Molecular Syndromology[JOURNAL]
Sun
200 papers
Erratum.
Mol Syndromol · 2025 Dec · PMID 41245231 · Full text
[This corrects the article DOI: 10.1159/000545192.].
[This corrects the article DOI: 10.1159/000545192.].
Erratum.
Mol Syndromol · 2025 Dec · PMID 41245230 · Full text
[This corrects the article DOI: 10.1159/000540570.].
[This corrects the article DOI: 10.1159/000540570.].
Comparative Small RNA Sequencing Reveals Candidate Functional miRNAs in Nonketotic Hyperglycinemia.
Bayrak H, Sharafi P, Özketen AÇ … +1 more , Kılıç M
Mol Syndromol · 2025 Oct · PMID 41245229 · Full text
INTRODUCTION: Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive-inherited disorder of amino acid metabolism known as glycine encephalopathy. Clinical manifestations arise because of the enzyme deficiency in...
INTRODUCTION: Nonketotic hyperglycinemia (NKH) is a rare, autosomal recessive-inherited disorder of amino acid metabolism known as glycine encephalopathy. Clinical manifestations arise because of the enzyme deficiency involved in glycine degradation. Currently, no effective treatment exists to alter the prognosis of NKH; available therapies focus primarily on reducing glycine accumulation in the body. MicroRNAs (miRNAs) are small noncoding RNAs that function as transcriptional and post-transcriptional regulators of gene expression. Here, we report the comparative profiling of small RNA sequencing (RNA-seq) data generated from clinical samples diagnosed with a specific condition. METHODS: We identified miRNAs using miRNA-seq with samples obtained from three NKH patients, five individuals with heterozygous variants in NKH genes, and seven control cases. Utilising pathways from the PubChem database, we identified NKH-related pathways and used bioinformatics tools for miRNA, pathway, and disease prediction. This was followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses to enrich the predicted target genes of differentially expressed miRNAs based on miRNA-target interactions. RESULTS: In our study, 10 known miRNAs were identified to be associated with NKH using at least two different tools. Our study is the first to demonstrate altered miRNA profiles in cases where the expression of and genes is reduced. CONCLUSION: NKH is an ultrarare and difficult-to-diagnose disease. This study determines the miRNA-based biomarkers for early detection of NKH and provides a robust framework for advancing future experimental research and diagnostic strategies.
A Single-Center Genotype-Phenotype Correlation Cohort Study of Hyperphenylalaninemia Patients: Genetic Analysis as a Deterministic Tool for Treatment Consistency.
Peker A, Uzuner SY, Clark ÖA … +4 more , Demirelli GD, Paksoy BA, Soyuçen E, Mıhçı E
Mol Syndromol · 2025 Oct · PMID 41245228 · Full text
BACKGROUND: Hyperphenylalaninemia (HPA, increased blood phenylalanine levels) refers to a disorder spectrum, with phenylketonuria (PKU) being the most common, caused by gene variants in an autosomal recessive inheritanc...
BACKGROUND: Hyperphenylalaninemia (HPA, increased blood phenylalanine levels) refers to a disorder spectrum, with phenylketonuria (PKU) being the most common, caused by gene variants in an autosomal recessive inheritance form. Genetic differences significantly influence phenotypical outcomes in HPA patients. This study investigates the genotype-phenotype correlation of HPA patients, aiming to evaluate treatment consistency based on specific genotypes and demonstrate that genotyping can provide guidance for optimal treatment. METHODS: Genomic DNA was obtained from 50 PKU, 2 tetrahydrobiopterin (BH4) deficiency, and 1 dihydropteridin reductase deficiency patients for next-generation sequencing of HPA-associated genes. Variants were analyzed using the Sophia DDM program, dbSNP, ClinVar, Ensembl information services, and ACMG 2015 criteria. Allelic phenotypical values consistent with enzyme functionality based on literature data were assessed using anamnesis information. RESULTS: Carriers of two null variants (homozygous/compound heterozygous) were unresponsive to BH4 therapy, reflecting the existing literature. Notably, BH4 therapy was also inadequate for two PKU patients who were compound heterozygous carriers with one null variant (P3, P10), even with other variants assumed protein function (PAH [NM_000277.3] c.1289T>C, c.143T>C). However, variants c.1169A>G (P21) and c.898G>T (P25) demonstrated positive BH4 responses when compounding a null variant, along with a c.782G>A homozygous patient benefiting from BH4. Two novel variants were observed in and genes, respectively. CONCLUSION: This study implies that genetic testing is plausible in predicting pretreatment BH4 testing outcomes, aiding in decision-making before patient evaluation, and providing valuable guidance to metabolism specialists during HPA treatment. With more HPA genotypes analyzed and clinical data published, genotyping will hold a better deterministic position toward patient prognosis and therapeutic management.
Chromosomal Microarray Analysis as a Diagnostic Tool in Congenital Heart Diseases.
Esener Z, Ates K, Ozturk M … +3 more , Karakurt C, Elkiran O, Tekedereli I
Mol Syndromol · 2025 Oct · PMID 41230209 · Full text
INTRODUCTION: Congenital heart diseases are a group of diseases present at birth, including anatomical and physiological abnormalities of the heart. They are the most common birth defects observed in the populations. The...
INTRODUCTION: Congenital heart diseases are a group of diseases present at birth, including anatomical and physiological abnormalities of the heart. They are the most common birth defects observed in the populations. The etiology is quite diverse. Although they mostly show a multifactorial inheritance pattern, chromosome abnormalities, copy number variations, single gene diseases, and environmental factors are involved in the etiology. Even though the etiology can be detected at a higher rate in syndromic cases, it has not been elucidated in most syndromic and non-syndromic cases. Our study aimed to detect copy number variations in syndromic and non-syndromic cases through chromosomal microarray analysis, to reveal the diagnostic value of the method, and to determine possible new loci. METHODS: Patient files, photographs, and laboratory results of 85 cases (55 syndromic and 30 non-syndromic) who had congenital heart disease and chromosomal microarray analysis were retrospectively evaluated. The differences between the groups were analyzed with Chi-square and Mann-Whitney U tests. RESULTS: Pathogenic/likely pathogenic copy number variations were detected in 32.7% (18/55) of the syndromic case group and 6.7% (2/30) of the non-syndromic case group. The diagnostic efficacy of chromosomal microarray analysis in the diagnosis and the age at the time of admission were statistically significant between groups. CONCLUSION: Our study suggest that the chromosomal microarray analysis is a valuable diagnostic tool to elucidate the etiology of congenital heart diseases.
Novel PIBF1 Pathogenic Variant in Three Siblings with Joubert Syndrome Type 33.
Aynekin B, Samur BM, Ozgul Gumus UG … +6 more , Bilguvar K, Gulec A, Efthymiou S, Gumus H, Caglayan AO, Per H
Mol Syndromol · 2025 Oct · PMID 41230208 · Full text
BACKGROUND: Joubert syndrome type 33 (JBTS33) is a rare autosomal recessive disorder characterized by developmental delay, severe renal disease, hypotonia/ataxia, cerebellar vermian hypoplasia/aplasia, optic nerve atroph...
BACKGROUND: Joubert syndrome type 33 (JBTS33) is a rare autosomal recessive disorder characterized by developmental delay, severe renal disease, hypotonia/ataxia, cerebellar vermian hypoplasia/aplasia, optic nerve atrophy, renal atrophy, and the "molar tooth sign" on imaging. Nearly 40 genes associated with Joubert syndrome have been identified, including CEP290, TMEM216, TMEM67, AHI1, and CC2D2A. METHODS: We report a consanguineous family with JBTS33 diagnosed through whole-exome sequencing. A novel biallelic homozygous nonsense mutation (ENST00000326291.11: c.1231C>T; p.Arg411Ter) in progesterone-induced blocking factor 1 (PIBF1) was identified. RESULTS: Our study included 3 patients with the same homozygous mutation in which contributed to clinical features such as psychomotor issues, dysmorphic features, hypotonia/ataxia, kidney failure, and possibly seizures. All 3 patient seizures have been eliminated after phenobarbital administration. This mutation has not been reported in public databases. CONCLUSION: This study confirmed as a disease-causing gene for JBTS33, expanding the molecular and clinical spectrum of JBTS. Our findings underscore the importance of identifying the genetic underpinnings and phenotypic expansions of mutations. Enhanced diagnostic awareness can facilitate early intervention and management. Further research is required to elucidate the relationship between mutations and associated clinical manifestations.
Clinical and Molecular Evaluation of Beckwith-Wiedemann Syndrome with the BWSICS Score.
Çetinkaya D, Altan M, Kılıç E
Mol Syndromol · 2025 Oct · PMID 41230207 · Full text
INTRODUCTION: Beckwith-Wiedemann syndrome (BWS, MIM#130650) is an overgrowth syndrome characterized by macroglossia, omphalocele, macrosomia, and a predisposition to neoplasia. The etiology of BWS involves genetic and ep...
INTRODUCTION: Beckwith-Wiedemann syndrome (BWS, MIM#130650) is an overgrowth syndrome characterized by macroglossia, omphalocele, macrosomia, and a predisposition to neoplasia. The etiology of BWS involves genetic and epigenetic alterations in the 11p15 region of the genome. In this study, we investigated how the International Consensus Clinical Scoring System (BWSICS) score can be used in clinical and molecular evaluations and examined its contribution to diagnostic processes. METHODS: This retrospective study included BWS patients who have been followed up in the pediatric genetics clinic of a center in the last 10 years. Clinical and molecular outcomes including chromosome analysis, microarray analysis, and MS-MLPA testing were evaluated. BWSICS scores were calculated for each patient based on their clinical symptoms. RESULTS: The study evaluated 18 patients who met BWS diagnostic criteria aged between 1 day and 10 years. The main presentations were macroglossia in 4 patients, omphalocele with macroglossia in 5 patients, and hypoglycemia in 2 patients and all but 1 patient was macrosomia. Significant congenital malformations included omphalocele and visceromegaly in 5 patients each. Hepatoblastoma was observed in 1 patient and 1 patient died due to sepsis. Two patients had autism spectrum disorder while the others had normal neuromotor development. According to the BWSICS, patients' scores ranged from 5 to 11. Molecular analysis revealed methylation alterations in 13/16 patients. CONCLUSION: This study examined the effectiveness of the BWSICS score in the diagnosis and follow-up of BWS in combination with clinical and molecular evaluation. This score provides a broad assessment in the diagnosis of BWS and can be considered as an important tool in clinical practice.
Clinical and Molecular Findings in 17 Patients with Cornelia de Lange Syndrome: Four Novel Variants and an Gene Variant.
Çetinkaya D, Altan M, Ceylan AC … +1 more , Kılıç E
Mol Syndromol · 2025 Oct · PMID 41230206 · Full text
INTRODUCTION: Cornelia de Lange syndrome is a rare congenital malformation syndrome characterized by prenatal-onset growth retardation, with typical facial findings that include bushy eyebrows, synophrys, long and thick...
INTRODUCTION: Cornelia de Lange syndrome is a rare congenital malformation syndrome characterized by prenatal-onset growth retardation, with typical facial findings that include bushy eyebrows, synophrys, long and thick eyelashes, ptosis, anteverted nostrils, long philtrum, and thin and downward sloping vermilion. The syndrome is caused by mutations in , , , , , and genes encoding cohesin complex proteins that maintain a chromatin structure in cell proliferation. In recently reported cases, new genes that are not involved in the cohesin complex but clinically cause CdLS have been identified. With these newly identified genes, the term chromatinopathies has been offered for this syndrome as it is more inclusive. Patients with the syndrome are classified as classical CdLS or CdLS-like phenotype according to their clinical features. METHODS: The clinical and molecular results of 17 new cases of CdLS are reported. RESULTS: The patients, who were between 2 months and 12 years of age, all had unique facial findings as well as growth retardation. Congenital malformations accompanying the syndrome in the patients were different. The molecular analysis showed genetic etiology in 13 patients, of which 2 were deletions and 11 were pathogenic missense variants in the , , and genes and of these variants, some had not been reported previously. CONCLUSION: By presenting the clinical and molecular results of these CdLS cases, it was aimed to expand the clinical spectrum, contribute to a better understanding of the genotype-phenotype relationship, and highlight the importance of molecular methods used in the diagnosis of genetic diseases.
Gene Panel-Based Genotyping of 279 Turkish Maturity-Onset Diabetes of the Young Patients from Eastern Anatolia.
Yarali O, Turkyilmaz A, Bayrak M … +2 more , Guler MC, Cayir A
Mol Syndromol · 2025 Oct · PMID 41230205 · Full text
INTRODUCTION: The aim of this study was to analyze the genotypic and clinical characteristics of Turkish patients with maturity-onset diabetes of the young (MODY) in Eastern Anatolia in order to improve the understanding...
INTRODUCTION: The aim of this study was to analyze the genotypic and clinical characteristics of Turkish patients with maturity-onset diabetes of the young (MODY) in Eastern Anatolia in order to improve the understanding of the genetic diversity and clinical manifestations of MODY. The findings should help to improve the diagnosis and management of monogenic diabetes. METHODS: This retrospective study included 279 patients with suspected MODY, selected for age at presentation, family history, no pancreas autoantibodies, and minimal/no need for insulin. A next-generation sequencing panel was used for genetic analysis. The panel included 15 different genes. RESULTS: Pathogenic variants were identified in 94% of the patients, with the majority being in GCK, HNF1A, and HNF4A. Variants in GCK were the most common (65%), followed by HNF1A (20%) and HNF4A (9%). Patients with GCK mutations exhibited mild fasting hyperglycemia, whereas HNF1A and HNF4A mutations were associated with progressive hyperglycemia. CONCLUSION: This study provides significant insights into the genotypic and clinical spectrum of MODY within a Turkish population. The detection of pathogenic variants in genes such as GCK, HNF1A, and HNF4A underscores the importance of comprehensive genetic testing in patients suspected of MODY. The results emphasize the need for personalized approaches to optimize the diagnosis and treatment of MODY. Detailed genetic and clinical assessments play a pivotal role in identifying at-risk individuals and tailoring management strategies. These findings could guide the development of targeted therapies and enhance the clinical outcomes of patients with monogenic diabetes.
Findings in Chromosomal Microarray Analysis during Prenatal Diagnosis in High-Risk Individuals.
Carrasco Salas P, Granell Escobar R, Serrano Mira A … +4 more , Pérez Saldaña A, Cosculluela Vidal M, Garrido C, Vázquez Rico I
Mol Syndromol · 2025 Oct · PMID 41230204 · Full text
INTRODUCTION: Chromosomal microarray analysis (CMA) allows the detection of submicroscopic chromosomal abnormalities such as unbalanced translocations and inversions. In recent years, its use in prenatal diagnosis has be...
INTRODUCTION: Chromosomal microarray analysis (CMA) allows the detection of submicroscopic chromosomal abnormalities such as unbalanced translocations and inversions. In recent years, its use in prenatal diagnosis has been implemented when certain ultrasound findings are detected. The purpose of this study was to analyze and describe the imbalances detected in prenatal samples collected from pregnancies followed in our center for having the indication to perform diagnosis using CMA. MATERIAL AND METHOD: On a population of pregnant women of 13,685, 216 CMAs were performed on chorionic villi and amniotic fluids during the period 2019-2023. The inclusion criteria were normal screening of common aneuploidies and at least one of the following features: nuchal translucency higher than percentile 99, fetal abnormalities, early-onset fetal growth restriction, parents' history of chromosomal imbalances, or cases with chromosomal imbalances. When a relevant variant was detected, it was analyzed in the parents' fetus and when available, the phenotype of the born children was collected. RESULTS: Pathogenic copy number variations (CNVs) were detected in 13 of 216 samples (6%). In a single sample, two concurrent CNVs were detected. Isolated CNVs had OMIM numbers and corresponded to already reported syndromes. Seven variants of unknown significance (3.7%) were observed. The study of the parents showed that 14 of 21 variants identified had arisen de novo (one pathogenic and five unknown CNVs had been inherited from an apparently healthy parent). Three microduplications specially drew our attention: duplication 5q35.2 which encompassed gene (because the reported phenotype is not consistent with what is expected for the genomic region) and duplications 1q21.1 and 16p11.2 (due to the ultrasound findings detected in fetuses had recently been postulated to be associated with these CNVs). CONCLUSION: The phenotype of CNVs identified in prenatal samples is highly variable prenatally, like postnatally. Some findings may be part of the syndromes to which they give rise and some phenotypes may be pending to define. Further studies are needed to better define these variants and to understand how haploinsufficiency or over-expression of genes included in these regions can cause such complex phenotypes.
Clinical and Genetic Insights into Congenital Generalized Lipodystrophy Type 4: A Case Report.
Bilgeç N, Eklioğlu BS, Gün Hİ … +3 more , Balasar Ö, Atabek ME, Çaksen H
Mol Syndromol · 2026 Jun · PMID 41220405 · Full text
INTRODUCTION: Lipodystrophy syndromes (LS) represent a clinically and genetically heterogeneous group of disorders of adipose tissue. LS are characterized by a partial or generalized deficiency of adipose tissue and vari...
INTRODUCTION: Lipodystrophy syndromes (LS) represent a clinically and genetically heterogeneous group of disorders of adipose tissue. LS are characterized by a partial or generalized deficiency of adipose tissue and variations in fat distribution throughout the body. Metabolic complications serve as significant determinants of morbidity and mortality in these syndromes. CASE PRESENTATION: The patient was assessed for general lipodystrophy and myopathy findings, and a mutation was identified by next generation sequencing. Our patient exhibited low leptin and vitamin D levels, categorized as metabolic disorders, alongside increased insulin resistance. Additionally, low insulin-like growth factor 1 levels and delayed puberty were noted as hormonal disorders. Osteoporosis, scoliosis, ventricular extrasystoles, and ventricular tachycardia were observed as morbid conditions during the follow-up. We detected hypoplasia of the anterior cerebral artery and the internal carotid artery, which are seen as ultrarare. A coexistent structural cerebral vascular anomaly has not been previously reported in congenital generalized lipodystrophy type 4. CONCLUSION: Congenital generalized lipodystrophy type 4 should be considered when associated with elevated liver enzyme levels and creatine phosphokinase values. Determining the underlying genetic cause enables an expeditious monitoring and treatment process.
High Diagnostic Yield of Next-Generation Sequencing in Charcot-Marie-Tooth Patients and a Novel Variant in the Gene.
Başdemirci M, Balasar Ö, Bulut O … +5 more , Tunçez E, Duymuş F, Çavdartepe BE, Şimşek L, Çelik H
Mol Syndromol · 2025 Aug · PMID 41169655 · Full text
INTRODUCTION: Charcot-Marie-Tooth (CMT) is a disorder that encompasses a group of hereditary neuropathies. The clinical features of CMT is variable due to genetic heterogeneity. This study aimed to evaluate the utility o...
INTRODUCTION: Charcot-Marie-Tooth (CMT) is a disorder that encompasses a group of hereditary neuropathies. The clinical features of CMT is variable due to genetic heterogeneity. This study aimed to evaluate the utility of targeted next-generation sequencing (NGS) panels in the molecular diagnosis of CMT in routine clinical practice and to determine the causative genetic variants. METHODS: NGS was used to detect the causative single nucleotide variants in 55 genes associated with CMT alongside multiplex ligation probe amplification (MLPA) for copy number variation (CNV) analysis of the gene. The period from the first clinical findings to genetic testing was considered as the "diagnostic odyssey." RESULTS: A total of 58 patients with suspected CMT were analyzed. MLPA was performed on 54 patients, while 4 underwent direct NGS due to suspicion of other CMT types. MLPA revealed pathogenic CNVs in 21 patients (36.2%). Among the 33 patients with negative MLPA results, 24 underwent NGS. Pathogenic/likely pathogenic variants were identified in 17 (60.7%) of total 28 patients. Overall, the diagnostic yield was 65.5% (38/58). Moreover, a novel likely pathogenic variant (c.637C>T) was detected in the gene. The average diagnostic odyssey in diagnosed patients was 5.6 years. CONCLUSION: Targeted NGS panels are a highly effective tool for the genetic diagnosis of CMT and increase the diagnostic rates when used in conjunction with MLPA. Molecular genetic diagnosis is critical for CMT patients, particularly in light of ongoing research into targeted therapies. Furthermore, presence of undiagnosed cases underscores the likelihood that additional causative genes and mechanisms in CMT etiology remain to be discovered.
A Novel Pathogenic TSPEAR Variant in a Family with Clinical Variability: Definition of Dental Anomalies and Review of the Literature.
Akalın A, Koç N, Özşin-Özler C … +6 more , Karaosmanoglu B, Ürel-Demir G, Taskiran EZ, Utine GE, Uzamış-Tekçiçek M, Şimşek-Kiper PÖ
Mol Syndromol · 2025 Aug · PMID 41163957 · Full text
INTRODUCTION: Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders marked by impaired development of multiple tissue derivatives originating from the human ectoderm, including teeth, hair, nai...
INTRODUCTION: Ectodermal dysplasias (EDs) represent a heterogeneous group of genetic disorders marked by impaired development of multiple tissue derivatives originating from the human ectoderm, including teeth, hair, nails, and sweat glands. Advances in next-generation sequencing technology have facilitated the identification of novel genes, such as , contributing to the emergence of the ectodermal dysplasia-14 of the hair/tooth type (ECTD14) phenotype, primarily characterized by hypotrichosis, hypodontia, and dysmorphic features. METHODS: Five individuals from the same family were included in the study, three of whom were heterozygous and two homozygous for a novel frameshift variant. All displayed ED and/or tooth loss. Exome sequencing was performed in the index case, and Sanger sequence analysis was carried out to detect the carrier status in parents and relatives. RESULTS: We identified a novel biallelic frameshift variant [NM_144991.2, c.1594_1595insA, p.(Phe532TyrfsTer26)] in two siblings who displayed oligodontia, sparse hair, and facial dysmorphism. The remaining heterozygous carriers manifested early tooth loss with non-syndromic isolated oligodontia. CONCLUSION: This study has identified individuals carrying biallelic and heterozygous variants, where heterozygous carriers often exhibit non-syndromic tooth agenesis. Moreover, the presence of inter- and intrafamilial variability emerges as a notable feature of the disease. This understanding underscores the complexity of the disease and the importance of considering genetic variability when diagnosing and managing affected individuals.
Novel Insights Aortic Root Dilatation in an Individual with 3p21.31 Deletion.
Zocche D, Platts L, Younes M … +4 more , Flemming A, Naqvi N, Cobben J, Van Dijk F
Mol Syndromol · 2025 Dec · PMID 41078619 · Full text
INTRODUCTION: Interstitial deletions in 3p21.31 are rare and have been associated with developmental delay, intellectual disability, and facial dysmorphism. To our knowledge, there are no reported individuals with a 3p21...
INTRODUCTION: Interstitial deletions in 3p21.31 are rare and have been associated with developmental delay, intellectual disability, and facial dysmorphism. To our knowledge, there are no reported individuals with a 3p21.31 interstitial deletion associated with aortic root dilatation. CASE PRESENTATION: We report a 2-year-old girl with 3p21.31p14.3 deletion, aortic root dilatation, global developmental delay, hypotonia, and distinctive facial features. The size of this interstitial deletion is 6.8 Mb and it encompasses 120 genes. None of these genes have a known association with aortic complications. A custom gene panel of 37 genes associated with familial thoracic aortic aneurysm did not identify a known monogenic cause of aortic dilatation in this individual. CONCLUSION: This case represents an expansion of the phenotypic spectrum associated with 3p21.31 deletions, highlighting the novel association with aortic root dilatation. Further studies are needed to explore potential mechanisms linking this chromosomal deletion to vascular complications.
Expanding the Genetic Landscape of RASopathies: Significance of Including in Targeted Panels.
Kendir-Demirkol Y, Yeter B, Eser M … +1 more , Yarar MH
Mol Syndromol · 2025 Dec · PMID 41078618 · Full text
INTRODUCTION: RASopathies are genetic disorders linked to the RAS/MAPK signaling pathway, including Noonan syndrome and related conditions. These disorders have overlapping features and variable phenotypes, making diagno...
INTRODUCTION: RASopathies are genetic disorders linked to the RAS/MAPK signaling pathway, including Noonan syndrome and related conditions. These disorders have overlapping features and variable phenotypes, making diagnosis challenging. This study examines the clinical and genetic characteristics of RASopathies in pediatric patients to improve diagnostic accuracy and identify novel pathogenic variants. METHODS: A total of 23 patients, who were not related to each other and were clinically diagnosed with RASopathy, participated in the study. Patients underwent next-generation sequencing (NGS) panel analyses of 14 RASopathy genes. RESULTS: Pathogenic variants were found in 18 out of 23 patients (78%). The most common variants were in and . Novel variants were identified in and expanding the known genetic spectrum. Frequent clinical features included distinctive facial features, growth delays, and heart defects, notably pulmonary stenosis. Intellectual disability was more common in patients with variants, while variants were associated with unique features such as previously unreported polydactyly and choanal atresia. CONCLUSION: Targeted NGS panels improve diagnosis of RASopathies, with a variant detection rate of 78%. Including the gene, even without signs of neurofibromatosis, enhances diagnostic success. This study adds to our understanding of genotype-phenotype relationships in RASopathies and highlights new clinical features tied to variants. Comprehensive genetic testing supports earlier and more personalized care for patients with RASopathies.
Ophthalmological and Orthoptic Findings in Down Syndrome: Is Genotype-Phenotype Correlation Possible?
Koyuncuoglu MA, Taylan Sekeroglu H, Urel Demir G … +3 more , Simsek Kiper O, Karakaya J, Utine GE
Mol Syndromol · 2025 Dec · PMID 41078617 · Full text
INTRODUCTION: This is a preliminary study to investigate a feasible genotype-phenotype correlation by defining ophthalmological findings in different genotypes of Down syndrome (DS). METHODS: The study included 62 eyes o...
INTRODUCTION: This is a preliminary study to investigate a feasible genotype-phenotype correlation by defining ophthalmological findings in different genotypes of Down syndrome (DS). METHODS: The study included 62 eyes of 31 DS patients. Patients were further subgrouped according to cytogenetic forms of DS. A comprehensive ophthalmological examination was performed and, biometric, keratometric, and pachymetric parameters were evaluated. RESULTS: The mean best-corrected visual acuity (BCVA) of trisomy 21 was 0.41 ± 0.14 (0.1-0.6) and was 0.6 ± 0.09 (0.5-0.7) for both mosaic and translocation trisomy 21 ( = 0.004). While 6 of the trisomy 21 patients (24%), 2 of the mosaic patients (66.7%), and all of the three translocation type patients had a normal accommodation response, the remaining patients had accommodation lags ( = 0.013). CONCLUSIONS: Lens opacities and fundus abnormalities were more common in trisomy 21 ( < 0.001). The angle kappa was larger in trisomy 21 and smallest in the translocation trisomy 21 ( = 0.014). K and corneal apex curvature were highest in trisomy 21 ( = 0.05 and = 0.006, respectively). BCVA and accommodation response were reduced whereas lenticular opacities and fundus abnormalities were more common in trisomy 21. In addition, central cornea was steeper and angle kappa was larger. Further studies with larger cohorts would display differences among subgroups of cytogenetic abnormality.
First Reported Co-Occurrence of Bardet-Biedl Syndrome Type 10 and Autism Spectrum Disorder: A Case Report and Clinical Review.
Güleç A, Gerik-Celebi HB
Mol Syndromol · 2026 Jun · PMID 41064058 · Full text
INTRODUCTION: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic ciliopathy, whereas autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction...
INTRODUCTION: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic ciliopathy, whereas autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and restricted, repetitive behaviors. While both conditions are independently associated with genetic etiologies, their co-occurrence is exceptionally rare. To date, no prior report has confirmed such co-occurrence through molecular genetic analysis. CASE PRESENTATION: We report a 4-year-old male diagnosed with both BBS type 10 and ASD. Whole exome sequencing (WES) revealed a homozygous pathogenic variant in the gene and a novel heterozygous intronic variant in the gene, classified as a variant of uncertain significance. Clinically, the patient exhibited features consistent with both disorders, including retinal degeneration, polydactyly, renal anomalies, hypotonia, and ASD-specific behavioral patterns. CONCLUSION: This case represents the first genetically confirmed co-occurrence of BBS10 and ASD. The identification of a potentially contributory non-coding variant in the gene provides novel insight into the shared genetic and pathophysiological mechanisms underlying ciliopathies and neurodevelopmental disorders. The findings emphasize the importance of dual diagnostic consideration in complex pediatric cases and demonstrate the value of genomic analysis in revealing rare genetic overlaps.
A Novel Intragenic Duplication of CREBBP in Rubinstein-Taybi Syndrome: A Case Report Expanding the Genotype-Phenotype Spectrum.
Dursun E, Uctepe E, Guler S … +2 more , Mancilar H, Yesilyurt A
Mol Syndromol · 2026 Apr · PMID 41064057 · Full text
INTRODUCTION: Rubinstein-Taybi syndrome (RSTS) is most often caused by loss-of-function variants in ; intragenic duplications are rare and extremely under-recognized. CASE PRESENTATION: We describe a 5-year-old girl with...
INTRODUCTION: Rubinstein-Taybi syndrome (RSTS) is most often caused by loss-of-function variants in ; intragenic duplications are rare and extremely under-recognized. CASE PRESENTATION: We describe a 5-year-old girl with global developmental delay, intellectual disability, frontal bossing, upslanted palpebral fissures, broad angulated halluces, and scoliosis. Whole-exome sequencing with copy number analysis revealed a heterozygous de novo duplication of approximately 13 kb encompassing exons 7-16 of (NM_004380.3). Multiplex ligation-dependent probe amplification confirmed the duplication in the proband and excluded it in both parents. The event is predicted to introduce a frameshift, leading to premature truncation. No additional pathogenic variants were detected. CONCLUSION: This is the first reported duplication spanning exons 7-16, expanding the mutational spectrum of RSTS and illustrating that intragenic duplications can manifest with a partially atypical craniofacial profile. The case underscores the value of incorporating high-resolution copy number interrogation into RSTS workflows when single nucleotide variant analysis is uninformative and supports systematic deposition of such variants to refine genotype-phenotype correlations.
Familial Hyperekplexia Caused by a Novel Homozygous Variant: A Case Report.
Yılmaz FH, Kahraman AB, Duymuş F … +5 more , Koçak Eker H, Çelik H, Büyükeren M, Özcan B, Keçeci R
Mol Syndromol · 2026 Jun · PMID 41064056 · Full text
INTRODUCTION: Hyperekplexia is a rare non-epileptic paroxysmal disorder characterized by a marked startle response and hypertonia to auditory, tactile, or visual sudden external stimuli. , , , and gene pathogenic varian...
INTRODUCTION: Hyperekplexia is a rare non-epileptic paroxysmal disorder characterized by a marked startle response and hypertonia to auditory, tactile, or visual sudden external stimuli. , , , and gene pathogenic variants have been identified in these patients. CASE REPORT: The girl was born 39+1 weeks and admitted to the neonatal intensive care unit with spasm-like contractions and followed by breath holding. Except for transient hyperammonemia, neurologic and metabolic tests were normal, and there was no seizure-like movement during hospitalization. In the 4th month of her life, the patient had spasm-like findings with stimulation, and the symptoms were controlled with clonazepam, considering hyperekplexia. Clinical exome sequencing revealed a previously undescribed homozygous variant [c.748T>C; p.(Ser250Pro) in exon 4] in the (NM_004211.5) gene. Sanger sequencing confirmed the c.748T>C variant in the family: both parents were heterozygous carriers, while the brother was homozygous. Her sibling also had stimulus-induced crying and stiffness in infancy, but these resolved within months without treatment, and his developmental milestones have been age-appropriate. CONCLUSIONS: This case highlights the importance of recognizing hereditary hyperekplexia in the differential diagnosis of neonatal seizures and supports the potential pathogenic relevance of the c.748T>C (p.Ser250Pro) variant, particularly in benign, nonrecurrent cases with transient hyperammonemia from catabolic stress and glycine transporter dysfunction.
-Related Osteogenesis Imperfecta: Clinical Variability and a Potential Founder Variant in .
Travessa AM, Romeu JC, Mirco T … +8 more , Vaz-de-Macedo C, Palma MJ, Modamio-Høybjør S, Barreiros C, Magalhães A, Barão RC, Heath KE, Sousa AB
Mol Syndromol · 2026 Jun · PMID 41064055 · Full text
INTRODUCTION: -related osteogenesis imperfecta (OI) is a form of OI that ranges from moderate (type IV) to extremely severe (type II) and is caused by biallelic variants in the gene. To date, only about 30 cases have be...
INTRODUCTION: -related osteogenesis imperfecta (OI) is a form of OI that ranges from moderate (type IV) to extremely severe (type II) and is caused by biallelic variants in the gene. To date, only about 30 cases have been reported in the literature. METHODS: We describe two adults and one fetus with molecularly confirmed -related OI. RESULTS: The phenotype varied extensively in terms of severity and clinical features, ranging from moderate (type IV) to severe (type III) and including cases with prenatal fractures as well as one case with a low number of fractures and no prenatal fractures. Interestingly, 1 patient presented with high myopia and bilateral retinal detachment, which have not been previously reported in OI type VII. Regarding molecular results, we identified three variants that have not been previously reported in the literature. One of the variants was found in both a woman and an unrelated fetus of Cape Verdean descent, suggesting that the carrier frequency of this variant in the Cape Verde population may be relatively high. CONCLUSION: We expand the clinical spectrum of patients with variants and highlight the clinical variability of this extremely rare type of OI, which may present with either prenatal or postnatal onset. Our findings also underscore the importance of investigating the role of in extra-skeletal tissues and assessing potential founder effects in underrepresented populations.
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