Molecular Syndromology最新文献

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Missense Variant Met119Val in ACTB in a Patient with Baraitser-Winter Syndrome Type 1 and Mild Intellectual Disability. 1型Baraitser-Winter综合征合并轻度智力障碍患者ACTB中错义变异Met119Val
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-13 DOI: 10.1159/000542536
Roseli Maria Zechi-Ceide, Henrique Regonaschi Serigatto, Ana Laura Galvanin, Marina Bigeli Rafacho, Nancy Mizue Kokitsu-Nakata, Maria Leine Guion-Almeida, Nataliya Di Donato
{"title":"Missense Variant Met119Val in <i>ACTB</i> in a Patient with Baraitser-Winter Syndrome Type 1 and Mild Intellectual Disability.","authors":"Roseli Maria Zechi-Ceide, Henrique Regonaschi Serigatto, Ana Laura Galvanin, Marina Bigeli Rafacho, Nancy Mizue Kokitsu-Nakata, Maria Leine Guion-Almeida, Nataliya Di Donato","doi":"10.1159/000542536","DOIUrl":"10.1159/000542536","url":null,"abstract":"<p><strong>Introduction: </strong>The Baraitser-Winter syndrome (BRWS) is a rare condition characterized by multiple congenital anomalies and developmental delay. Most cases present moderate to severe global delay and intellectual disability. The etiology of BRWS is heterogeneous, caused by heterozygous gain-of-function variants in <i>ACTB</i> or <i>ACTG1</i> genes.</p><p><strong>Case report: </strong>Here we report on a Brazilian female patient with dysmorphic craniofacial features of the BRWS, oligodontia, partial agenesis of the corpus callosum, pineal cyst, cervical cystic hygroma, pterygium colli, axillary pterygium, duplicated left hallux, seizures, and mild developmental delay. Sanger sequencing of the <i>ACTB</i> gene showed the heterozygous missense variation NM_001101.5 (ACTB):c.355A>G (p.Met119Val).</p><p><strong>Conclusion: </strong>The clinical findings are compatible with the diagnosis of BRWS type 1. Our case includes oligodontia as a new feature of the BRWS type 1 phenotype. Functional study of the variant here described could contribute to elucidate the pathogenetic pathway that results in the severe craniofacial phenotype associated with mild developmental delay.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"390-396"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Next-Generation Sequencing in Diagnosis of Monogenic Cholestatic Liver Disorders: A Single-Center Experience. 新一代测序诊断单基因胆汁淤积性肝病:单中心经验。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-13 DOI: 10.1159/000542594
Engin Demir, Fatma Derya Bulut, Berrak Bilginer-Gürbüz, Mehmet Ercüment Döğen, Ali İşlek, Serdar Mermer, Burak Başer, Gizem Ürel-Demir
{"title":"Next-Generation Sequencing in Diagnosis of Monogenic Cholestatic Liver Disorders: A Single-Center Experience.","authors":"Engin Demir, Fatma Derya Bulut, Berrak Bilginer-Gürbüz, Mehmet Ercüment Döğen, Ali İşlek, Serdar Mermer, Burak Başer, Gizem Ürel-Demir","doi":"10.1159/000542594","DOIUrl":"10.1159/000542594","url":null,"abstract":"<p><strong>Introduction: </strong>Cholestasis in childhood is a rare clinical condition, yet a definitive diagnosis is crucial for initiating treatment of these curable diseases and preventing related morbidity and mortality. The most common cause of infant cholestasis is biliary atresia (25-40%), followed by monogenic cholestatic diseases (25%), metabolic diseases (20%), and cryptogenic cholestasis. This study focuses on assessing the clinical utility of next-generation sequencing (NGS) panels, including clinical exome sequencing and whole exome sequencing, in diagnosing cholestatic diseases when the etiology cannot be elucidated through conventional methods.</p><p><strong>Materials and methods: </strong>We conducted a retrospective examination of pediatric patients who sought care at a single-center pediatric gastroenterology department between August 2020 and March 2022 and were diagnosed with cholestasis. A total of 36 patients underwent a thorough investigation to rule out infectious, toxic, metabolic, structural, chromosomal, and endocrine causes. Patients whose diagnoses were established through traditional investigations were excluded from the study. The remaining 14 patients underwent either whole exome sequencing or targeted NGS methods.</p><p><strong>Results: </strong>A definitive diagnosis was achieved for 12 patients, while 2 patients remained undiagnosed despite comprehensive genetic examinations. The most commonly encountered diseases in this cohort were progressive familial intrahepatic cholestasis, linked to mutations in the <i>ABCB11</i>, <i>ATP8B1</i>, and <i>TJP2</i> genes, as well as Dubin-Johnson syndrome associated with <i>ABCC2</i> mutations. NGS demonstrated a diagnostic accuracy of 85.7% in patients for whom a diagnosis could not be established through extensive traditional workup.</p><p><strong>Conclusion: </strong>NGS emerges as a valuable diagnostic tool in cases of cholestasis where traditional methods fall short in providing a definitive diagnosis. Moreover, our study unveiled three previously undocumented variants in the <i>ABCB11</i> [c.1165G>C; p.(Ala389Pro) and c.783 + 1G>A] and <i>ABCC2</i> [c.4246_4247del; p.(Lys1416ValfsTer46)] genes.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"320-326"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Novel NOTCH3 Variant Leading to Lateral Meningocele Syndrome: Prenatal Diagnosis and Possible Expansion of the Phenotype. 一种新的NOTCH3变异导致侧脑膜膨出综合征:产前诊断和可能的表型扩展。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-07 DOI: 10.1159/000542432
Isabela Dorneles Pasa, Alessandra Caren Frey, Suelly Fazio Ferraciolli, Leandro Tavares Lucato, Mariana Azevedo Carvalho, Mario Vitor Caldeira Pagotto, Mario Henrique Burlacchini De Carvalho, Rossana Pulcineli Vieira Francisco, Rachel Sayuri Honjo, Debora Romeo Bertola, Chong Ae Kim
{"title":"A Novel <i>NOTCH3</i> Variant Leading to Lateral Meningocele Syndrome: Prenatal Diagnosis and Possible Expansion of the Phenotype.","authors":"Isabela Dorneles Pasa, Alessandra Caren Frey, Suelly Fazio Ferraciolli, Leandro Tavares Lucato, Mariana Azevedo Carvalho, Mario Vitor Caldeira Pagotto, Mario Henrique Burlacchini De Carvalho, Rossana Pulcineli Vieira Francisco, Rachel Sayuri Honjo, Debora Romeo Bertola, Chong Ae Kim","doi":"10.1159/000542432","DOIUrl":"10.1159/000542432","url":null,"abstract":"<p><strong>Introduction: </strong>NOTCH3, one of the four mammalian Notch receptors, acts as a transcriptional activator in a variety of tissues. Variants in <i>NOTCH3</i> lead to distinct phenotypes, depending on variant type and location. Truncating variants in the last exon generate a protein lacking the PEST domain, responsible for degradation, leading to a gain-of-function effect and causing Lateral Meningoceles syndrome (LMS), characterized by dysmorphisms and variable cardiac, skeletal, and connective tissue abnormalities; motor delay may occur, but the cognitive function is usually normal.</p><p><strong>Case presentation: </strong>We report the first case of prenatal molecular diagnosis of LMS, which was made using prenatal exome sequencing after an ultrasound with findings of fetal cystic hygroma, mild bilateral ventriculomegaly, and facial dysmorphisms. After birth, magnetic resonance imaging confirmed the presence of lateral meningoceles. A complete clinical evaluation was performed and unexpected biliary anomalies were found.</p><p><strong>Conclusion: </strong>The occurrence of biliary anomalies has not been previously reported in LMS but may have biological plausibility. Expression of <i>NOTCH3</i> has been demonstrated in biliary development and is thought to play a role in the differentiation of hepatoblasts into biliary epithelial cells, and also in liver regeneration and repair. We hypothesize that the findings reported here might expand the phenotype of LMS.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"384-389"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Report of Dual Presentations of Pseudo-TORCH Syndrome 1 and MCC2 Deficiency and Review of the Literature. 伪torch综合征1和mc2缺乏症双重表现报告及文献复习。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-27 DOI: 10.1159/000542145
Ali Talea, Shiva Bayat, Golazin Shahbodagh Khan, Neda Pak, Solmaz Aziz-Ahari, Roya Sinaei, Ali Reza Tavasoli, Mahmoud Reza Ashrafi, Morteza Heidari
{"title":"A Report of Dual Presentations of Pseudo-TORCH Syndrome 1 and MCC2 Deficiency and Review of the Literature.","authors":"Ali Talea, Shiva Bayat, Golazin Shahbodagh Khan, Neda Pak, Solmaz Aziz-Ahari, Roya Sinaei, Ali Reza Tavasoli, Mahmoud Reza Ashrafi, Morteza Heidari","doi":"10.1159/000542145","DOIUrl":"10.1159/000542145","url":null,"abstract":"<p><strong>Introduction: </strong>Pseudo-TORCH syndrome, named as such due to the mimicry of intrauterine TORCH infections in the absence of infection, is a neurological disorder presenting primarily with congenital microcephaly, intracranial calcifications, simplified gyration and polymicrogyria, and severe developmental delay, which can be attributed to variants in the <i>OCLN</i> gene. MCC2 deficiency, a neurometabolic disorder due to impairments in the catabolism of Leucine, with highly variable clinical presentations in addition to landmark metabolic features is put down to variants in <i>MCCC2</i> gene.</p><p><strong>Case presentation: </strong>Known as independent conditions, the intriguing presence of dual manifestations in a 3.5-year-old boy was investigated in the study. The patient was referred to our Myelin Disorders Clinic due to congenital microcephaly, developmental regression, and medication-resistant epilepsy. WES was performed on patient's samples for variant detection and subsequent confirmation. Bioinformatics analysis was performed for prioritization and validation according to the standard criteria. The resultant findings were consequently confirmed in the proband and his parents by Sanger sequencing. WES revealed the presence of two concurrent variants in <i>OCLN</i> and <i>MCCC2</i> on the same chromosome, chromosome 5, both in homozygous state in the proband. Both variants are classified as pathogenic according to ACMG classification system having been previously reported in the literature.</p><p><strong>Conclusion: </strong>The two variants observed in our patient, a homozygous missense change and a homozygous deletion interestingly occurring on the same chromosome, lead us to think that either these two conditions may be totally independent of each other, having co-occurred by chance, or there may be an underlying association between the two variants, rendering their co-occurrence as a haplotype more possible.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"366-373"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
C.655C>T Variant of Sepiapterin Reductase Deficiency: Genetic and Bioinformatic Analysis. C.655C . >t变异体:遗传和生物信息学分析。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-29 DOI: 10.1159/000542176
Hosein Eslamiyeh, Fatemeh Sefid, Farzaneh Iravani
{"title":"C.655C>T Variant of Sepiapterin Reductase Deficiency: Genetic and Bioinformatic Analysis.","authors":"Hosein Eslamiyeh, Fatemeh Sefid, Farzaneh Iravani","doi":"10.1159/000542176","DOIUrl":"10.1159/000542176","url":null,"abstract":"<p><strong>Background: </strong>Sepiapterin reductase deficiency (SRD) is a very rare psychomotor disorder related to enzyme defects in synthesizing tetrahydrobiopterin (BH4) with a spectrum of symptoms. The most common of which are developmental delay and hypotonia. To elucidate the genetic cause of SRD, the patient was analyzed by whole-exome sequencing (WES) followed by mutation analysis.</p><p><strong>Methods: </strong>A complete clinical examination was performed by a pediatric neurologist. Brain imaging and a thorough neuro-metabolic investigation were applied along with biochemical tests including high-performance liquid chromatography (HPLC) to quantify the concentrations of cerebrospinal fluid (CSF) pterins. Genomic DNA was extracted and evaluated through WES. This was followed by bioinformatic analysis of mutated sepiapterin reductase (SPR) protein structure and identification of the functional protein amino acids.</p><p><strong>Results: </strong>Biochemical analysis of biogenic amines of CSF with HPLC showed very low levels of homovanillic acid and 5-hydroxyindolacetic acid in favor of neurotransmitter metabolism disorder. WES analysis displayed a homozygous nonsynonymous variant in exon 3 of the SPR gene (C.655C>T, p.Arg219Ter). The molecular graphic of SPR protein structure with 4HWK PDB code was generated by MOE software in comparison with P.Arg219* mutated protein which is predicted by a Swiss model homology modeling server determining the ligand-binding site residues using COFACTOR software and indicated that the (R219*) mutation destroyed the ligand-binding site from the position of 219. Another important codon including 254 and 256 positions is omitted.</p><p><strong>Conclusion: </strong>Whole exome sequencing and bioinformatic analysis could overcome lengthy, expensive, and emotional diagnostic adventures of challenging neurodevelopmental cases leading to improved management and prevention of irreversible side effects.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"335-341"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cerebrotendinous Xanthomatosis Disease Prevalence in Patients with Autism Spectrum Disorder: A Prospective Observational Study. 自闭症谱系障碍患者脑腱黄瘤病患病率:一项前瞻性观察研究
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-11 DOI: 10.1159/000542453
Mehmet Karadag, Mehmet Ibrahim Turan, Canan Celebi, Tahir Caglar
{"title":"Cerebrotendinous Xanthomatosis Disease Prevalence in Patients with Autism Spectrum Disorder: A Prospective Observational Study.","authors":"Mehmet Karadag, Mehmet Ibrahim Turan, Canan Celebi, Tahir Caglar","doi":"10.1159/000542453","DOIUrl":"10.1159/000542453","url":null,"abstract":"<p><strong>Background: </strong>Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive congenital metabolic disorder, which is characterized by the impairment of the enzymatic activity of sterol 27-hydroxylase. CTX, a rare neurodegenerative disease of sterol metabolism, can affect multiple systems, including the nervous system. It has been demonstrated that many congenital metabolic diseases like CTX are associated with autism spectrum disorder (ASD). The aim of this study was to identify the prevalence of CTX disease in patients with ASD.</p><p><strong>Method: </strong>The clinical conditions of all patients were evaluated using the Mignarri Scoring Index. A sociodemographic form and Gilliam Autism Rating Scale-2 were applied to all participants.</p><p><strong>Results: </strong>In total, 101 children and adolescents with ASD were analyzed for genes. Following genetic analyses, 4 patients with mutations in the <i>CYP27A1</i> gene, two homozygous variants, and two different heterozygous mutations were identified. Most common symptom was diarrhea. Overall, 67.3% of all patients and 3 in 4 cases with <i>CYP27A1</i> gene mutation had gone through psychiatric evaluation. A family history of a psychiatric disorder was present in 19.8% of all cases and in 75% of cases with mutations. Moreover, all mutant cases had comorbid oppositional defiant disorder. A total of 81.2% of all patients and all mutant patients were diagnosed with a behavioral disorder.</p><p><strong>Conclusion: </strong>Psychiatric manifestations ranging from personality changes to behavioral disorders might accompany CTX. Better understanding and knowledge of the CTX disease by distinguishing specific psychiatric and systemic symptoms might help prevent missed diagnoses, progressive neurological deterioration, and permanent disability through early initiation of chenodeoxycholic acid treatment.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"354-365"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genotype-Phenotype Correlation in Lipoid Proteinosis: 15 Cases from Turkiye. 土耳其15例脂质蛋白沉积症基因型-表型相关性分析。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-19 DOI: 10.1159/000542675
Firdevs Dinçsoy Bir, Zehra Oya Uyguner, Birsen Karaman, Can Baykal, Nesimi Büyükbabani, Beyhan Tüysüz, Asuman Gedikbaşı, Bülent Uyanık, Güven Toksoy, Bülent Kara, Hülya Kayserili
{"title":"Genotype-Phenotype Correlation in Lipoid Proteinosis: 15 Cases from Turkiye.","authors":"Firdevs Dinçsoy Bir, Zehra Oya Uyguner, Birsen Karaman, Can Baykal, Nesimi Büyükbabani, Beyhan Tüysüz, Asuman Gedikbaşı, Bülent Uyanık, Güven Toksoy, Bülent Kara, Hülya Kayserili","doi":"10.1159/000542675","DOIUrl":"10.1159/000542675","url":null,"abstract":"<p><strong>Introduction: </strong>Lipoid proteinosis (LP), a rare autosomal recessive disorder typified by generalized thickening of the skin, mucosa, and certain viscera, is associated with pathogenic <i>ECM1</i> variants. Skin lesions like beaded eyelid papules, acneiform scars, wavy, yellow papules and nodules typically appear in early childhood. Some patients may exhibit neurological abnormalities like temporal lobe or hippocampi-amygdala complex calcification, epilepsy, and neuropsychiatric abnormalities.</p><p><strong>Methods: </strong>We included 15 individuals with LP from 10 unrelated families. The study includes clinical evaluations of family history, radiological findings, histopathological examination of the skin, and genetic investigations.</p><p><strong>Results: </strong>All affected individuals exhibited skin and mucosal lesions. Among the 15 cases, five (33%) showed neurological symptoms, four (26%) presented neuropsychiatric findings, and three (20%) had diabetes mellitus. We observed characteristic intracranial calcifications in all patients with epileptic seizures. Four out of the five cases with epilepsy and intracranial calcifications also had neuropsychiatric findings. All patients with neurological and neuropsychiatric findings had a frame-shift variant, but the same frame-shift variant was not associated with these findings in other individuals. In our study, no patient with variants other than frame-shift variants exhibited neurological or neuropsychiatric findings. Adrenal calcification, which was observed in 1 patient, was not previously linked to LP.</p><p><strong>Conclusion: </strong>Our study observed diverse variations in LP cases among the Turkish population, with varying clinical presentation even among individuals with identical variations within the same family. In our series, the lack of correlation between genotype and phenotype makes providing specific genetic counseling to families challenging.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"327-334"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Co-Occurrence of Variants in 3 Genes in a Patient with Congenital Skeletal Dysplasia and Cardiac Anomalies: Diagnostic Challenge Posed by a Blended Phenotype. 先天性骨骼发育不良和心脏异常患者中3个基因变异的共同出现:混合表型带来的诊断挑战。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-28 DOI: 10.1159/000542345
Pratibha Nair, Sami Bizzari, Cybel Mehawej, Eliane Chouery, Perla Audi, Sandra Corbani, Rima Korban, Daniel Mahfoud, Andrea Superti-Furga, Stepahny El-Hayek, Andre Megarbane
{"title":"Co-Occurrence of Variants in 3 Genes in a Patient with Congenital Skeletal Dysplasia and Cardiac Anomalies: Diagnostic Challenge Posed by a Blended Phenotype.","authors":"Pratibha Nair, Sami Bizzari, Cybel Mehawej, Eliane Chouery, Perla Audi, Sandra Corbani, Rima Korban, Daniel Mahfoud, Andrea Superti-Furga, Stepahny El-Hayek, Andre Megarbane","doi":"10.1159/000542345","DOIUrl":"10.1159/000542345","url":null,"abstract":"<p><strong>Introduction: </strong>Blended phenotypes resulting from the contribution of two or more genetic variants to the disease of a patient pose a significant diagnostic challenge. Correlating between the phenotypes and the genotypes of the affected patients is difficult in these cases, especially in the absence of a large family segregating the condition.</p><p><strong>Case presentation: </strong>We report a child born to consanguineous Syrian parents with a complex phenotype including a skeletal dysplasia, characterized by a small thorax and phalangeal shortening, as well as cardiac anomalies and sensorineural hearing loss. Molecular analysis identified the presence of three potentially disease-causing genetic variants. These include homozygous variants in the <i>IHH</i> and <i>TTC12B</i> genes, known to be associated with acrocapitofemoral dysplasia (OMIM# 607778) and a form of short-rib thoracic dysplasia (OMIM# 613819), respectively, in addition to a heterozygous variant in the <i>COL11A1</i> gene, associated with dominant forms of skeletal dysplasia, such as Marshall (OMIM# 154780) and Stickler (OMIM# 608481) syndromes, and hearing loss (OMIM# 618533).</p><p><strong>Conclusion: </strong>We propose that the complex phenotype observed in the patient results from the contribution of l three of these variants. This case highlights some of the challenges encountered in the genetic counseling of families with rare genetic conditions.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"374-383"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring Molecular and Phenotypic Characteristics of NAGLU Arg234Gly and Asp312Asn Variants. 探讨NAGLU Arg234Gly和Asp312Asn变异的分子和表型特征。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-08-01 Epub Date: 2024-11-06 DOI: 10.1159/000542367
Hande Kaymakcalan Celebiler, Tanyeri Barak, Devendra K Rai, Ilyas Kaya, Seda Erbilgin, Merve Cikili Uytun, Didem Oztop, Hakan Gumus, Huseyin Per, Serdar Ceylaner, Icten Bozkurt, Maria I Kontaridis, Kaya Bilguvar, Nilay Akhun, Ayse Kilincaslan, Ahmet Okay Caglayan, E Zeynep Erson-Omay, Murat Gunel, A Gulhan Ercan-Sencicek
{"title":"Exploring Molecular and Phenotypic Characteristics of <i>NAGLU</i> Arg234Gly and Asp312Asn Variants.","authors":"Hande Kaymakcalan Celebiler, Tanyeri Barak, Devendra K Rai, Ilyas Kaya, Seda Erbilgin, Merve Cikili Uytun, Didem Oztop, Hakan Gumus, Huseyin Per, Serdar Ceylaner, Icten Bozkurt, Maria I Kontaridis, Kaya Bilguvar, Nilay Akhun, Ayse Kilincaslan, Ahmet Okay Caglayan, E Zeynep Erson-Omay, Murat Gunel, A Gulhan Ercan-Sencicek","doi":"10.1159/000542367","DOIUrl":"10.1159/000542367","url":null,"abstract":"<p><strong>Introduction: </strong>Mucopolysaccharidosis type IIIB is an autosomal recessive lysosomal disorder caused by variants in the α-n-acetylglucosaminidase (<i>NAGLU</i>) gene. It is a progressive neurodegenerative disorder with no treatment. Previous enzyme therapies have been unsuccessful. It is important to understand the mechanism of the disease to be able to find new treatments.</p><p><strong>Methods: </strong>We did whole-exome sequencing and standard Sanger sequencing on 7 cases of four consanguineous families diagnosed with autism spectrum disorder.</p><p><strong>Results: </strong>We identified two recurrent damaging biallelic Asp312Asn and p.Arg234Gly variants in the <i>NAGLU</i> gene. Structure modeling of these variants suggested that each variant affects the stability of the enzyme and results in a loss of activity. All affected individuals' enzymatic assay in leukocytes clearly showed that α-n-acetylglucosaminidase was completely inactive. Our patients underwent magnetic resonance imaging (MRI), revealing normal findings in two of them despite progressive clinical neurodegenerative symptoms. To our knowledge, these cases represent the second and third instances of normal MRI findings documented in the literature.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 4","pages":"342-353"},"PeriodicalIF":0.9,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144795889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
First Reported Co-Occurrence of Bardet-Biedl Syndrome Type 10 and Autism Spectrum Disorder: A Case Report and Clinical Review. 首次报道Bardet-Biedl综合征10型与自闭症谱系障碍共发:1例报告及临床回顾。
IF 0.9 4区 医学
Molecular Syndromology Pub Date : 2025-07-17 DOI: 10.1159/000547413
Ahmet Güleç, Hamide Betul Gerik-Celebi
{"title":"First Reported Co-Occurrence of Bardet-Biedl Syndrome Type 10 and Autism Spectrum Disorder: A Case Report and Clinical Review.","authors":"Ahmet Güleç, Hamide Betul Gerik-Celebi","doi":"10.1159/000547413","DOIUrl":"10.1159/000547413","url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Case presentation: </strong>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 <i>BBS10</i> gene and a novel heterozygous intronic variant in the <i>OGT</i> 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.</p><p><strong>Conclusion: </strong>This case represents the first genetically confirmed co-occurrence of BBS10 and ASD. The identification of a potentially contributory non-coding variant in the <i>OGT</i> 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.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.9,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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