Molecular Syndromology最新文献

{"title":"A Novel <i>HERC2</i> Variant in Two Siblings with Autosomal Recessive Intellectual Developmental Disorder-38 and Cardiomyopathy.","authors":"Hüseyin Bahadır Şenol, Çağatay Günay, Ayşe İpek Polat, Adem Aydın, Ayşe Semra Hız, Uluç Yiş","doi":"10.1159/000543054","DOIUrl":"https://doi.org/10.1159/000543054","url":null,"abstract":"<p><strong>Background: </strong><i>HERC2</i> encodes an E3 ubiquitin ligase that plays a critical role in brain development. Loss-of-function variants are associated with severe neurodevelopmental phenotypes, including intellectual disability, epilepsy, and various structural anomalies. This report aimed to expand phenotypic spectrum of <i>HERC2</i>-related disorders, including an unusual cardiac manifestation.</p><p><strong>Case presentation: </strong>The proband, a male infant born to consanguineous parents, presented with myoclonia-like eyelid movements at 50-days old and subsequently developed severe neuromotor regression and choreoathetotic movements. Brain magnetic resonance imaging revealed diffuse cerebral atrophy, corpus callosum thinning, and bilateral pachygyria. He also exhibited distinct dysmorphic features and dilated cardiomyopathy, confirmed by echocardiography. His sibling presented with similar features, including severe developmental delay and dilated cardiomyopathy. Whole-exome sequencing identified a homozygous likely pathogenic c.7645C>T (p.Gln2549Ter) variant in the <i>HERC2</i> gene. This case report is significant as it describes dilated cardiomyopathy in MRT38, a manifestation not previously associated with HERC2 variants. The unusual cardiac phenotype suggests a potential link between HERC2 dysfunction and mitochondrial impairment, contributing to cardiomyopathy.</p><p><strong>Conclusion: </strong>These patients underscore the importance of recognizing novel clinical features associated with the <i>HERC2</i> LoF variants, which can guide disease characterization and patient management.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 5","pages":"469-475"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245562","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}

{"title":"Hereditary Spastic Paraplegy Associated with the AP4S1 Gene: A Case Series Highlighting Diagnostic Pitfalls and Phenotypic Variability.","authors":"Çağatay Günay, Hande Gazeteci Tekin","doi":"10.1159/000547189","DOIUrl":"https://doi.org/10.1159/000547189","url":null,"abstract":"<p><strong>Introduction: </strong>Complex hereditary spastic paraplegias (HSPs) are defined by progressive spasticity with diverse neurological manifestations, complicating the diagnostic process. Pathogenic variants in genes encoding subunits of the adaptor protein complex-4 (AP4), including the <i>AP4S1</i> gene, have been implicated in a subset of HSPs.</p><p><strong>Case presentation: </strong>We report three siblings with complex HSP harboring pathogenic <i>AP4S1</i> gene variants, focusing on the clinical characteristics and the diagnostic challenges and pitfalls. The patients exhibited common clinical features such as progressive spasticity, distinctive craniofacial features, and neurodevelopmental delays. Neuroimaging findings included agenesis of the corpus callosum and ventricular enlargement in two siblings, whereas one sibling demonstrated normal brain imaging. Initially, these cases were misdiagnosed as cerebral palsy, leading to unwarranted surgical interventions for tethered cord syndrome. Copy number variation analysis identified homozygous deletions in the <i>AP4S1</i> gene.</p><p><strong>Conclusion: </strong>In patients with progressive spasticity, seizures, distinctive craniofacial features, and neuroimaging anomalies, <i>AP4S1</i>-related HSP should be considered in the differential diagnosis. Enhanced awareness and further studies are vital for improving diagnostic precision and management of these intricate neurogenetic disorders.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 5","pages":"489-497"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245557","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}

{"title":"A Family of <i>LBR</i> Biallelic Pathogenic Variants Resulting in Rhizomelic Skeletal Dysplasia with Pelger-Huët Anomaly.","authors":"Esra Dirimtekin, Çekdar Kapazan, Barış Yılmaz, Ahmet Mert Yanık, Bilgen Bilge Geckinli","doi":"10.1159/000544916","DOIUrl":"https://doi.org/10.1159/000544916","url":null,"abstract":"<p><strong>Introduction: </strong>The lamin-B receptor (LBR) gene has two primary functions: maintaining the structural integrity of the nuclear envelope and playing a role in cholesterol biosynthesis. Heterozygous variants in the LBR gene have been associated with Pelger-Huët anomaly (PHA, OMIM #169400), while homozygous or compound heterozygous mutations have been associated with rhizomelic skeletal dysplasia, with or without PHA (OMIM #618019) and Greenberg dysplasia (OMIM #215140).</p><p><strong>Case presentation: </strong>We report a 4-year-old boy presenting with short stature and short limbs and his mother exhibiting milder findings. Genetic analysis revealed a heterozygous c.1640A>G (p.Asn547Ser) and c.43C>T (p.Arg15*) variants in the <i>LBR</i> gene in both the boy and his mother. The father was identified as a heterozygous carrier of the c.43C>T (p.Arg15*) variant. Peripheral blood smears confirmed the PHA in the patient and his parents.</p><p><strong>Conclusion: </strong>The phenotypic differences observed between the mother and male child in our study highlight the genetic variability and regressive nature of LBR-related skeletal dysplasias. This report shows the complexity of <i>LBR</i>-related phenotypes and expands the clinical spectrum of <i>LBR</i> mutations in rhizomelic skeletal dysplasia with PHA.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 5","pages":"498-506"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500306/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245559","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}

{"title":"A Novel Premature Termination Codon Mutation in TRAPPC2 Is Associated with X-Linked Spondyloepiphyseal Dysplasia Tarda.","authors":"Deniz Yasar, Naz Güleray Lafcı, Gülin Karacan Küçükali, Aslıhan Araslı Yılmaz, Beyhan Özkaya Dönmez, Burak Tahir Yazar, Berna Uçan, İclal Okur, Behiye Sarıkaya Özdemir, Erdal Kurnaz, Melikşah Keskin, Şenay Savaş Erdeve","doi":"10.1159/000543039","DOIUrl":"https://doi.org/10.1159/000543039","url":null,"abstract":"<p><strong>Introduction: </strong>Spondyloepiphyseal dysplasia tarda (SEDT) is an inherited disorder that is typically diagnosed in childhood or adolescence. It is characterized by disproportionate short stature and premature osteoarthritis, and it frequently affects males. Here, we described a novel nonsense mutation, c.406A>T; p(Lys136Ter), in <i>TRAPPC2</i> (NM_001011658.4) in a Turkish patient with X-linked SEDT.</p><p><strong>Case presentation: </strong>A 15-year-old boy, born to non-consanguineous Turkish parents, exhibited a decline in height velocity over 3 years and complained of back pain despite minimal physical activity. Growth and development were normal until adolescence, with the patient's weight at 35 kg (SDS -3.85), height at 134 cm (SDS -5.44), and a predicted adult height of 137.6 cm. Dysmorphic facial features, microtia, synophrys, hypotelorism, and barrel chest were noted. Radiological examination revealed osteopenic bone structure, hypoplastic odontoid process, platyspondyly, scoliosis, short femoral necks, and coxa vara. Genetic analysis identified a hemizygous novel stop codon mutation (c.406A>T; pLys136Ter) in <i>TRAPPC2</i>, also detected as heterozygous in the patient's mother.</p><p><strong>Conclusion: </strong>In adolescence or childhood, X-linked SEDT should be considered in cases of disproportionate short stature, short trunk, osteoarthritis, and a family history that is appropriate for X-linked inheritance. Skeletal survey should be performed to suspect SEDT, and radiological findings may support diagnosis.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 5","pages":"461-468"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245625","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}

{"title":"Genetics of Mitochondrial Aminoacyl-tRNA Synthetases Associated with Sensorineural Hearing Loss.","authors":"Baicheng Xu, Jing Chai, Panpan Bian, Yufen Guo","doi":"10.1159/000542981","DOIUrl":"https://doi.org/10.1159/000542981","url":null,"abstract":"<p><strong>Background: </strong>Aminoacyl-tRNA synthetases are highly conserved proteins that catalyze the tRNA aminoacylation reaction to produce aminoacyl-tRNAs involved in protein synthesis, which are required to translate cytoplasmic and mitochondrial proteins. The mt-ARS genes encode the mitochondrial aminoacyl-tRNA synthetase (mt-ARSs), and variants in mt-ARS genes affect mitochondrial protein synthesis. This can impair the translation of mitochondrial proteins, adversely affecting oxidative phosphorylation and leading to related diseases. To date, 19 mt-ARS genes have been identified and found to be strongly associated with the development of mitochondrial disorders. Hearing loss (HL) is one of the most common chronic conditions in children and a leading cause of communication disorders. Genetic studies of sensorineural HL are critical to diagnosing and treating sensorineural HL. The relationship between mt-ARS genes and sensorineural HL is gradually surfacing as cases of HL phenotypes caused by variants in the mammalian mt-ARS genes continue to be reported. Seven mt-ARS genes have been reported to contribute to various hereditary sensorineural HL.</p><p><strong>Summary: </strong>This article reviews studies on mitochondrial aminoacyl-tRNA synthetase, mt-ARS genes, and variants associated with HL phenotypes. Investigating their genetic characteristics provides deeper insights into the pathophysiology and molecular mechanisms of sensorineural hearing loss.</p><p><strong>Key messages: </strong>Disease phenotypes resulting from variants in mt-ARS genes exhibit significant clinical heterogeneity. The varying degrees of sensorineural HL phenotypes caused by mt-ARS gene variants warrant the attention of otologists and researchers. At least seven of the currently reported mt-ARS genes are associated with sensorineural HL. However, the molecular mechanisms by which these genes contribute to HL remain incompletely understood. Further studies of the mt-ARS genes still await additional case reports, as well as related model animal studies and combined functional studies.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 5","pages":"449-460"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245592","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}

{"title":"Homozygous PGAP2 Mutation Causes Hyperphosphatasia with Mental Retardation Syndrome-3: Genetic and Clinical Evaluation of the Ultra-Rare Inherited Glycosylphosphatidylinositol Biosynthesis Defect.","authors":"Aynur Küçükçongar Yavaş, Sümeyra Zeynep Özbey, Bora Ergin, Yasemin Ünal, Berrak Bilginer Gürbüz, Betül Karaatmaca, Hamit Özyürek, Ofcan Oflaz, Hacer Basan, Çiğdem Seher Kasapkara","doi":"10.1159/000542617","DOIUrl":"https://doi.org/10.1159/000542617","url":null,"abstract":"<p><strong>Introduction: </strong>Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that results from mutations in the genes encoding proteins participating in glycosylphosphatidylinositol biosynthesis and modification. Glycosylphosphatidylinositol anchor proteins play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response, and signaling. Hyperphosphatasia with mental retardation syndrome-3 is one of the glycosylphosphatidylinositol anchor defects, characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures, and persistent hyperphosphatasia. The aims of this study were to investigate the clinical implications of the <i>PGAP2</i> gene and identify the severe phenotype.</p><p><strong>Case presentation: </strong>A male patient with dysmorphic features, neurodevelopmental delay, seizures, hearing loss, Hirschsprung disease, central fever, and elevated alkaline phosphatase was included in the study. The magnetic resonance imaging showed cerebral atrophy and corpus callosum hypoplasia. The whole-exome sequencing analysis of the individual and Sanger sequencing were performed for segregation. Additionally, next-generation sequencing, whole transcriptome sequencing, and homology modeling and analysis were performed. Whole-exome sequencing revealed a homozygous c.651C>G (p.His217Gln) in the <i>PGAP2</i> gene. The Sanger sequencing confirmed the parents were heterozygous. There is no splicing variant detected by whole transcriptome sequencing. The AlphaFold model was interpreted hypothetically. It observed the substitution of histidine, with glutamine, and may affect the stability of protein.</p><p><strong>Discussion: </strong>Homozygous PGAP2 mutations in the patient we reported in our study resulted in a severe clinical picture including severe developmental delay and intellectual disability, severe epilepsy, dysmorphic features, central fever, biochemical, hormonal, and immunological abnormalities. This patient would be the youngest case published in the literature. We showed that the instability of mutant PGAP2 protein that causes hyperphosphatasia with mental retardation syndrome-3 leads to more severe phenotypes.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":"16 5","pages":"476-488"},"PeriodicalIF":0.9,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12500300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145245594","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}

{"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}

{"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}

{"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}

{"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}