Molecular Syndromology[JOURNAL]
Sun
200 papers
Association of MicroRNA-146a-5p Polymorphism with Cognitive Impairment in Adolescents with Depressive Disorder.
Xie C, Hu Q, Zhang C … +1 more , Deng K
Mol Syndromol · 2025 May · PMID 40475169 · Full text
INTRODUCTION: The incidence of depression in adolescents is increasing and is associated with severe cognitive impairment. This paper aimed to investigate the relationship between polymorphisms in microRNA-146a-5p (miR-1...
INTRODUCTION: The incidence of depression in adolescents is increasing and is associated with severe cognitive impairment. This paper aimed to investigate the relationship between polymorphisms in microRNA-146a-5p (miR-146a-5p) and cognitive impairment in adolescent depression patients. METHODS: Quantitative real-time polymerase chain reaction was used to quantify miR-146a-5p in serum. Detection of miR-146a-5p gene polymorphism was performed by TaqMan SNP Genotyping Assay. Odds ratios and 95% confidence intervals (CIs) were calculated by chi-square test (χ) and logistic regression analysis. RESULTS: Genotyping of miR-146a rs2910164 showed that CC (OR = 0.443, 95% CI, 0.264-0.741, = 0.002) and GC (OR = 0.445, 95% CI, 0.279-0.712, = 0.001) genotype reduced the risk of cognitive impairment in adolescent depression. The C allele (OR = 0.794, 95% CI, 0.694-0.741, = 0.001) was a protective factor for cognitive impairment in adolescent depression compared to the rs2910164 G allele. Rs2910164 (OR = 0.425, 95% CI = 0.273-0.662, = 0.000) showed a negative correlation with adolescents with cognitive impairment in depression by logistic regression analysis. The level of miR-146a-5p was decreased in carriers of the CC and CG genotypes. CONCLUSION: Rs2910164 C allele carriers have a low risk of cognitive impairment in adolescent depression and could reduce miR-146a-5p level.
The Opportunities and Challenges in the Molecular Mechanism Research of Congenital Heart Disease: A Review.
Li M, Wang S, Zhang H … +2 more , Meng B, Wu Y
Mol Syndromol · 2025 May · PMID 40475168 · Full text
BACKGROUND: Advanced molecular mechanism research incorporated with multidisciplinary collaborations on congenital heart disease has prompted new insight into its cause, development, and outcomes. SUMMARY: This literatur...
BACKGROUND: Advanced molecular mechanism research incorporated with multidisciplinary collaborations on congenital heart disease has prompted new insight into its cause, development, and outcomes. SUMMARY: This literature review aims to comprehensively examine the genetic molecular mechanisms of congenital heart disease and explain current prospects and challenges in this field. Through a systematic exploration of etiology, embryology, clinical outcomes, algorithms, and ethics, we seek to shed light on the path toward improved diagnostics, treatments, and outcomes for patients. KEY MESSAGE: Collaboration among genetic researchers, clinicians, data scientists, ethicists, and policymakers is crucial to address challenges and translate research findings into tangible benefits for CHD patients.
Evaluation of Cardiomyopathy-Related Target Genes by Next-Generation Sequencing Method and Investigation of the Phenotype-Genotype Relationship.
Sezginer Guler H, Zhuri D, Yalcintepe S … +7 more , Altay S, Deveci M, Demir S, Gurlertop HY, Atli E, Atli Eİ, Gurkan H
Mol Syndromol · 2025 May · PMID 40475167 · Full text
BACKGROUND: Primary heart muscle diseases called cardiomyopathy (CMP) constitute an important group of subsequent heart disorders. CMPs are basically divided into four subgroups associated with the heart muscle but clini...
BACKGROUND: Primary heart muscle diseases called cardiomyopathy (CMP) constitute an important group of subsequent heart disorders. CMPs are basically divided into four subgroups associated with the heart muscle but clinically distinguishable: hypertrophic CMP (HCM), dilated CMP (DCM), restrictive CMP (RCM), and left ventricular non-compaction CMP. MATERIAL AND METHODS: The results of the patients who applied to the Genetic Diseases Evaluation Center with the preliminary diagnosis of clinical CMP were evaluated retrospectively in the current study. In the current study, 103 cases were included and evaluated for phenotype-genotype association with the CMP next-generation sequencing (NGS) panel. RESULTS: Fifty-eight different variants were identified in 45 patients. Sixteen out of those 58 variants were novel. Of these variants, 19 (32.75%) were likely pathogenic (LP)/pathogenic (P), and 35 (60.34%) were variants of uncertain significance. CONCLUSION: The prevalence of pathogenic variants in target genes associated with CMP is important for our current country's population, and multiple gene groups associated with CMP can be screened through NGS. The contribution rate to the clinical diagnosis was 18.44% in terms of the individual population who applied to our medical genetics center and were compatible with the CMP indication.
A Colombian Boy with a Novel de novo Variant: A Case Report.
Sinisterra-Díaz SE, Vasquez-Forero DM, Ordoñez L … +2 more , Prieto LE, Pachajoa H
Mol Syndromol · 2025 May · PMID 40475166 · Full text
INTRODUCTION: syndrome is a neurodevelopmental disease caused by de novo pathogenic variants in encoding the purine-binding element alpha protein. It is characterized by autosomal dominant inheritance and a heterogeneo...
INTRODUCTION: syndrome is a neurodevelopmental disease caused by de novo pathogenic variants in encoding the purine-binding element alpha protein. It is characterized by autosomal dominant inheritance and a heterogeneous phenotype. CASE PRESENTATION: We describe a 7-year-old patient with history of congenital pneumonia, accompanied by hypotonia, convulsive episodes, poor sucking ability, neurodevelopmental delay. Physical examination revealed some dysmorphic features. Molecular analysis identified a de novo, heterozygous variant in (NM_005859.5): c.692T>C; p.Phe231Ser, which was classified as pathogenic. CONCLUSION: In this report, we present a Colombian case of PURA syndrome. This case highlights the challenges associated with the early diagnosis of a newly described syndrome, in a limited-resources health system.
Distribution of Variants and Identification of Novel Variants in Patients with Obesity Using Next-Generation Sequencing in Genes Associated with Obesity: A Single-Center Experience in Turkey.
Anlas O, Ozalp O, Cetinkunar S
Mol Syndromol · 2025 May · PMID 40475165 · Full text
BACKGROUND: Obesity has become a common public health problem all over the world today. In recent years, studies on the genetic etiology of obesity have gained importance. As a result of these studies, 127 obesity-relate...
BACKGROUND: Obesity has become a common public health problem all over the world today. In recent years, studies on the genetic etiology of obesity have gained importance. As a result of these studies, 127 obesity-related loci have been identified. OBJECTIVES: The aim of this work was to screen obesity-related genes and review the literature. METHODS: In this retrospective study, 41 obesity-related genes were screened in 116 patients by next-generation sequencing. These genes are , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . RESULTS: Seventy-six of our patients were female, and 40 were male. As a result, 43 variants were detected in 39 (34.4%) patients. Of these, c.152G>A, c.496G>A, SH2B1 c.2083G>A, c.548G>A, c.268G>A, and c.5C>T variants have been previously reported in the literature. In addition to the aforementioned variants, there are 37 novel variants that have not been previously reported. Among these, we classified the c.126 + 1G>T variant as "Pathogenic" according to the American College of Medical Genetics and Genomics (ACMG) criteria. Four of 37 novel variants, respectively, c.1160_1163delTTGT (p.Phe387Trp*55), c.895C>T (p.Pro299Ser), c.304C>T (p.Gln102*), and c.265C>T (p.Gln89*), were classified as "Likely Pathogenic." A total of 32 novel variants among 37 novel variants were categorized as variants of uncertain significance. CONCLUSIONS: Understanding the genetics of obesity is an essential step toward treating and preventing this disease, which has become a global health problem. With this study, we wanted to contribute to the literature by reporting previously reported and novel variants we detected in our patients with obesity.
A Novel Variant (c.4354G>A; p. Gly1452Ser) in a Chinese Patient with Developmental Delay, Neurodevelopmental Delay, and Hypotonia.
Zeng L, Nie J, Zhu S … +5 more , Wang J, Deng Y, Zhu H, Wang X, Xi N
Mol Syndromol · 2026 Feb · PMID 40469502 · Full text
INTRODUCTION: Neurodevelopmental disorders (NDDs) due to the (MIM:617245), the pathogenic variant, are extremely rare. HECW2-related disorder has been established through the identification of de novo variants in gene...
INTRODUCTION: Neurodevelopmental disorders (NDDs) due to the (MIM:617245), the pathogenic variant, are extremely rare. HECW2-related disorder has been established through the identification of de novo variants in gene in patients with NDDs with hypotonia, seizures, and absent language. CASE PRESENTATION: In this study, the clinical and genetic features of a Chinese girl with neurodevelopmental delay, developmental language disorder, and hypotonia are described. Trio whole exome sequencing revealed a novel likely pathogenic variant in (exon26: c.4354G>A; p. Gly1452Ser) in the patient, while the variant was absent in her parents with Sanger sequencing. CONCLUSION: Our objective was to identify the potential site of , combined with the literature review, to find the correlation between clinical phenotype and genotype.
Focal Dermal Hypoplasia with Unusual Cardiac Anomalies Presentation: A Report of Two Cases and Literature Review.
Bilgeç N, Gökdemir M, Balasar Ö … +2 more , Bedel FM, Çaksen H
Mol Syndromol · 2026 Apr · PMID 40416445 · Full text
INTRODUCTION: Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is an exceedingly rare multisystemic disease with X-linked dominant inheritance involving meso-ectodermal tissues. FDH is characterized by specif...
INTRODUCTION: Focal dermal hypoplasia (FDH), also known as Goltz syndrome, is an exceedingly rare multisystemic disease with X-linked dominant inheritance involving meso-ectodermal tissues. FDH is characterized by specific cutaneous lesions, ectodermal findings, craniofacial abnormalities, ocular malformations, and limb deformities. Congenital diaphragmatic hernia, urinary anomalies, heart anomalies, lung defects, or central nervous system malformations rarely accompany it. CASE PRESENTATION: We report 2 patients with focal dermal hypoplasia with concurrent cardiac findings and variants. In the first case, hemitruncus, an aortic arch, severe isthmus hypoplasia, and pulmonary arterial hypertension were observed. In the second case, a secundum-type atrial septal defect was observed. CONCLUSION: Genotype-phenotype correlations are limited in the literature. We aimed to establish the genotype-phenotype relationship of the novel variants detected and better understand the correlation between the clinical features of focal dermal hypoplasia and the Wnt signaling mechanism.
D-Bifunctional Protein Deficiency Type III: Two Turkish Cases and a Novel Gene Variant.
Erdal AE, Gürbüz BB, Yavaş AK … +1 more , Kasapkara ÇS
Mol Syndromol · 2026 Feb · PMID 40416444 · Full text
INTRODUCTION: Bi-allelic variants in the 17-hydroxysteroid dehydrogenase type 4 gene () cause the extremely rare autosomal recessive disorder known as peroxisomal D-bifunctional protein deficiency (D-BPD) (#OMIM 261515)....
INTRODUCTION: Bi-allelic variants in the 17-hydroxysteroid dehydrogenase type 4 gene () cause the extremely rare autosomal recessive disorder known as peroxisomal D-bifunctional protein deficiency (D-BPD) (#OMIM 261515). This protein mediates hydration and dehydrogenation in the peroxisomal fatty acid β-oxidation pathway. Because of this, very long-chain fatty acids (VLCFAs), branched fatty acids (pristanic acid), and bile acid components cannot be broken down without it. Clinically, it causes developmental delay with neonatal hypotonia, seizures, and dysmorphic features. The D-BPD is divided into four subtypes according to the region affected by the variant causing the disorder. CASE PRESENTATION: Two newborns presented with severe hypotonia, intractable seizures, and dysmorphic facial features (microretrognathia, hypertelorism). These cases showed high levels of VLCFAs and were diagnosed by next-generation gene sequencing tests. We found a known homozygous variant (c.46G>A/p.Gly16Ser) in the gene of case 1, which had been linked to D-BPD type III before. Case 1 developed adrenal insufficiency during follow-up. In case 2, we discovered a novel homozygous variant (c. 559A>T, p. Ile187Phe) in the gene in exon 8 that led to the development of D-BPD type III. The American College of Medical Genetics and Genomics (ACMG) classifies this missense variant as likely pathogenic. DISCUSSION: The D-BPD type III cases profiled in this report exhibit a severe phenotype, which includes dysmorphic facial features, severe hypotonia, and refractory seizures that manifest from birth. One month after the VLCFAs analysis revealed something suggestive of a peroxisomal disorder, a targeted gene panel analysis could confirm the diagnosis.
A Novel Frameshift Variant Causes GATAD2B-Associated Neurodevelopmental Disorder with Camptodactyly.
Tan CW, Lim JY, Rafi'ee K … +6 more , Goh J, Choong CT, Chao SM, Chang B, Jamuar SS, Tan EC
Mol Syndromol · 2026 Feb · PMID 40371175 · Full text
INTRODUCTION: GATAD2B-associated neurodevelopmental disorder (GAND) is caused by pathogenic variants in which encodes p66beta, a subunit of a transcription repressor. The main presentations of GAND are intellectual disa...
INTRODUCTION: GATAD2B-associated neurodevelopmental disorder (GAND) is caused by pathogenic variants in which encodes p66beta, a subunit of a transcription repressor. The main presentations of GAND are intellectual disability, speech impairment, and dysmorphism. However, these features overlap with other neurodevelopmental syndromes and are not specific enough to be recognised for a particular clinical diagnosis without molecular confirmation. METHODS: Macrocephaly was detected prenatally and at birth. Postnatal brain MRI also revealed ventriculomegaly. Chromosomal microarray analysis and metabolites in plasma, serum, or urine were investigated due to microcephaly and dysmorphism, and all results were normal. Next-generation sequencing using a targeted gene panel did not identify any pathogenic variant. Exome sequencing was subsequently performed. RESULTS: A heterozygous single nucleotide deletion in exon 5 of (p.His216Metfs*24) was detected and Sanger validated. Targeted Sanger sequencing of parental samples showed that it is de novo. CONCLUSION: We describe the first patient with GAND from Southeast Asia with Korean-Chinese parentage. The identification of a pathogenic variant in clarifies her diagnosis and adds to the genotypic and phenotypic spectrum of this disorder. This report illustrates the use of genetic testing to obtain a definite diagnosis.
Siblings with a Homozygous Variant in the Gene: A Case Report and Review of Literature.
Sürücü Kara İ, Duman D, Bademci G … +4 more , Kuloglu Z, Kaynak Sahap S, Tekin M, Eminoğlu FT
Mol Syndromol · 2025 Dec · PMID 40352450 · Full text
INTRODUCTION: Dyskeratosis congenita is a hereditary short telomere syndrome that is characterized by dysplastic nails, reticular pigmentation, oral leucoplakia and may have other progressive systemic manifestations. Her...
INTRODUCTION: Dyskeratosis congenita is a hereditary short telomere syndrome that is characterized by dysplastic nails, reticular pigmentation, oral leucoplakia and may have other progressive systemic manifestations. Here, we report two affected siblings in a family with dyskeratosis congenita. CASE PRESENTATION: A two-year-old girl (index patient) was admitted to our hospital with complaints of inability to walk and decreased vision, as well as developmental delay and cataracts. Her parents were consanguineous, and she had an 18-year-old brother with cataracts, intellectual disability, liver cirrhosis, pancytopenia, and hypersplenism. Magnetic resonance imaging of the brain of the index case revealed hypointense foci in the bilateral basal ganglia, thalamus, and parietal white matter, while the results of detailed metabolic tests were unremarkable. After 8 years of follow-up, the index patient was identified with additional findings that included intellectual disability, liver disease, pancytopenia, nail dystrophy, multiple foci of calcification on magnetic resonance imaging of the brain, while over the past 2 years, her brother developed nail dystrophy, oral leucoplakia, graying hair, and reticular pigmentation on his neck. Genome sequencing revealed a c.415T>C (p.Tyr139His) disease-causing variant in the NHP2 gene in the index case that was heterozygous in the parents and homozygous in the index case and her older brother. CONCLUSIONS: In cases of multisystem involvement, consanguineous marriage, and multiple affected family members, patients may develop very rare diseases, such as dyskeratosis congenita, and physicians should be aware that new clinical findings may emerge during long-term follow-up, the diagnosis of which may count on genome sequencing.
A Patient with Organic Acidemia, Hyperammonemia, and a Variant Suggesting Mitochondrial DNA Depletion Syndrome.
Keser M, Demirci B, Uçar HK … +3 more , Anlaş Ö, Arslan İ, Gürbüz BB
Mol Syndromol · 2026 Feb · PMID 40352449 · Full text
INTRODUCTION: Mitochondrial DNA depletion syndromes encompass rare genetic disorders stemming from various gene defects, including encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), an autosomal recessive conditio...
INTRODUCTION: Mitochondrial DNA depletion syndromes encompass rare genetic disorders stemming from various gene defects, including encephalomyopathic mtDNA depletion syndrome 13 (MTDPS13), an autosomal recessive condition linked to gene variants. Although its prevalence is estimated at 1/100,000-400,000, the mechanism behind MTDPS13 remains incompletely understood. Recent studies suggest variants disrupt mitophagy, contributing to its pathogenesis. CASE PRESENTATION: A 3-year and 4-month-old male presented with respiratory distress, diarrhea, and unconsciousness. His medical history revealed developmental delay and dysmorphic features. Physical examination unveiled characteristic dysmorphisms, while neurological assessment indicated abnormalities. Laboratory findings exhibited metabolic disturbances consistent with MTDPS13, confirmed by genetic analysis revealing a homozygous c.1555C>T variant. CONCLUSION: FBXL4 defects, found in approximately 0.7% of suspected mitochondrial disease cases, lead to varied phenotypes with nonspecific facial dysmorphisms. The patient's presentation aligned with reported features, including growth delay, hypotonia, and developmental delay. Notably, the diagnosis occurred later than typical onset, highlighting the variability in disease manifestation. Treatment focused on symptom management, with dichloroacetic acid effectively addressing lactic acidosis. This case underscores the importance of considering mitochondrial diseases, particularly FBXL4-related MTDPS13, in patients presenting with metabolic disturbances and dysmorphic features. Early recognition facilitates appropriate management and genetic counseling for affected families.
A Novel Homozygous Missense Variant with Protein Modeling in a Patient Diagnosed as Short Stature, Facial Dysmorphism, and Skeletal Anomalies with or without Cardiac Anomalies 2.
Yeter B, Sezgin BI, Dilek YE … +5 more , Kendir Demirkol Y, Selamioğlu A, Kırmızıbekmez H, Kaymakçalan Çelebiler H, Bayram Akçapınar G
Mol Syndromol · 2025 Mar · PMID 40331102 · Full text
INTRODUCTION: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 is a very rare genetic disorder caused by biallelic pathogenic variants in the gene and has been reported in ap...
INTRODUCTION: Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 is a very rare genetic disorder caused by biallelic pathogenic variants in the gene and has been reported in approximately 20 patients to date. SCUBE3 protein exhibits significant expression in various tissues, including primary osteoblasts, long bones, and the cartilage of the axial skeleton throughout development, while also playing a regulatory role in the FGF, Hedgehog, and TGF-β signaling pathways. CASE PRESENTATION: We report a 13-year-old female patient from a consanguineous Turkish family with a novel homozygous missense variant, c.908G>C (p.Cys303Ser) in the gene identified, through exome sequencing. The patient exhibited prenatal growth retardation, short stature, microcephaly, distinctive facial traits, such as long face, high arched eyebrows, epicanthus, blepharoptosis, hypotelorism, high nasal bridge, micrognathia, and large ears, dental anomalies, and skeletal abnormalities, including scoliosis, eleven pairs of ribs, mild radial bowing, irregular endplates in the lower thoracic vertabrae, and narrow iliac wings. CONCLUSION: Protein modeling using AlphaFold3 revealed disruption of a critical disulfide bridge within the seventh epidermal growth factor-like repeat, likely affecting protein stability. In this study, we aimed to further characterize the clinical, radiological, and molecular features of this disorder with protein modeling.
Clinical Characterization and Cytogenetic-Molecular Study of a Patient with a Ring Chromosome 12.
da Nóbrega VA, Dos Santos GR, Melaragno MI … +1 more , Maia RE
Mol Syndromol · 2025 Dec · PMID 40331101 · Full text
INTRODUCTION: Ring chromosomes generally result from the fusion of breaks at the ends of both arms of a chromosome, typically leading to the loss of genetic material from these ends. CASE PRESENTATION: We report the case...
INTRODUCTION: Ring chromosomes generally result from the fusion of breaks at the ends of both arms of a chromosome, typically leading to the loss of genetic material from these ends. CASE PRESENTATION: We report the case of a four-year-old patient who exhibits multiple café-au-lait spots, hypochromic spots, bitemporal narrowing, bilateral epicanthus, patent foramen ovale, and multiple brain abnormalities identified through magnetic resonance imaging. Karyotyping revealed a ring chromosome: r(12). Chromosomal microarray analysis revealed a ∼3.6 Mb deletion in the short arm and a ∼1.2 Mb deletion in the long arm of chromosome 12. The patient's phenotype is consistent with these genetic imbalances. To investigate ring chromosome instability and mosaicism, 200 metaphases were analyzed using G-banding and FISH with a whole chromosome painting probe, identifying 166 cells with a 46,XX,r(12) karyotype, 20 cells with monosomy 12, eight with a dicentric ring chromosome, three with two monocentric rings, two with two interlocked dicentrics, and one with an open ring chromosome. CONCLUSION: This study provided a detailed characterization of the ring rearrangement of chromosome 12, the first with SNP array, enhancing the understanding of its genetic and phenotypic implications and contributing to expanding knowledge about this condition. Additionally, the findings can aid in better understanding the patient's prognosis, clinical follow-up, and genetic counseling.
Erratum.
Mol Syndromol · 2025 May · PMID 40331100 · Full text
[This corrects the article DOI: 10.1159/000543315.].
[This corrects the article DOI: 10.1159/000543315.].
A Novel de novo Exceptional Complex Chromosomal Rearrangement Involving 5 Chromosomes Resulting in Neurodevelopmental Delay and Dysmorphism.
Aynacı S, Kocagil S, Yarar C … +4 more , Tosumoğlu E, Gökalp EE, Mutlu MB, Artan S
Mol Syndromol · 2025 Dec · PMID 40331099 · Full text
INTRODUCTION: Complex chromosomal rearrangements (CCRs) are constitutive structural aberrations involving three or more chromosomal breaks on three or more chromosomes resulting from complex events such as fork stalling...
INTRODUCTION: Complex chromosomal rearrangements (CCRs) are constitutive structural aberrations involving three or more chromosomal breaks on three or more chromosomes resulting from complex events such as fork stalling and template switching, microhomology-mediated break-induced repair, or breakage-fusion-bridge cycles. CASE PRESENTATION: Here we report an 11-year-old female that was referred to our outpatient clinics for learning disability and dysmorphic features. Due to clinical findings, karyotype analysis was done initially, and a CCR involving five chromosomes was detected. Fluorescence in situ hybridization (FISH) analysis and chromosomal microarray analysis were done subsequently. Balanced translocations were observed between chromosomes 1, 5, 7, and 10, a balanced paracentric inversion of chromosome 2, and two interstitial deletions in the long arm of the chromosome 5. Optical genome mapping was done to further investigate this exceptional CCR and a paracentric inversion that was associated with the two interstitial deletions was detected in the long arm of chromosome 5. CONCLUSION: Molecular cytogenetic techniques, such as microarray and FISH, are essential for detecting copy number variations at CCRs that appear to be balanced by karyotyping. Nonetheless, optical genome mapping enhances the resolution offering a valuable complement to traditional cytogenetic techniques.
Phenotypic Delineation of Combined Oxidative Phosphorylation Deficiency-12: Clinical Features of 2 Patients.
Bahar Ister M, Cinar M, Ceylaner S … +1 more , Uzun OU
Mol Syndromol · 2025 Apr · PMID 40176842 · Full text
INTRODUCTION: Combined oxidative phosphorylation deficiency-12 (COXPD12) is a rare autosomal recessive disorder. Neurological findings and lactic acidosis can be presenting signs of COXPD12. CASE PRESENTATION: Here, we p...
INTRODUCTION: Combined oxidative phosphorylation deficiency-12 (COXPD12) is a rare autosomal recessive disorder. Neurological findings and lactic acidosis can be presenting signs of COXPD12. CASE PRESENTATION: Here, we present identical dysmorphic facial features that have not been described before in the literature, in 2 patients with two different gene variants. Case 1 was a 2.5-month-old male who presented with hypotonia and lactic acidosis. Cranial magnetic resonance imaging (MRI) showed diffusion restriction in the supratentorial deep white matter, around the ventricle, in the bilateral periaqueductal gray matter at the level of the basal ganglia, and in the dentate nuclei in the tegmentum. Case 2 was a 2-month-old boy who also presented with lactic acidosis and hypotonia. Diffusion MRI reported hypomyelination. Dysmorphic facial features including slight metopic ridge, ptosis, wide palpebral fissure length, sparse eyebrows, bulbous nose, thin upper lip, full cheeks, small chin, large ears, thin ear helix, and prominent antihelix were common findings in both patients. Molecular genetic analysis indicated c.319C>T(p. Arg107Cys) common genetic variant in our 2 patients. In case 2, the second allele was a novel genetic variant. CONCLUSION: For COXPD12 disease, facial features are considered the main diagnostic clue, such as hypotonia or lactic acidosis; thus, the characteristic facial phenotype will help clinicians diagnose the disease.
Exploring the Genetic Etiology of Pediatric Epilepsy: Insights from Targeted Next-Generation Sequence Analysis.
Ozturk O, Ozturk M, Ates K … +6 more , Esener Z, Erguven NN, Ozgor B, Gungor S, Sigirci A, Tekedereli I
Mol Syndromol · 2025 Apr · PMID 40176841 · Full text
INTRODUCTION: Epilepsy is a group of neurologic disorders with clinical and genetic heterogeneity. Epilepsy often affects children; thus, early diagnosis and precise treatment are vital to protecting the standard of life...
INTRODUCTION: Epilepsy is a group of neurologic disorders with clinical and genetic heterogeneity. Epilepsy often affects children; thus, early diagnosis and precise treatment are vital to protecting the standard of life of a child. Progress in epilepsy-related gene discovery has caused enormous novelty in specific epilepsy diagnoses. Genetic testing using next-generation sequencing is now reachable, leading to higher diagnosis ratios and understanding of the disease's underlying mechanisms. The study's primary aim was to identify the genetic etiology based on targeted next-generation sequence analysis data and to calculate the diagnostic value of the epilepsy gene panel in the 0-17 age-group diagnosed with epilepsy. The secondary aim was to demonstrate the significance of periodic reinterpretation of variant of uncertain significance (VUS) variants and genotype-phenotype correlation. METHODS: This retrospective study comprised 107 patients with epilepsy aged 8 months to 17 years, for whom a targeted gene panel covered 110 genes. VUS variants were reanalyzed, and genotype-phenotype correlation was performed. RESULTS: In the initial evaluation, causal variants were described in 23 patients (21.5%). After reinterpretation of VUS, we detected causal variants in 30 out of 107 patients (28%). By reinterpreting the VUS and evaluating genotype-phenotype correlations, we enhanced our diagnostic value by 30.32%. After reinterpretation of VUS variants, the ACMG classification of 36 variants, including 15 benign (31%), 15 likely benign (31%), 5 likely pathogenic (10%), and 1 pathogenic (2%), were redefined. We most frequently detected causal variants in ( = 5), ( = 4), and ( = 4) genes. CONCLUSION: The predictive value for epilepsy panel testing was 28% in the cohort. Our study revealed the importance of reanalysis of VUS variants and contributed to enriching the mutation spectrum in epilepsy.
A Novel Loss of Function Variant in Gene Underlies Early Infantile Epileptic Encephalopathy 24 [EIEE24].
Mujahid, Waqas A, Almazni IA … +8 more , Zaman G, Alam Q, Eid TM, Alanazi MA, Hamadi A, Afsar T, Razak S, Umair M
Mol Syndromol · 2025 Apr · PMID 40176840 · Full text
BACKGROUND: Early infantile epileptic encephalopathy (EIEE) is a rare neurological condition characterized by frequent seizures in the early stages of life, resulting in severely impaired cognitive and motor development....
BACKGROUND: Early infantile epileptic encephalopathy (EIEE) is a rare neurological condition characterized by frequent seizures in the early stages of life, resulting in severely impaired cognitive and motor development. Although the specific causes of EIEE remain unknown, one of the primary causes is gene pathogenicity (even in the absence of consanguinity). Hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are essential for proper brain function. They are regulated by multiple genes, and mutations in these genes induce channel malfunction, which can result in various severe conditions, including EIEE. Herein, we have reported a patient presenting hallmarks of EIEE. METHODS: The patient underwent clinical, radiographic, and genetic analysis. A thorough clinical examination and molecular study were conducted utilizing whole exome sequencing and Sanger sequencing. RESULTS: Whole exome sequencing of the proband revealed a novel de novo nonsynonymous/nonsense variant (c.1468A>T; (p.Lys490Ter) in exon 6 of the gene. This variant may cause channel dysfunction via nonsynonymous/nonsense-mediated decay or aberrant protein, which may be associated with EIEE phenotypes. CONCLUSIONS: This evidence backs the idea that HCN1 has a vital role in brain development and lose of function can cause a range of debilitating conditions. Still, the functional characterization study of the variants will be the fundamental tool for a better understanding of EIEE in the near future.
Classification of Brain Magnetic Resonance Imaging Abnormalities and Spectrum of Neurological Findings in a Cohort with Copy Number Variation-Related Disorders.
Türkyılmaz A, Sağer SG, Caliskan E … +4 more , Akçay M, Demir O, Baytar B, Akın Y
Mol Syndromol · 2025 Apr · PMID 40176839 · Full text
INTRODUCTION: Copy number variation (CNV) is the difference in the sequence of genomic segments, which can vary from one kilobase to several megabases. Certain CNVs have been linked to various human disorders, such as in...
INTRODUCTION: Copy number variation (CNV) is the difference in the sequence of genomic segments, which can vary from one kilobase to several megabases. Certain CNVs have been linked to various human disorders, such as intellectual disability, multiple congenital anomalies, autism spectrum disorders, neurodegenerative and neuropsychiatric conditions, and cancer. The present study aims to classify brain magnetic resonance imaging (MRI) findings, describe neurological manifestations, and discuss the findings within the context of genotype-phenotype correlations in a cohort of patients with recurrent and nonrecurrent CNVs. METHODS: A total of 21 patients with pathogenic CNV detected using microarray analysis were included in the study. RESULTS: Analysis of the clinical findings of the patient cohort showed that 16 (76%) had microcephaly, 14 had epilepsy (66%), 20 had facial dysmorphism (95%), and all had developmental delay (100%). Novel brain MRI findings were detected in six (6/13, 46%) patients with recurrent CNV and five (5/8, 63%) patients with nonrecurrent CNV. CONCLUSION: CNV-related disorders should be considered in the differential diagnosis of patients with brain MRI findings suspicious for metabolic disorders. Brain MRI differences in patients with the same chromosomal deletion can be explained by the second-hit hypothesis. Additional single nucleotide variations and epigenetic factors in these cases may have led to the involvement of different regions of the brain. Revealing the phenotypic and genotypic characteristics of cases in rare disorders will contribute to the widespread use of precision medicine and genetic treatment approaches in the near future.
Plastic Bronchitis in Noonan Syndrome: Further Evidence Suggesting a Higher Risk of Lymphatic Abnormalities in Individuals Harboring Variants in PTPN11 Residue p.Phe285.
Pires LVL, Da Cás E, de Melo LC … +6 more , Nakaie CMA, Aiello VD, Yamamoto GL, Honjo RS, Kim CA, Bertola DR
Mol Syndromol · 2025 Apr · PMID 40176838 · Full text
INTRODUCTION: Noonan syndrome (NS) is a Mendelian phenotype, member of the RASopathies, a group of clinically overlapping multisystem disorders caused by germline variants in the RAS-MAPK signaling pathway genes. Among t...
INTRODUCTION: Noonan syndrome (NS) is a Mendelian phenotype, member of the RASopathies, a group of clinically overlapping multisystem disorders caused by germline variants in the RAS-MAPK signaling pathway genes. Among the clinical findings in NS, lymphatic abnormalities (LAs) are diagnosed in approximately 30%, mostly in individuals harboring variants in and . This genotype-phenotype correlation is not precise, and recent evidence suggests a higher prevalence of LAs in individuals harboring variants on p.Phe285 residue in , the main gene responsible for NS. CASE PRESENTATION: Here, we report a novel case of NS harboring the :p.Phe285Ser variant that evolved with chylothorax and presented the rare finding of plastic bronchitis, an uncommon and underdiagnosed pulmonary disease, characterized by production of cohesive and branching casts filling the airways. We also provide a review of other individuals with NS and LA harboring variants on Phe285 residue in from our service and from the literature and compared its prevalence with the most commonly affected residue in -related NS (p.Asn308), which indicated that variants in the p.Phe285 residue might predispose to LA. CONCLUSION: We suggest that, when this variant is identified in an individual, clinicians should be warned of a possible higher prevalence of LA and a prompt evaluation should be performed if any clinical signs are noticed.
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