missense variant c.4283G>A (p.Arg1428Gln) in the GEFD1 domain of the gene was identified. This variant is known to reduce GEF activity toward Rac1, impacting neuronal signaling pathways. Segregation analysis did not detect the variant in the parents, and mosaicism remains a possibility that could not be fully ruled out due to the limitations of this technique. Despite the lack of a definitive molecular diagnosis in the parents, detailed genetic counseling was provided to the family. CONCLUSION: These findings highlight the diagnostic value of CES in rare neurodevelopmental disorders and suggest a plausible but unproven parental germline or early postzygotic mosaic event, while acknowledging alternative explanations.
Diagnostic Utility of Optical Genome Mapping in X-Linked Dominant Genodermatoses: Incontinentia Pigmenti and CHILD Syndrome.
Vergara A, Monge I, Garoz BF … +4 more , Ruiz S, Alonso M, Torrelo A, Ortiz Cabrera NV
Mol Syndromol · 2025 Dec · PMID 41625319 · Full text
INTRODUCTION: Incontinentia pigmenti and CHILD syndrome are genodermatoses characterized by an X-linked dominant inheritance pattern, resulting from pathogenic variants in the and genes, respectively. METHODS: This stu...
INTRODUCTION: Incontinentia pigmenti and CHILD syndrome are genodermatoses characterized by an X-linked dominant inheritance pattern, resulting from pathogenic variants in the and genes, respectively. METHODS: This study examines 3 pediatric patients exhibiting a compatible phenotype with inconclusive genetic studies, aiming to evaluate the diagnostic utility of optical genome mapping (OGM) in detecting alterations that could elucidate these conditions. RESULTS: The identified structural variants consisted of deletions of varying sizes in the Xq28 cytoband, encompassing regions that contain exons. CONCLUSION: OGM demonstrates advantages over other techniques for identifying structural variants. This observation highlights how advancements in cytogenomics enhance the resolution with which cases previously inaccessible through conventional cytogenetics can now be investigated.
A Case of -Associated Kenny-Caffey Syndrome Type 2 with New Clinical Features: Microtia, Lacunar Skull Appearance, and Arnold-Chiari Malformation.
Doğan Arı AB, Türkyılmaz A, Keçeli AM … +2 more , Önen M, Kılıç E
Mol Syndromol · 2025 Dec · PMID 41607649 · Full text
INTRODUCTION: Kenny-Caffey syndrome type 2 (KCS2, #OMIM127000) is an extremely rare skeletal dysplasia characterized by characteristic facial features, relative macrocephaly, short stature, hypoparathyroidism, hypocalcem...
INTRODUCTION: Kenny-Caffey syndrome type 2 (KCS2, #OMIM127000) is an extremely rare skeletal dysplasia characterized by characteristic facial features, relative macrocephaly, short stature, hypoparathyroidism, hypocalcemia, cortical thickening of tubular bones, and medullary stenosis. It is caused by the Family with Sequence Similarity 111 Member A () gene. CASE PRESENTATION: Herein, we report a 7-year-old boy with microphthalmia, delayed anterior fontanelle closure, short stature, hypoparathyroidism, hypocalcemia, cortical thickening of tubular bones, and medullary stenosis. The presented patient had microcephaly, maculopathy, and craniosynostosis as rare distinct features. Microtia, lacunar skull appearance, and Arnold-Chiari malformation were present only in the reported patient. A diagnosis of KCS2 was considered with the clinical and radiological findings. Whole-exome sequencing identified a heterozygous pathogenic hotspot variant, c.1706G>A p.Arg569His (NM_001312909.2), in the gene. CONCLUSION: Accurate diagnosis plays a critical role in enhancing clinical awareness, improving patient management, and offering appropriate genetic counseling for affected families.
Symptomatic Benefit of Acetyl-DL-Leucine for Cerebellar Ataxia in Juvenile Tay-Sachs Disease: A Pediatric Case and Literature Review.
Calisgan K, Aghakıshılı HB, Soylu EI … +5 more , Col TA, Cansever MS, Zubarioglu T, Aktuglu Zeybek AC, Kiykim E
Mol Syndromol · 2025 Dec · PMID 41607648 · Full text
INTRODUCTION: Juvenile Tay-Sachs disease (TSD) is a GM2 gangliosidosis that commonly progresses with cerebellar ataxia, while evidence for symptomatic therapies remains limited. Acetyl-leucine has shown short-term benefi...
INTRODUCTION: Juvenile Tay-Sachs disease (TSD) is a GM2 gangliosidosis that commonly progresses with cerebellar ataxia, while evidence for symptomatic therapies remains limited. Acetyl-leucine has shown short-term benefit for ataxia in several lysosomal storage disorders, but pediatric data in GM2 gangliosidosis are scarce. We report a child with juvenile TSD treated off-label with racemic acetyl-dl-leucine (ADLL) and review the related literature. CASE PRESENTATION: A six-year-old girl with previously normal early development was referred for autism spectrum features and a strong family history of metabolic disease. During follow-up, she developed seizures and neurodevelopmental regression, and juvenile TSD was diagnosed by molecular analysis and confirmed by enzymatic testing. Progressive cerebellar ataxia subsequently developed, and ADLL was initiated off-label for symptomatic treatment. After 6 months, ataxia improved clinically, with the Scale for the Assessment and Rating of Ataxia score decreasing from 29 to 25. The family reported better gait stability and increased participation in daily life, and no adverse effects were reported. CONCLUSION: Consistent with emerging data in GM2 gangliosidoses and other lysosomal storage disorders, this case supports the use of ADLL as a potential symptomatic treatment for progressive cerebellar ataxia in juvenile TSD. ADLL was well tolerated and was associated with clinically meaningful improvements in gait, daily participation, and ataxia scores. These findings add pediatric support to the growing evidence that ADLL may be used safely as symptomatic therapy in TSD-related ataxia.
A Novel Inflammatory Autoimmune-Like -Associated Phenotype in an Adult Man.
Karabinos A, Tomkova E, Sprincova A … +4 more , Tothova K, Repiska V, Jesenak M, Krizan P
Mol Syndromol · 2025 Dec · PMID 41584031 · Full text
INTRODUCTION: Neurotrophic tyrosine receptor kinase 1 () encodes a 796 amino-acid-long transmembrane nerve growth factor (NGF) receptor, which is abundantly expressed in neuromuscular tissues. Deficiency of is typically...
INTRODUCTION: Neurotrophic tyrosine receptor kinase 1 () encodes a 796 amino-acid-long transmembrane nerve growth factor (NGF) receptor, which is abundantly expressed in neuromuscular tissues. Deficiency of is typically clinically presented as autosomal recessive infantile congenital insensitivity to pain with anhidrosis (CIPA), characterized by decreased pain and temperature perception, anhidrosis, and, sometimes an intellectual disability and a premature death. So far, over 170 different mutations have been reported in the literature, including the missense disease-causing variants p.R748W. CASE PRESENTATION: In this case report, we present a 40-year-old man with CIPA based on the known and novel heterozygous p.R748W and c.575-15G>A mutation, respectively. This man exhibited progressive arthralgias, bursitis, folliculitis, fatigue, and pancreatitis with a slight variation of some immunological parameters that started about 3 years ago after vaccination. CONCLUSION: The finding of an inflammatory autoimmune-like disease in the presented 40-year-old patient with a normal intelligence and a reduced sweating and pain sensation indicates that this phenotype represents, besides the typical serious infantile CIPA, a novel adult-onset clinical expression of the -induced disease. In addition, the data here also support the recent suggestion that the defective NGF signaling of the neural, immune, and endocrine systems in CIPA may link this congenital disease to autoimmunity.
New Insights into the Relation between Cognition, Behavior, and the Gene: A Case-Report of an Adult Male with Parenti-Mignot Neurodevelopmental Syndrome.
Melgers C, Roelofs R, van Bon B … +3 more , Wingbermühle E, Pfundt R, Egger JIM
Mol Syndromol · 2025 Dec · PMID 41584030 · Full text
INTRODUCTION: Parenti-Mignot neurodevelopmental syndrome is caused by pathogenic variants of the gene - involved in brain development - and is characterized by developmental delay, intellectual disability, and behaviora...
INTRODUCTION: Parenti-Mignot neurodevelopmental syndrome is caused by pathogenic variants of the gene - involved in brain development - and is characterized by developmental delay, intellectual disability, and behavioral disturbances (i.e., autism spectrum disorder or related social problems, obsessive-compulsive tendencies, and aggressive behavior) as well as subtle facial dysmorphisms, epilepsy, hypotonia, and craniosynostosis. To date, cognition, behavior, and psychopathology in patients are either scarcely studied (in children, adolescents, and young adults) or not studied at all. Therefore, this case report aimed to provide additional insights into the cognitive and behavioral phenotype of Parenti-Mignot neurodevelopmental syndrome and discuss possibilities for support and treatment. CASE PRESENTATION: This study presents the case of a 54-year-old male with Parenti-Mignot neurodevelopmental syndrome (nonsense variant in the gene), who struggles with mood problems and aggressive behaviors. Intelligence, cognitive functioning, and psychopathology are described by using neuropsychological assessment. Moderate to mild intellectual disability was found. Levels of adaptive functioning and performance on measures of attention, executive functioning, and memory were within the expected range considering intelligence level, whereas social cognition constituted a weakness within the profile. Additionally, results indicated internalizing and externalizing behavioral problems and deficits in emotion regulation skills. CONCLUSION: It is hypothesized that behavioral disturbances of patients with the Parenti-Mignot neurodevelopmental syndrome are likely to result from an underlying cognitive profile that is characterized by low intelligence, social cognitive impairments, and poor emotion regulation. involvement in cortical brain development may be an explanation for these cognitive deficits. In clinical practice, neuropsychological assessment can provide helpful pointers for treatment and support in daily functioning.
Identification of miRNAs Associated with Infantile-Onset Pompe Disease.
Bayrak H, Tosun F
Mol Syndromol · 2025 Nov · PMID 41552667 · Full text
INTRODUCTION: Infantile-onset Pompe disease (IOPD), which presents with a broad spectrum of nonspecific findings in newborns and lacks a clearly defined clinical picture, is a significant factor that delays patients' acc...
INTRODUCTION: Infantile-onset Pompe disease (IOPD), which presents with a broad spectrum of nonspecific findings in newborns and lacks a clearly defined clinical picture, is a significant factor that delays patients' access to diagnosis and treatment. In this disease, insufficient diagnosis rates, low levels of clinical suspicion, and delays in diagnosis are the main problems that hinder early and accurate diagnosis. This study aims to address diagnostic and therapeutic challenges by elucidating the functional roles and associations of microRNAs (miRNAs) in the pathogenesis of IOPD. As a result of comparative data analysis, an inventory of known and novel miRNA sequences predicted to target pathogenic pathways associated with IOPD was established. METHODS: In this study, IOPD and control samples from GSE38680 data were normalized on the Affymetrix platform. Differential gene expression analysis was performed using the limma package, and common differentially expressed (DEGs) were identified. Subsequently, significant signaling pathways were identified using WebGestalt and Reactome, Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases, and the false discovery rate (FDR) correction was applied. Finally, miRNA expression analysis and miRNA interactions associated with IOPD genes were examined using R packages such as miRNATap and multiMiR. RESULTS: In this study, 1,967 DEGs (1,108 upregulated, 859 downregulated) were identified in the GSE38680 data. GO and KEGG analyses revealed biological processes associated with IOPD, particularly muscle function and the lysosome pathway. In the analysis of miRNAs associated with the DEGs, 10 miRNAs were predicted to bind directly to the 3'-untranslated region (UTR) of the gene. CONCLUSION: Early diagnosis is critical to prevent or mitigate irreversible organ damage associated with the progression of IOPD, and circulating miRNAs may serve as additional biomarkers for diagnosis, disease severity, and treatment response. This study used high-throughput technology to identify potential miRNAs for IOPD.
Erratum.
Mol Syndromol · 2026 Jun · PMID 41510140 · Full text
[This corrects the article DOI: 10.1159/000540925.].
[This corrects the article DOI: 10.1159/000540925.].
Characterisation of Type-1 Fibrillinopathies in a Sri Lankan Cohort: Genotype-Phenotype Correlations and Novel FBN1 Variants.
Kolambage YD, Cooray AL, Priyawansha YGT … +3 more , Hendalage DPB, Liyanage UA, Dissanayake VHW
Mol Syndromol · 2025 Nov · PMID 41502793 · Full text
INTRODUCTION: Type-1 fibrillinopathies, caused by pathogenic variants in the gene, show complex genotype-phenotype correlations. Studying these patterns in under-researched populations like Sri Lanka can provide valuabl...
INTRODUCTION: Type-1 fibrillinopathies, caused by pathogenic variants in the gene, show complex genotype-phenotype correlations. Studying these patterns in under-researched populations like Sri Lanka can provide valuable insights into their genetic basis. The objective of this study was to analyse genotype-phenotype correlations in Sri Lankan patients with type-1 fibrillinopathies. METHODS: The genotype and clinical data of all patients undergoing exome sequencing in our centre have been maintained in a database since 2014. In January 2024, this database was searched to identify all patients who were reported to have variants in the (NM_000138.5) gene. The genotype and phenotype data of these patients were analysed using bioinformatics tools and standard descriptive statistics. RESULTS: There were 12 unrelated patients. A total of 6 (50%) were male. Age ranged from 1 to 18 years. All were sporadic and had a distinct heterozygous variant. The phenotype found in these patients together with the associated genotype was as follows: Marfan syndrome - 6 (50%) [c.7487G>C, c.6496G>A, c.4245delT, c.3037G>A, c.2797_2807delTTCAAGTGTCA, c.3472G>A]; MASS syndrome - 5 (41.7%) [c.2926C>T, c.2419G>A, c.5674A>G, c.3338-1G>C, c.3089A>G]; and ectopia lentis syndrome - 1 (8.3%) [c.355T>G]. Four (33.3%) variants were novel. Frameshift and splice-site variants were associated with pronounced skeletal and facial dysmorphic features. However, neonatal region variants did not consistently cause severe disease. CONCLUSIONS: This is the first study to report type-1 fibrillinopathies in the Sri Lankan population. The lack of strong genotype-phenotype correlation suggests the possibility of other genetic modifiers in the Sri Lankan population.
Molecular and Clinical Profiles of Patients with RASopathies: Targeted Next-Generation Sequencing Panel Results and Identification of 14 Novel Disease-Causing Variants.
Ates K, Ozturk M, Esener Z … +10 more , Dogan M, Gezdirici A, Sarac H, Yeninarcilar B, Fettahlioglu A, Camtosun E, Dundar I, Güngör S, Ozgor B, Tekedereli I
Mol Syndromol · 2025 Nov · PMID 41496802 · Full text
INTRODUCTION: RASopathies are among the most prevalent genetic syndromes caused by variants in the Ras/MAPK signaling pathway, affecting various systems such as the heart, craniofacial features, skin, musculoskeletal sys...
INTRODUCTION: RASopathies are among the most prevalent genetic syndromes caused by variants in the Ras/MAPK signaling pathway, affecting various systems such as the heart, craniofacial features, skin, musculoskeletal system, hearing, and vision. They can also increase the risk of secondary malignancies. Despite clinical overlaps, distinguishing features are crucial for diagnosis, as different variants lead to distinct clinical implications. This study reviews the molecular and clinical characteristics of RASopathies, focusing on neurofibromatosis type 1 (NF1) and non-NF1 RASopathies. METHODS: The study analyzed 76 patients referred to our outpatient clinic over a 6-year period, all of whom were clinically diagnosed with RASopathy and confirmed in most cases by molecular testing. Patient files, clinical photographs, and laboratory results were reviewed and analyzed. A targeted multigene next-generation sequencing panel test was performed, followed by Sanger sequencing for both confirmation and segregation analysis. Multiplex ligation-dependent probe amplification was conducted in a patient with normal sequence results but strong clinical suspicion, to identify potential deletions. RESULTS: We identified 44 pathogenic, 25 likely pathogenic variants, and 6 variants of uncertain significance based on American College of Medical Genetics and Genomics (ACMG) criteria. Among these, 14 novel variants were found - 13 in the gene and one in . variants were present in 51 cases. Additional variants, likely to represent clinically significant findings, were identified in ( = 11), ( = 4), ( = 3), RIT1 ( = 3), ( = 1), ( = 1), ( = 1), and ( = 1). Diagnoses included 49 patients with NF1, 21 with Noonan syndrome, 2 with neurofibromatosis-Noonan syndrome, 2 with Noonan syndrome with multiple lentigines, and 1 with cardiofaciocutaneous syndrome. Here, 12% of variants were located in exon 21, 36% of variants in exon 3, and 75% of variants in exon 7. CONCLUSION: RASopathies have a broad molecular and clinical spectrum, complicating diagnosis and management. Accurate clinical correlation and molecular analysis are essential, as different RASopathy syndromes can result from variants in the same genes, while the same syndrome may arise from different genetic alterations. This study identifies novel variants and emphasizes the need for precise diagnostic approaches in these complex disorders.
CAPOS and Beyond: Variants in Pediatric Movement Disorders - Case Reports.
Yanartaş MS, Köken ÖY, Ceylan AC … +3 more , Bozacı AE, Kara TT, Haspolat Ş
Mol Syndromol · 2025 Nov · PMID 41480049 · Full text
INTRODUCTION: -related disorders encompass a clinically heterogeneous spectrum that includes previously defined dominantly inherited phenotypes such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-park...
INTRODUCTION: -related disorders encompass a clinically heterogeneous spectrum that includes previously defined dominantly inherited phenotypes such as alternating hemiplegia of childhood (AHC), rapid-onset dystonia-parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome, as well as more complex and overlapping presentations. CASE PRESENTATION: In this study, we present 2 pediatric cases that expand the phenotypic and genotypic spectrum of -associated disease. Both patients presented with "Guillain-Barré syndrome (GBS)-like episodes" characterized by acute-onset encephalopathy, ataxia, areflexia, and sensorimotor deterioration following febrile infections. Prominent paroxysmal postural abnormalities and dystonia were noted in both cases; however, the overall clinical features blurred the classical boundaries between CAPOS and other -associated phenotypes. The first patient carried the previously reported heterozygous (NM_001256214.2):c.2491G>A(p.Glu831Lys) variant, classically associated with CAPOS, and also exhibited sensorineural hearing loss with a positive family history. The second patient harbored a novel (NM_152296.5):c.2266C>T p.(Arg756Cys)(Clinvar: VCV000425189.38) variant and displayed oculomotor apraxia and chorea during episodes. CONCLUSION: These cases underscore the importance of considering variants in children presenting with GBS-like features, infection-triggered neurological attacks, and mixed movement disorders. Our findings highlight the diagnostic value of genetic testing in atypical neuroregression syndromes and contribute to the recognition of "blended" phenotypes beyond classical diagnostic entities. The novel pathogenic variant further supports ongoing efforts to refine genotype-phenotype correlations within this evolving group of neurological disorders.
Bathrocephaly and Serpentine Fibula as Underrated Features of Osteogenesis Imperfecta Type I: A Case Report.
de Freitas Netto F, de Oliveira Sobrinho RP, de Almeida TF … +2 more , Steiner CE, Brazilian Rare Genomes Project Consortium
Mol Syndromol · 2025 Nov · PMID 41450726 · Full text
INTRODUCTION: Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias characterized mainly by bone fragility and propensity to fractures. The most common forms include classic types I, II, III...
INTRODUCTION: Osteogenesis imperfecta (OI) comprises a heterogeneous group of skeletal dysplasias characterized mainly by bone fragility and propensity to fractures. The most common forms include classic types I, II, III, and IV, according to the classification of Sillence, caused by variants in the or genes. This report describes a case series of patients with OI type I confirmed by whole genome sequencing, highlighting the clinical and radiological manifestations of one atypical family. CASE PRESENTATION: Six individuals (1M:5F), aged 8 months to 34 years at their first consultation, were enrolled. All were clinically classified as OI type I due to the presence of osteopenia associated with blue sclerae and bone fractures; four presented with short stature, two with hearing loss, and one with fragile teeth; molecular testing confirmed that all presented with heterozygous pathogenic or likely pathogenic variants in the gene. In one family, an unusual presentation was observed in the patient and her daughter, both of whom presented with severe short stature (Z-score <-6), abnormal skull shape (bathrocephaly), codfish vertebrae, bowing of the long bones in the lower limbs, and serpentine fibulas. CONCLUSION: Bathrocephaly and serpentine fibula are rarely reported in classical OI types and are more frequently associated with other skeletal dysplasias, such as Hajdu-Cheney syndrome. This case report highlights the importance of recognizing underrated manifestations in OI and underscores the need for molecular confirmation.
-Related Phenotypes due to Germline and Somatic Mosaic Variants: A two-Case Report.
Acikgoz NB, Yildiz D, Urel-Demir G … +2 more , Utine GE, Simsek-Kiper PO
Mol Syndromol · 2025 Nov · PMID 41439243 · Full text
OBJECTIVE: Somatic mosaic activating variants are a well-established cause of segmental overgrowth phenotypes, whereas germline variants are rare and clinically heterogeneous. We report 2 unrelated patients - 1 with a...
OBJECTIVE: Somatic mosaic activating variants are a well-established cause of segmental overgrowth phenotypes, whereas germline variants are rare and clinically heterogeneous. We report 2 unrelated patients - 1 with a somatic mosaic and 1 with a de novo germline variant - with longitudinal clinical follow-up. CASE PRESENTATION: Patient 1 carried NM_006218.4:c.1412C>T; p.(Pro471Leu) in the C2 domain and presented with macrocephaly, generalized overgrowth, epilepsy, and structural brain anomalies; mosaicism was supported by an attenuated mutant signal on Sanger sequencing. Patient 2 harbored a de novo NM_006218.4:c.323G>A; p.(Arg108His) in the N-terminal p85-binding region and showed macrocephaly, attention-deficit/hyperactivity disorder, and mitral annular disjunction/mitral valve prolapse with aortic root dilatation. CONCLUSION: These 2 cases illustrate -related phenotypes arising from somatic mosaic and germline contexts and document their clinical course over time. Larger, well-characterized cohorts and complementary functional assays are needed to refine genotype-phenotype relationships, inform clinical care, and evaluate targeted therapies.
Prenatally Diagnosed De Novo Interstitial Duplication in 2p21p24.3 with Unique Manifestations: Case Report.
Kablan A, Sezer A, Bakir A … +2 more , Kolkiran A, Saat H
Mol Syndromol · 2025 Nov · PMID 41415324 · Full text
INTRODUCTION: Partial duplications involving chromosome 2p are rare genomic events associated with variable phenotypic outcomes, ranging from craniofacial abnormalities, organ malformations to developmental delays. Prena...
INTRODUCTION: Partial duplications involving chromosome 2p are rare genomic events associated with variable phenotypic outcomes, ranging from craniofacial abnormalities, organ malformations to developmental delays. Prenatal identification of such duplications has become increasingly common with advances in chromosomal microarray technology, but predicting postnatal manifestations remains challenging. This report presents a de novo 32 Mb duplication of 2p21p24.3, detected prenatally, in a male patient who demonstrated unique clinical features and multisystem involvement postnatally. CASE PRESENTATION: A 29-year-old pregnant female was referred for genetic evaluation following prenatal detection of flat nasal bridge, frontal bossing, short extremities, micropenis, and suspected hypospadias. Chromosomal microarray analysis revealed a 32 Mb duplication of 2p21p24.3, confirmed as de novo by parental testing. Postnatally novel features such as subglottic haemangioma, preauricular pit, and behavioural symptoms related to facial contact were noted. Growth delay, craniofacial dysmorphism, congenital heart defects, and genital anomalies were also observed. A multidisciplinary approach involving clinical genetics was critical for addressing the patient's complex medical needs. Despite ongoing supportive care, the patient continues facing significant developmental and medical challenges, underscoring the need for long-term follow-up as well as genotype-phenotype correlations. CONCLUSION: This case broadens the clinical spectrum of partial trisomy 2p by documenting unique features, including subglottic haemangioma, behavioural symptoms, and preauricular pit. It highlights the value of integrating prenatal diagnostics with detailed postnatal phenotypic assessment to improve understanding of genotype-phenotype correlations in rare chromosomal duplications. Although the gene within the region is considered a plausible candidate for explaining some of the patient's cardinal features, dysmorphism (prominent forehead, preauricular ear pits, low-set, posteriorly rotated ears), cardiac-neurological problems, other genes associated with defined syndromes - whose clinical manifestations overlap to varying degrees - were also considered as potential contributors to the clinical picture, such as , , , and . These insights can aid clinicians in genetic counselling, anticipatory guidance, and management of similar cases in the future.
Identification of Novel and Recurrent Gene Mutations in Two Unrelated Turkish Families with Isolated Ectopia Lentis: A Case Report with Insights from a Literature Review.
Heidargholizadeh GS, Sharifi S, Palanduz S … +1 more , Nazemi A
Mol Syndromol · 2025 Nov · PMID 41409312 · Full text
INTRODUCTION: This study aimed to identify the potential genetic defects underlying familial clustering of lens dislocation in two unrelated Turkish families, consistent with the clinical features of isolated ectopia len...
INTRODUCTION: This study aimed to identify the potential genetic defects underlying familial clustering of lens dislocation in two unrelated Turkish families, consistent with the clinical features of isolated ectopia lentis (IEL). The investigation seeks to determine whether the detected findings overlap with those observed in other syndromic conditions that present with lens dislocation. Additionally, a focused review of IEL within the scientific literature was conducted to contextualize the molecular and phenotypic spectrum associated with lens abnormalities. The results of this study are expected to contribute to a deeper understanding of the molecular basis of IEL and to enhance diagnostic precision, genetic counseling, and clinical management strategies for affected individuals. CASE PRESENTATION AND CONCLUSION: Comprehensive family histories and clinical evaluations revealed lens dislocation and associated ocular manifestations without systemic abnormalities or extraocular features suggestive of connective tissue disorders. Whole-exome sequencing (WES) in affected individuals identified two heterozygous missense variants. The first variant, ENST00000316623.5:c.2920C>T, which has been previously reported in the literature, is located within the TB5 domain and was identified in ten affected members of family 1. The second variant, ENST00000316623.5:c.7018T>C, located within the TB9 domain, was identified in a single affected individual from family 2 and is reported here for the first time in association with IEL. Segregation analysis demonstrated that both variants co-segregated with the ectopia lentis phenotype and were completely absent in unaffected family members as well as in WES data from 200 ophthalmologically normal in-house controls. Besides, our study focused review of the literature on -associated IEL revealed that approximately 66.7% of reported variants involve missense substitutions affecting cysteine residues. Our study further reinforces this pattern by identifying two rare missense variants that co-segregate with the phenotype, thereby expanding the known mutational spectrum of IEL. These findings also underscore the phenotypic heterogeneity of IEL, as reflected by the variable age of onset among affected individuals, and emphasize the critical role of domain-specific cysteine-altering mutations in the pathogenesis of IEL.
Esophageal Atresia, an Anomaly of VACTERL Association or Novel Feature of the FGF10 Gene: A Case Report.
Escalante-Reyes M, García-Payá E, Re VA … +3 more , Sirera PS, Navarro de Miguel M, Martínez RS
Mol Syndromol · 2025 Oct · PMID 41409311 · Full text
INTRODUCTION: VACTERL association (VA) is defined as the nonrandom co-occurrence of at least three of the following six features: Vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula...
INTRODUCTION: VACTERL association (VA) is defined as the nonrandom co-occurrence of at least three of the following six features: Vertebral anomalies (V), Anal atresia (A), Cardiac defects (C), Tracheo-esophageal fistula (TE), Renal defects (R), and Limb anomalies (L). The genetic basis of VA remains undiscovered. CASE PRESENTATION: In this study, we report a 22-year-old male patient suspected of VA at birth (TE: esophageal atresia (EA), C: dextrocardia, without heterotaxy, and L: hypoplasia of thumb phalanges). Additionally, the patient presented lacrimal gland aplasia, xerostomia, and pulmonary hypoplasia (PH). Whole exome sequencing identified a novel loss-of-function variant: c.2T>C; p.(Met1Thr). Pathogenic variants in the gene are known causes of lacrimo-auriculo-dento-digital syndrome 3 or aplasia of lacrimal and salivary glands, but their association has been scarcely described in the literature. This variant was also detected in other family members exhibiting a wide range of clinical variability; however, PH and EA were observed only in our index case. CONCLUSION: This report supports the involvement of the gene in EA and PH, and expands the phenotypic spectrum of pathogenic variants. We hypothesize that while contributes to the development of PH or VACTERL association (VA), a yet unidentified second hit is likely necessary.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe