Molecular Syndromology最新文献

{"title":"Phenotype-Driven Whole-Exome Sequencing Reanalysis Identifies a Homozygous PPP2R3C Variant in Syndromic 46,XY and 46,XX Gonadal Dysgenesis: Case Report and Review of the Literature.","authors":"Fatma Yavuzyilmaz Simsek, İlknur Arslanoglu","doi":"10.1159/000552785","DOIUrl":"10.1159/000552785","url":null,"abstract":"<p><strong>Introduction: </strong>PPP2R3C-related syndromic gonadal dysgenesis is a rare disorder of sex development (DSD) characterized by gonadal failure, extragonadal anomalies, and a recognizable facial gestalt, reported in both 46,XY and 46,XX individuals. We report two siblings with myoectodermal gonadal dysgenesis syndrome due to homozygous PPP2R3C variants, diagnosed through phenotype-driven reanalysis of whole-exome sequencing (WES).</p><p><strong>Case presentation: </strong>We describe two siblings with syndromic gonadal dysgenesis who were diagnosed through phenotype-driven reanalysis of WES. The index patient, a 14-year-old phenotypic female with a 46,XY karyotype, presented with complete gonadal dysgenesis, renal agenesis, congenital heart disease, hearing loss, and intellectual disability. Her 8-year-old sister, with a 46,XX karyotype, showed ovarian dysgenesis, renal agenesis, and a similar craniofacial gestalt. Both carried a homozygous <i>PPP2R3C</i> c.1049T>C (p.Phe350Ser) variant, which was initially missed on routine WES but identified upon targeted reanalysis guided by their clinical features.</p><p><strong>Conclusion: </strong>These cases highlight the rarity of <i>PPP2R3C</i>-related syndromic gonadal dysgenesis and provide further evidence that the condition affects both chromosomal sexes. Our findings underscore the diagnostic importance of combining detailed phenotyping - including appreciation of distinctive facial gestalt - with systematic WES reanalysis. This approach is particularly valuable in unresolved syndromic DSD, where variable expressivity may obscure recognition of the underlying genetic defect.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13363279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148438583","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 Homozygous Frameshift <i>GTPBP2</i> Variant in Jaberi-Elahi Syndrome: First Case Report from Türkiye.","authors":"Merve Soğukpınar, Yavuz Ataş, Gülcan Üner, Perver Arslan, Hazal Ceren Tuğrul, Havva Akmaz Ünlü, Başak Uzunyayla Sayıcı","doi":"10.1159/000552675","DOIUrl":"10.1159/000552675","url":null,"abstract":"<p><strong>Introduction: </strong>Jaberi-Elahi syndrome is a rare autosomal recessive neurodevelopmental disorder caused by biallelic loss-of-function variants in <i>GTPBP2</i>, a gene involved in ribosome-associated quality control. The condition shows marked phenotypic heterogeneity, including microcephaly, hypotonia or spasticity, developmental delay, intellectual disability, movement disorders, epilepsy, and variable neuroimaging findings.</p><p><strong>Case presentation: </strong>We report a 4-month-old female infant born to consanguineous parents, presenting with severe microcephaly, developmental delay, hypotonia, and craniofacial features. Additional findings included left-sided pes equinovarus, secundum atrial septal defect, and periventricular white matter abnormalities on brain magnetic resonance imaging (MRI). No overt ectodermal abnormalities were observed. Ophthalmological examination revealed no structural anomalies; however, detailed retinal evaluation and electroretinography could not be performed. During follow-up, the patient developed early-onset seizures requiring antiepileptic treatment. Exome sequencing identified a novel homozygous frameshift variant in <i>GTPBP2</i> (c.1165_1166del; p.(Leu389GlufsTer26)), classified as likely pathogenic. This homozygous variant was absent in population databases, and segregation analysis confirmed parental heterozygosity. This represents the first reported case with Jaberi-Elahi syndrome from Turkey.</p><p><strong>Conclusion: </strong>Jaberi-Elahi syndrome should be considered in infants with severe congenital microcephaly, developmental delay, seizures, and craniofacial features, particularly in the context of consanguinity and abnormal brain MRI. This report expands the molecular and clinical spectrum of Jaberi-Elahi syndrome.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13436975/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674436","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":"Complimentary Episignature Testing for Variant Reclassification: Case Reports with Variant Classification Guideline Consideration.","authors":"Pratibha Bawa, Jessica Rzasa, Jennifer Kerkhof, Michael A Levy, Bekim Sadikovic, Shifali Gupta, Rajni Sharma, Priyanka Srivastava, Inusha Panigrahi, Anupriya Kaur","doi":"10.1159/000552586","DOIUrl":"10.1159/000552586","url":null,"abstract":"<p><strong>Introduction: </strong>Variants of uncertain significance (VUS) are being increasingly encountered in contemporary clinical genetics practice. Peripheral blood derived global DNA methylation pattern or Episignatures have been established for several Mendelian disorders.</p><p><strong>Case presentation: </strong>We describe in detail the phenotype, genotype and episignature analysis of two children with atypical presentations of Rubinstein-Taybi and Cornelia de Lange syndromes. Whole exome sequencing showed missense VUS (<i>CREBBP</i>:c.3503A>G p.(Asn1168Ser) and <i>NIPBL</i>:c.6535T>G p.(Tyr2179Asp). Infinium Human Methylation 935 (EPICv2 array) was performed followed by methylation analysis using the EpiSign^™ METRIC (Methylation based Episignature Testing and Reference based Interpretation and Classification) V5 assay. METRIC score of 1 suggesting high confidence concordance with the episignature pattern associated with pathogenic variants in <i>CREBBP</i> and <i>NIPBL</i> was obtained.</p><p><strong>Conclusion: </strong>We introduce the METRIC scoring component of the EpiSign^™ assay, which provides an integrated assessment of concordance between a patient's methylation profile and established episignatures, representing an evolution from earlier approaches using Methylation Variant Probability (MVP) scoring. While formal guidance for Bayesian point-based use of episignature results is not yet established, this functional evidence has clear potential for future incorporation and may enhance variant interpretation when combined with genomic data.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13354298/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148425449","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":"Detailed Clinical Report of Four Individuals from a Nusayri Family with a Rare TNXB Variant: Classical-Like and Hypermobile Types of Ehlers-Danlos Syndrome.","authors":"Sabri Aynacı, Sinem Kocagil, Oğuz Çilingir","doi":"10.1159/000552325","DOIUrl":"10.1159/000552325","url":null,"abstract":"<p><strong>Introduction: </strong>Ehlers-Danlos syndrome (EDS, MIM #606408) is a group of clinically and genetically heterogeneous connective tissue disorders characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. EDS, Classical-like, 1 (clEDS, MIM #606408) is one of the rarest subtypes caused by biallelic pathogenic variants in <i>TNXB</i> (MIM *600985). <i>TNXB</i> haploinsufficiency has been suggested to be associated with EDS, hypermobility type (hEDS; OMIM %130020), which is considered one of the most common EDS subtypes. However, the underlying molecular mechanisms of hEDS remain largely unknown, and heterozygosity for <i>TNXB</i> variants has been proposed as a potential contributing factor rather than a definitive cause.</p><p><strong>Methods: </strong>We report four siblings from a consanguineous Nusayri family with three siblings affected with clEDS and one sibling with hEDS phenotypes. Whole-exome sequencing and RT-PCR analysis from peripheral blood samples were performed in affected siblings and parents.</p><p><strong>Results: </strong>A homozygous pathogenic <i>TNXB</i> variant (c.3763dup) was identified in three siblings with clEDS. Oldest brother, who met the criteria for hEDS, was heterozygous for this rare variant similar to the parents who were asymptomatic. TNXB expression analysis was significantly lower in homozygous individuals compared to heterozygotes but no significant difference was observed between symptomatic and asymptomatic heterozygotes.</p><p><strong>Conclusion: </strong>This is the first detailed clinical report of a Nusayri family in which a homozygous <i>TNXB</i> variant is associated with clEDS, and in which one heterozygous carrier presents with clinical features consistent with hEDS. Our findings contribute to the limited literature on clEDS, particularly in understudied populations. The clinical findings suggest the potential role of <i>TNXB</i> haploinsufficiency in hEDS; however, further research is needed to elucidate the variable expressivity and possible incomplete penetrance associated with hmEDS.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13363281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148438551","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":"Acute Liver Failure following Valproate Exposure in a Teenager with Homozygous POLG c.2243G>C (p.Trp748Ser) Mutation: Late-Onset Presentation and Successful Liver Transplantation - A Case Report.","authors":"Ibrahim Bingol, Ozge Umur, Sare Guntulu Sık, Tonguc Utku Yilmaz, Remzi Emiroglu, Agop Citak","doi":"10.1159/000552241","DOIUrl":"10.1159/000552241","url":null,"abstract":"<p><strong>Introduction: </strong>Valproic acid (VPA)-induced acute liver failure (ALF) is a severe and potentially fatal complication, particularly in pediatric patients with mitochondrial dysfunction. Mutations in the polymerase gamma (<i>POLG</i>) gene, especially those associated with Alpers-Huttenlocher syndrome, significantly increase susceptibility to VPA hepatotoxicity.</p><p><strong>Case presentation: </strong>We report a previously healthy 17-year-old girl who developed ALF after 1 month of VPA therapy prescribed for refractory focal seizures. Despite prompt discontinuation of VPA, she developed progressive jaundice, coagulopathy, hyperammonemia, and hepatic encephalopathy. Liver biopsy revealed microvesicular steatosis and centrilobular necrosis, consistent with drug-induced liver injury. Her condition deteriorated with hypertension, refractory seizures, and radiological features of posterior reversible encephalopathy syndrome (PRES). Whole-exome sequencing identified a NM_002693.3(<i>POLG</i>):c.2243G>C (p.Trp748Ser; p.W748S). Due to worsening hepatic function and neurological status, she underwent emergency orthotopic liver transplantation. Post-transplantation, liver function normalized, and seizures became intermittently controllable with levetiracetam and topiramate.</p><p><strong>Conclusion: </strong>This case is notable for its late adolescent onset, homozygous <i>POLG</i> c.2243G>C (p.Trp748Ser) genotype, association with PRES, and successful emergency liver transplantation, thereby expanding the clinical spectrum of <i>POLG</i>-related VPA-ALF. These findings underscore the importance of <i>POLG</i> testing prior to VPA exposure in patients with suspected mitochondrial disease, even beyond early childhood.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13300030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346983","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":"Broken and Reassembled: The Molecular Mechanisms and Clinical Consequences of Structural Genomic Variation.","authors":"Mohammad Fahad Ullah","doi":"10.1159/000552262","DOIUrl":"10.1159/000552262","url":null,"abstract":"<p><strong>Background: </strong>Structural variants (SVs) are a major class of genomic variation that profoundly influences human genetic diversity, evolution, and disease. Historically underappreciated due to detection challenges, SVs are now recognized as key drivers of both constitutional disorders and cancer. Understanding their origins and consequences is fundamental to modern genomics and clinical medicine.</p><p><strong>Summary: </strong>SVs arise from the complex interplay between endogenous sources of DNA damage - such as reactive oxygen species, replication stress, and transcription-replication conflicts - and error-prone repair mechanisms including non-allelic homologous recombination, microhomology-mediated end joining, fork stalling and template switching, and break-induced replication. The formation and patterns of these variants are critically constrained by the three-dimensional architecture of the nucleus, particularly topologically associating domains, which determine the spatial proximity of potential translocation partners. Key insights into these processes are provided by genomic instability syndromes (e.g., Bloom syndrome, Fanconi anemia, Werner syndrome, Nijmegen breakage syndrome), where specific repair pathway defects result in characteristic SV signatures and clinical phenotypes. Similarly, cancer genomes serve as detailed molecular archives of repair failures, with distinct SV patterns now enabling prediction of underlying deficiencies such as <i>BRCA</i> loss. Thus, the pattern of SVs in a tumor genome can serve as a retrospective molecular archive of underlying repair failure, enabling 'signature-based' prediction of HR deficiency even when germline BRCA status is unknown. Emerging technologies, especially long-read sequencing, have revolutionized the field by achieving >95% sensitivity for SV detection and resolving previously intractable rearrangements. Furthermore, recent discoveries regarding biomolecular condensates in DNA repair (e.g., PARP1, MRNIP phase separation) reveal previously unrecognized regulatory layers governing repair pathway choice and SV formation.</p><p><strong>Key messages: </strong>(i) SVs are generated by specific DNA lesions and error-prone repair processes, with their patterns shaped by nuclear architecture and three-dimensional genome organization. (ii) Genomic instability disorders and cancer genomes provide crucial mechanistic insights by linking specific repair pathway defects to characteristic SV signatures. (iii) Technological advances, particularly long-read sequencing, now enable comprehensive and sensitive detection of SVs, including those in complex repetitive regions. (iv) A unified framework for understanding SVs as products of DNA damage, cellular metabolism, and chromatin context has profound clinical implications for diagnostic reverse phenotyping, synthetic lethality strategies in oncology, and the development of targeted therapies.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13322703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148370416","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":"Maternally Inherited Atypical 22q11.2 Microduplication Presenting with Unilateral Microtia and Aural Atresia: A Case Report of Evidence for an Association with Severe Ear Malformations.","authors":"Hyun Ho Kim, Woori Jang, Namsu Kim, Joonhong Park","doi":"10.1159/000552122","DOIUrl":"10.1159/000552122","url":null,"abstract":"<p><strong>Introduction: </strong>22q11.2 Microduplication syndrome is a genomic disorder characterized by extreme phenotypic variability and reduced penetrance. While minor ear anomalies are common, severe malformations like microtia and aural atresia are rarely reported. We present a unique case of maternally inherited 22q11.2 microduplication with severe external ear defects but superior neurodevelopment.</p><p><strong>Case presentation: </strong>A male neonate was diagnosed with a 2.7-Mb atypical proximal 22q11.1-q11.21 duplication involving 0.7-Mb LCR22A-LCR22B region via chromosomal microarray analysis. Multiplex ligation-dependent probe amplification confirmed the duplication was inherited from his phenotypically normal mother. Clinical evaluation revealed Marx grade III microtia and complete aural atresia of the right ear, along with mild pulmonary stenosis. Despite these physical findings, the patient demonstrated exceptional cognitive outcomes, achieving a full-scale IQ of 135 and advanced language skills at 36 months.</p><p><strong>Conclusion: </strong>This case described a rare and atypical inherited 22q11.2 microduplication and expands the phenotypic spectrum of the syndrome associated with this genomic disorder by associating it with severe primary ear malformations. The presence of dosage-sensitive genes like <i>IL17RA</i>, <i>CECR2</i>, and <i>SLC25A18</i> likely drives these craniofacial anomalies and may help explain the phenotypic overlap with the Oculo-Auriculo-Vertebral Spectrum.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346933","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":"Novel Clinical and Genetic Findings in Laurin-Sandrow Syndrome: A Case Report.","authors":"Pankaj Prasun, Katelyn J Watkin","doi":"10.1159/000552214","DOIUrl":"10.1159/000552214","url":null,"abstract":"<p><strong>Introduction: </strong>Laurin-Sandrow syndrome is a very rare developmental disorder characterized by polysyndactyly of the hands and feet, as well as nasal anomalies. Often, there is associated ulnar and/or fibular duplication. It is caused by microduplications on chromosome 7q36 that encompass the Sonic hedgehog limb enhancer region, the zone of polarizing activity regulator sequence (ZRS).</p><p><strong>Case presentation: </strong>We describe here an individual with triplication encompassing the ZRS region. In addition to the other characteristic features of this condition, he has an unerupted single central maxillary incisor tooth.</p><p><strong>Conclusion: </strong>Laurin-Sandrow syndrome is caused by interrupted signaling of Sonic hedgehog pathway due to duplications encompassing its enhancer region (ZRS) on chromosome 7q36. ZRS plays a crucial role in limb development by regulating the Sonic hedgehog signaling. Nasal anomalies are well-recognized features of Laurin-Sandrow syndrome. Single median maxillary central incisor has not been described in Laurin-Sandrow syndrome, but it is associated with Sonic hedgehog signaling interruption. The presence of nasal anomalies and dental abnormality in Laurin-Sandrow syndrome may suggest a potential role of ZRS in craniofacial development beyond its known role in limb development.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148346944","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 Intracellular Domain Missense Variant in <i>GRM7</i> Associated with Early-Onset Neurodevelopmental Encephalopathy.","authors":"Zehra Manav Yigit, Hulya Kayilioglu, Ibrahim Onder Yeniceri","doi":"10.1159/000551886","DOIUrl":"10.1159/000551886","url":null,"abstract":"<p><strong>Introduction: </strong>Biallelic pathogenic variants in the <i>GRM7</i> gene, which encodes the metabotropic glutamate receptor 7 (mGlu7), have been associated with early-onset neurodevelopmental disorders characterized by epilepsy, developmental delay, and white matter abnormalities. However, reported cases predominantly involve variants affecting the extracellular or transmembrane domains, and the full phenotypic spectrum remains unclear.</p><p><strong>Case presentation: </strong>We present the case of a male patient exhibiting early-onset focal epilepsy, global developmental delay, and neuroimaging evidence of corpus callosum thinning alongside normal myelination. Clinical exome sequencing identified a novel homozygous missense variant in the intracellular C-terminal domain of <i>GRM7</i> (c.2528C>T; p.(Pro843Leu)). This variant is present at extremely low frequency in population databases and has not been reported in the homozygous state. It also affects a highly conserved residue. In silico prediction tools support the assessment of its pathogenicity. While the patient's clinical features partially overlap with those reported in other <i>GRM7</i>-associated cases, they are notable for the absence of primary microcephaly and the presence of isolated motor delay, along with preserved myelination.</p><p><strong>Conclusion: </strong>This report adds further clinical and genetic evidence to the growing literature on <i>GRM7</i>-associated neurodevelopmental disorders and highlights the potential relevance of intracellular domain variants, which are underrepresented in the current literature. <i>GRM7</i> should be included in diagnostic gene panels for infantile-onset epilepsy and developmental delay, particularly in populations with high consanguinity rates. Further functional studies are needed to clarify the impact of intracellular <i>GRM7</i> variants on receptor signaling and clinical outcome.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13293610/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148333406","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":"PHRINL Syndrome: A Case of Infantile Cataract and Cardiomyopathy.","authors":"Aliye Gülbahçe, Adnan Deniz, İsmihan Merve Tekin, Bülent Kara","doi":"10.1159/000551787","DOIUrl":"10.1159/000551787","url":null,"abstract":"<p><strong>Introduction: </strong>Pontocerebellar Hypoplasia, Hypotonia, and Respiratory Insufficiency Syndrome, Neonatal Lethal (PHRINL Syndrome) is a rare genetic disorder caused by impaired oxidative phosphorylation due to reduced activity of mitochondrial complexes I, IV, and V. The condition results from homozygous or compound heterozygous pathogenic variants in the <i>ATAD3A</i> gene, and is inherited in an autosomal recessive manner. Affected individuals typically present in early infancy with hypotonia, encephalopathy, corneal clouding, cardiomyopathy, and respiratory failure, and often die during infancy.</p><p><strong>Case presentation: </strong>A 40-day-old female infant was referred for evaluation of a possible inherited metabolic disorder following the death of her brother at 9 months of age. No abnormalities were detected in the metabolic workup. Hypotonia was identified on physical examination at 3 months of age, brain magnetic resonance imaging (MRI) revealed pontocerebellar hypoplasia. Whole-exome sequencing (WES) identified two genetic alterations in the <i>ATAD3A</i> gene, leading to the diagnosis of PHRINL Syndrome. <i>ATAD3A</i> (NM_001170535.3: c.229C>G; p.Leu77Val) c.229C>G heterozygous missense variant was detected, along with a 0.61 kb heterozygous deletion encompassing exons 3-4 of the <i>ATAD3A</i> gene. The patient diagnosed with hypotonia at 3 months of age, developed cataracts at 5 months, and died in the eighth month due to refractory seizures.</p><p><strong>Conclusion: </strong>In hypotonic infants presenting with cataracts and cardiomyopathy, elevated plasma lactate levels and increased urinary excretion of 3-methylglutaconate and 3-methylglutarate may suggest PHRINL syndrome; however, the diagnosis should not be excluded solely on the basis of normal metabolic test results when characteristic clinical features are present.</p>","PeriodicalId":48566,"journal":{"name":"Molecular Syndromology","volume":" ","pages":""},"PeriodicalIF":0.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13200845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148036754","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}