Case Reports in Genetics最新文献

{"title":"<i>RAPSN</i>-Associated Congenital Myasthenic Syndrome due to Biallelic Single Nucleotide Variants at the Same Position.","authors":"Laura Keehan, Jennefer N Carter, Elijah Kravets, Matthew T Wheeler, Jonathan A Bernstein, Ricardo A Maselli, Jacinda B Sampson, Suha Bachir","doi":"10.1155/crig/1882021","DOIUrl":"10.1155/crig/1882021","url":null,"abstract":"<p><p>Biallelic pathogenic variants in <i>RAPSN</i> cause a form of congenital myasthenic syndrome (CMS), which is typically characterized by fatiguable muscle weakness, hypotonia, and feeding difficulties that present in the neonatal period or early childhood. <i>RAPSN</i>-associated CMS can be treated with acetylcholinesterase inhibitors. Here, we present a 4-year-old male with a history of neonatal respiratory distress, hypotonia, and muscle weakness exacerbated by illness who underwent trio genome sequencing and was found to have biallelic single nucleotide variants at the same position in <i>RAPSN</i>, encoding NM_005055.5:c.264C > A p.(N88K) and NM_005055.5:c.264C > G p.(N88K). The paternally inherited c.264C > G variant has not been previously reported. Interestingly, only the maternally inherited c.264C > A variant was reported on the patient's prior clinical exome sequencing, which delayed diagnosis and initiation of treatment for this patient. This case highlights the complexity of identifying multiallelic variants during exome and genome sequencing analysis. Additionally, this case is the first report of facial malformations in a patient with <i>RAPSN</i>-associated CMS due to variants outside of the promoter region. <b>Trial Registration:</b> ClinicalTrials.gov identifier: NCT02450851.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"1882021"},"PeriodicalIF":0.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12558694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145393694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone Marrow Failure Associated With Short Telomeres and Digenic Variants of Uncertain Significance in Telomere Biology Genes.","authors":"Akhila Vadivelan, Geraldine Aubert, Julian A Martinez, Alan Ikeda, Satiro De Oliveira, Theodore B Moore, Vivian Chang","doi":"10.1155/crig/2075063","DOIUrl":"10.1155/crig/2075063","url":null,"abstract":"<p><p>Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by short telomeres. We report two patients that presented with bone marrow failure (BMF), who were identified to have low telomere length (TL) and variants of uncertain significance (VUS) in two different telomere genes inherited from their parents. At age 6, Patient 1 had stage 4 neuroblastoma. He was treated with chemotherapy, surgery, immunotherapy, and autologous stem cell rescue. At age 10, he developed pancytopenia. Bone marrow biopsy revealed hypocellular marrow and der (1; 7), associated with myelodysplastic syndrome. Germline genetic evaluation showed a pathogenic variant in DNAJC21 (from father) and VUS in NAF1 (c.1375C > T) (from father) and RTEL1 (c.533T > C) (from mother). The patient was found to have very low TL (VLTL) (< 1st percentile) in 4/6 white blood cell subsets. The patient's mother was found to have borderline low TL (VLTL) ( 1 and < 10th percentiles) in 4/6 subsets and VLTL in 1/6 subsets. Father had VLTL in 1/6 but normal TL in other subsets. Neither parent reported any symptoms of TBD. Patient 2 presented with a depressed skull fracture at age 15. He was found incidentally to have pancytopenia. Bone marrow biopsy showed hypocellular marrow and no cytogenetic abnormalities. The patient had VLTL in all 6/6 subsets. Genetic evaluation showed VUSs in TERT (c.3158-80G > A) (from mother), TINF2 (c.814T > C) (from mother) and SRP72 (c.1928C > T) (from father). Mother was also found to have VLTL in all 6 subsets but has reported good health except for premature graying of hair. These two patients presented with BMF, identified to have VUSs in more than one TBD-associated gene with functional evidence of shortened telomeres, highlighting the potential for a digenic mode of inheritance. Synergy between two VUSs could contribute to a penetrant phenotype and resulting in earlier or more severe onset of disease.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"2075063"},"PeriodicalIF":0.0,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12549202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145373062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Variant in the <i>BICRA</i> Gene, Expanding the Phenotype: A Case Report.","authors":"Catherine Kentros, Wendy K Chung, Mythily Ganapathi","doi":"10.1155/crig/4041217","DOIUrl":"10.1155/crig/4041217","url":null,"abstract":"<p><p>We report a 71-year-old female patient with a history of intellectual disabilities, dysmorphic features, schizoaffective disorder, bipolar type, and psychosis. Exome sequencing revealed a novel, heterozygous, predicted loss-of-function variant in the <i>BICRA</i> gene (NM_015711.3: c.1910del, p.[Leu637ArgfsTer87]). Heterozygous rare variants in <i>BICRA</i> have been associated with Coffin-Siris Syndrome 12 (CSS-12; OMIM #619325). This is the oldest patient to date with a pathogenic variant in <i>BICRA</i>. This case report expands the clinical phenotype associated with <i>BICRA</i> variants and sheds light on the long-term prognosis.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"4041217"},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12543444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145356195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emanuel Syndrome: A Case Report With Isolated Nuchal Translucency Thickening.","authors":"Bondarenko Maya, Nikolenko Marharyta, Dutchak Anastasiia, Kupchak Iryna, Ivanova Irina, Arbuzova Svitlana","doi":"10.1155/crig/5541504","DOIUrl":"10.1155/crig/5541504","url":null,"abstract":"<p><strong>Introduction: </strong>Emanuel syndrome is a rare chromosomal disorder characterized by severe developmental disability and variable clinical manifestations. Although congenital anomalies are relatively common, there is no pathognomonic prenatal pattern. In some cases, structural defects are absent or not detectable prenatally, making the potential role of soft ultrasound markers particularly relevant.</p><p><strong>Case presentation: </strong>We report a case of Emanuel syndrome in which no structural malformations were identified prenatally. First-trimester ultrasound revealed an isolated increased nuchal translucency of 3.2 mm. Postnatally, the infant exhibited severe hypotonia, dysmorphic features, and profound developmental delay, but no gross structural defects were observed. Cytogenetic and FISH analyses confirmed an additional der(22)t(11; 22) chromosome inherited from the mother.</p><p><strong>Discussion: </strong>A review of the limited literature on first-trimester findings suggests that increased nuchal translucency has been observed in several cases of Emanuel syndrome, although the available data remain insufficient to assess predictive value. Nevertheless, the recurrence of this observation across independent reports indicates that NT enlargement may warrant attention as a potential prenatal marker.</p><p><strong>Conclusion: </strong>While current evidence is insufficient to draw definitive conclusions, this case highlights that isolated NT thickening may represent the only prenatal sign of Emanuel syndrome. Evaluation in larger cohorts and future prospective studies will be essential to determine the sensitivity and specificity of this marker for early diagnosis of the syndrome and the timely identification of balanced translocation carriers.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"5541504"},"PeriodicalIF":0.0,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12527601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Dysfunction in Sickle Cell Trait Carriers With Exertional Collapse.","authors":"Kristen A Cofer, Liam Friel, Mingqiang Ren, Carolyn Dartt, Francesca Cariello, Kyung Kwon, Patricia A Deuster, Nyamkhishig Sambuughin, Tianzheng Yu, Francis G O'Connor","doi":"10.1155/crig/4478581","DOIUrl":"10.1155/crig/4478581","url":null,"abstract":"<p><p>Sickle cell trait (SCT) increases the risk of sudden death and exertional rhabdomyolysis (ER) in athletes and Service Members (SMs) during intense exercise. Exertional injuries in SCT carriers can result in exercise collapse associated with SCT (ECAST), an under-recognized condition characterized by variable clinical presentations ranging from ischemic muscle pain to fulminant collapse. This study presents clinical and genetic findings of two independent Black SMs with history of ECAST triggered by strenuous exercise. ECAST cases carried pathogenic heterozygous mutations <i>POLG</i>: p.Gly848Ser and <i>RRM2B:</i> p.Met282Ile associated with mitochondrial DNA depletion syndromes. Mononuclear cell mitochondria extracted from ECAST cases showed impaired mitochondrial profiles and resilience, demonstrating the potential contribution of mitochondrial dysfunction to exertional collapse in SCT carriers.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"4478581"},"PeriodicalIF":0.0,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12520808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145303668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Extremely Preterm Infant With <i>PIK3CA-</i>Related Overgrowth Spectrum (PROS): Alpelisib Treatment and Outcome.","authors":"Sharon Anderson, Milen Velinov","doi":"10.1155/crig/6839348","DOIUrl":"10.1155/crig/6839348","url":null,"abstract":"<p><p>Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (<i>PIK3CA</i>)-related overgrowth spectrum (PROS) is a group of rare genetic asymmetric and atypical overgrowth disorder syndromes. Affecting skin, adipose and connective tissues, brain, bone, and vasculature and severity influenced by the gestational age at which the change occurred, PROS is phenotypically heterogeneous. This paper shares the case report of a former extremely preterm infant diagnosed with a subtype of PROS, megalencephaly-capillary malformation/megalencephaly-capillary malformation polymicrogyria (MCAP) syndrome, for whom treatment with alpelisib was initiated at 10 months of age (7 months corrected age). To our knowledge, this patient is the third and youngest to be included in this expanded access program for compassionate use for patients under 2 years of age.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"6839348"},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Case of <i>NOTCH1</i> Variant and Nonimmune Hydrops Fetalis: A Case Report.","authors":"Genevieve R Mazza, Alesandra R Rau, Madushka Y De Zoysa","doi":"10.1155/crig/6865742","DOIUrl":"10.1155/crig/6865742","url":null,"abstract":"<p><p>Nonimmune hydrops fetalis (NIHF) refers to the pathologic accumulation of fluid within the fetus due to causes other than red cell alloimmunization and now accounts for up to 90% of fetal hydrops cases. Fetal hydrops is associated with significant morbidity and mortality, and the exact prognosis is largely dependent on the underlying etiology. The most common etiologies include cardiovascular causes and chromosomal or genetic abnormalities. Despite this, diagnostic testing with karyotype or chromosomal microarray only identifies approximately 25% of cases, and up to 20% of cases remain idiopathic or unknown. We report the first known case of NIHF related to a <i>NOTCH1</i> pathogenic variant. In this case, NIHF was diagnosed at 30 weeks' gestation in a fetus with low-risk prenatal genetic screening, noncontributory anatomic survey, and normal chromosomal microarray. The hydrops was uniquely localized to scalp edema and pleural effusions requiring bilateral thoracentesis and never progressed to involve pericardial effusion or ascites. Whole exome sequencing diagnosed a novel pathogenic variant in the <i>NOTCH1</i> gene. This is the first reported case of NIHF in the setting of <i>NOTCH1</i> pathogenic variant and is an important addition to the existing literature on this incredibly diverse, high-risk pathology.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"6865742"},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145030991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Unexpected Case of Somatic Mosaicism of the Dutch p16-<i>Leiden</i> Founder Variant in the <i>CDKN2A</i> Gene.","authors":"M van der Meulen, J T van Wezel, D Terlouw, J Morreau, E M P Steeghs, R van Doorn, M E van Leerdam, A M Onnekink, M C de Ruiter, N van der Stoep, T P Potjer","doi":"10.1155/crig/6261903","DOIUrl":"10.1155/crig/6261903","url":null,"abstract":"<p><p><i>CDKN2A</i> is the primary high-risk predisposition gene for familial cutaneous melanoma. In the Netherlands, most carriers of pathogenic germline variants in <i>CDKN2A</i> harbor a unique, population-specific founder variant, c.225_243del, commonly referred to as p16-<i>Leiden</i>. For decades, this distinctive 19 base-pair deletion in <i>CDKN2A</i> had been identified exclusively as a germline variant. Here, we report an exceptional case of somatic mosaicism for the p16-<i>Leiden</i> variant in an Irish male with a concurrent diagnosis of Kartagener's syndrome but no history of malignancy. The variant was first identified through targeted next-generation sequencing (NGS) of a fundic gland polyp in the distal esophagus, showing a variant allele frequency (VAF) of 40%. Subsequent analysis also detected the variant in the patient's buccal swab DNA (VAF 0.3%), while it was notably absent in multiple other tissue samples, including blood, urine, skin, and several additional samples from the proximal gastrointestinal tract. We explore several hypotheses that could explain these intriguing findings.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"6261903"},"PeriodicalIF":0.0,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12411021/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145016357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infant Born With Autosomal Recessive Glycogen Storage Disease Type IV due to Complete Maternal Isodisomy of Chromosome 3.","authors":"Sigrid Skovby Olsen, Anja Ernst, Pia Sønderby Christensen, Ellen Dagmar Björnsdóttir, Lasse Ringsted Mark, Albert Vejlin Stefansen, Allan Thomas Højland","doi":"10.1155/crig/5577571","DOIUrl":"10.1155/crig/5577571","url":null,"abstract":"<p><p>Uniparental disomy (UPD), the inheritance of two copies of a chromosome from one parent, can lead to recessive genetic disorders or imprinting effects. We report a case of autosomal recessive glycogen storage disease type 4 (GSD IV) due to maternal UPD of chromosome 3, representing the first reported instance of UPD leading to this rare disorder. To avoid an unjustified claim of misattributed paternity, the possibility of UPD should always be kept in mind in cases with the unique finding of the homozygous pathogenic variant only present in one parent. This case highlights the critical role of genetic counseling in uncovering rare genetic conditions and emphasizes the need for continued awareness of UPD in clinical genetics.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"5577571"},"PeriodicalIF":0.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12408131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chromosome 1p31.1 Deletion: A Case With Developmental Delay, Hypotonia, Cryptorchidism, Abnormal Oral Frenulum, and Feet Deformity.","authors":"Tatiana Mikhailova, Ria Garg","doi":"10.1155/crig/6152118","DOIUrl":"10.1155/crig/6152118","url":null,"abstract":"<p><p>Deletions within the chromosomal locus 1p31.1 are rare, with only a limited number of documented cases. The typical clinical presentation includes intellectual disability, failure to thrive, and craniofacial abnormalities. Some cases may also present with cardiac, gastrointestinal, and genitourinary malformations. Variability in deletion size contributes to a broad spectrum of clinical phenotypes, and a comprehensive understanding of the syndrome's manifestations is still evolving. This case study aims to provide additional insights into 1p31.1 microdeletion syndrome, enhancing knowledge of its genetic and phenotypic characteristics to improve recognition by clinicians. Here, we report a case featuring a 14.385 Mb deletion isolated to the 1p31.1 region, encompassing 41 genes. The deletion manifested with microcephaly, distinctive facial morphology, hypotonia, developmental delay, bilateral cryptorchidism, and flat feet. Notably, our case also exhibited congenital thickening of the lingual and labial frenulum, a trait not typically associated with this deletion.</p>","PeriodicalId":30325,"journal":{"name":"Case Reports in Genetics","volume":"2025 ","pages":"6152118"},"PeriodicalIF":0.0,"publicationDate":"2025-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12318624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144776334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}