American Journal of Medical Genetics Part A最新文献

{"title":"Prenatal Diagnosis of HSPG2-Related Dyssegmental Dysplasia: The First Report From Turkey.","authors":"Mehmet Berkay Akcan, Raziye Torun, Tuba Sözen Türk, Özgür Kırbıyık, Atalay Ekin, Altuğ Koç","doi":"10.1002/ajmg.a.64152","DOIUrl":"https://doi.org/10.1002/ajmg.a.64152","url":null,"abstract":"<p><p>Silverman-Handmaker type dyssegmental dysplasia (DDSH) is a rare and lethal skeletal dysplasia caused by biallelic null variations in the HSPG2 gene, which encodes the extracellular matrix proteoglycan perlecan. Here, we report a prenatal case of DDSH identified at 18 weeks of gestation, referred due to ultrasonographic findings of limb shortening, retrognathia, and irregularities in the lumbar vertebrae. Targeted skeletal dysplasia panel testing via next-generation sequencing (NGS) revealed a novel homozygous splice site variant, c.1355 + 1 G>T, located at the canonical donor site of intron 11 in HSPG2. The fetus died shortly after birth, consistent with the expected DDSH phenotype. Our case expands the mutational spectrum of HSPG2-related skeletal dysplasias and underscores the diagnostic and prognostic challenges of novel splicing variants in prenatal genetic counseling. It also emphasizes the value of combining prenatal imaging with molecular diagnostics to improve diagnostic accuracy and support informed reproductive decision-making.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64152"},"PeriodicalIF":1.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"De Novo SLC12A2 Variant Presenting as Congenital Hearing Loss With Vestibular Areflexia.","authors":"Katja Ludin, Anna M Kopps, Celine Richard, Sheila Unger","doi":"10.1002/ajmg.a.64150","DOIUrl":"https://doi.org/10.1002/ajmg.a.64150","url":null,"abstract":"<p><p>Since 2016, variants in SLC12A2 have been implicated in human disease, with several different phenotypes being linked to the gene. The first report concerned a child with a complex syndrome marked by metabolic derangement but normal hearing and cognition and a de novo heterozygous loss of function variant. Subsequently, several patients with severe developmental delay, sensorineural hearing loss, and bi-allelic loss of function variants were reported; this condition is known as Kilquist syndrome. The SLC12A2 knockout mouse model has a phenotype that is quite similar to Kilquist patients. In 2020, heterozygous variants in SLC12A2 were identified as a cause of non-syndromic deafness associated with vestibular areflexia (DFNA78; MIM 619081). In addition, de novo heterozygous SLC12A2 variants have also been implicated in developmental delay with autistic features. SLC12A2 encodes a Na+K+2Cl- cotransporter (NKCC) that is widely expressed in neurons, glial cells, the trachea, salivary glands, intestine, sweat glands, and the cochlea. In the inner ear, K+ transport is required for the mechano-transduction of auditory stimuli. SLC12A2 functions as a dimer and has several isoforms; only one isoform contains exon 21, and this isoform is almost exclusively expressed in the inner ear/cochlea. This isoform is necessary for homeostasis of the endolymph. To date, the published pathogenic variants causing DFNA78 are missense mutations located within exon 21 or in the 3' splice site of exon 21. We report a patient with profound congenital hearing loss and vestibular areflexia with a de novo variant in SLC12A2 located in the splice donor site: NM_001046.2: c.2977+4_2977+7del causing an in-frame skip of exon 21, as shown by cDNA analysis. Our case adds to the evidence that loss of exon 21 of SLC12A2 leads to a cochlear restricted phenotype. From a genetic counseling point of view, it reminds us that beyond syndromic forms such as Usher syndrome, several non-syndromic forms of genetically determined sensorineural hearing loss, including those involving the SLC12A2 gene, may also present with vestibular areflexia. This underscores the need for a broad sequencing approach when faced with this clinical scenario.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64150"},"PeriodicalIF":1.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144273949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the Clinical Spectrum of NR4A2-Related Disorder: A Systematic Literature Review and Case Series.","authors":"Chloe Borden, Muhammad Bin Nasir, Mary-Beth Roberts, Lauren Palange, Xiangling Wang","doi":"10.1002/ajmg.a.64145","DOIUrl":"https://doi.org/10.1002/ajmg.a.64145","url":null,"abstract":"<p><p>NR4A2 encodes a nuclear transcription factor in the steroid-thyroid hormone-retinoid receptor family. Pathogenic variants in NR4A2 are rare and until now have been associated exclusively with neurodevelopmental phenotypes. A systematic literature review of NR4A2-related disorder was conducted using the PubMed and ClinVar databases. We also report two novel cases. Twenty-eight PubMed records and 55 ClinVar reports were screened, and 16 studies were included in the final report. Thirty-two patients with 31 unique pathogenic variants in NR4A2 have been reported. This cohort is 53% female with a median age of 12 years (IQR 8-25). The neurodevelopmental phenotypic spectrum included intellectual disability and/or developmental delay in 93%, language impairment in 63%, recurrent seizures or epilepsy in 41%, and movement disorders in 31%. Extra-neurologic phenotypes were present in 47% and included craniofacial dysmorphism in 25%, musculoskeletal anomalies in 28%, gastrointestinal anomalies in 19%, and renal anomalies in 6%. Endocrine anomalies and dysregulated glucose and lipid metabolism were present exclusively in our two novel cases. The clinical spectrum of NR4A2-related disorder is likely much broader and more heterogeneous than originally suspected. This heterogeneity has likely contributed to under-detection of NR4A2 pathogenic variants.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64145"},"PeriodicalIF":1.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Describing the First Canadian Cohort of Oculogastrointestinal Neurodevelopmental Syndrome Caused by CAPN15 Pathogenic Variants.","authors":"Eric Lin, Tania Cruz-Marino, Nicolas Chrestian, Josianne Leblanc, Nadie Rioux, Yvan Labrie, Serge Rivest, Baiba Lace, Samantha Colaiacovo, Maha Saleh","doi":"10.1002/ajmg.a.64133","DOIUrl":"https://doi.org/10.1002/ajmg.a.64133","url":null,"abstract":"<p><p>Oculogastrointestinal neurodevelopmental syndrome (OGIN; OMIN #619318) is a rare autosomal recessive disorder resulting from pathogenic variants in the CAPN15 gene. OGIN syndrome has been previously seen to affect many different body systems and has been described to cause coloboma, imperforate anus, structural cardiac defects, and horseshoe kidneys. There is still little information about the phenotypic spectrum of this disease. This case series aims to describe the phenotypic spectrum and development of affected individuals. Our study includes eight patients-five patients previously described, and three newly identified patients from centers in Ontario and Quebec ranging from three to 15 years of age. All the French-Canadian patients in our cohort were homozygous for the c. 1838C>T (p. Ser613Leu) variant. We also describe a non-French-Canadian patient who is compound heterozygous for the variants c.1957G>A (p. Gly653Ser) (paternally inherited) and c.2520delC p. Val841Trpfs133 (maternally inherited). Through this cohort, we describe some rare manifestations of OGIN syndrome; all four female patients had vaginal fistulae, and four of the patients had sensorineural hearing loss. All eight patients had pancreatic insufficiency requiring pancreatic enzyme replacement. More research is needed to investigate the genotype-phenotype correlation, as well as assess long-term complications and natural history of the disease.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64133"},"PeriodicalIF":1.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rothmund-Thomson Syndrome Type 2 in an African American/Puerto Rican Child Demonstrates Diagnostic Challenges in Diverse Population.","authors":"Eden Teferedegn, Kosuke Izumi, Rebecca Ahrens-Nicklas, Elizabeth Bhoj, Alyssa Rippert","doi":"10.1002/ajmg.a.64132","DOIUrl":"https://doi.org/10.1002/ajmg.a.64132","url":null,"abstract":"<p><p>Rothumnd-Thomson syndrome (RTS) is a rare genetic condition characterized by poikiloderma, sparse hair, short stature, skeletal abnormalities, cataracts, and increased risk for malignancies. The presenting symptom is often a classic rash with erythema on the cheeks and face with spread to extensor surfaces of extremities. Gradually over months to years, this rash develops into poikiloderma (reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy). Identification of this characteristic rash may facilitate early diagnosis and management in patients with RTS; however, this may be more challenging in patients from diverse populations, especially with darker skin. Herein, we report an African-American/Puerto Rican 4-year, 11-month-old male who presented with feeding difficulties, scaly patches of skin, sparse hair, short stature, hypertelorism, and developmental delay. Initially, poikiloderma on his extremities was considered to be psoriasiform dermatitis. Exome sequencing revealed compound heterozygous pathogenic variants in the RECQL4 gene, c.1568_1573delGCCCCTinsCCCCC (p.Ser523fs) and c.2412_2420delGGCCGGGCG (p.Ala805_Arg807del) confirming a diagnosis of RTS type 2. This report underscores the risk of misdiagnosis or delayed diagnoses of RTS in diverse populations and highlights the importance of comprehensive molecular evaluation in diagnosing and managing rare conditions.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64132"},"PeriodicalIF":1.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular Gaucher Disease Type 3c Associated With Homozygous Asp448His GBA1 Variant: First Case Series From Kuwait.","authors":"Hind Alsharhan, Fay Alkurd, Mohammad A Ebrahim, Nawal Y Ali, Alshyamaa A Ali, Reem M Elshafie, Dina G Ramadan, Kefaya Abdulmalek, Gursev S Dhaunsi, Buthaina Albash, Laila Bastaki","doi":"10.1002/ajmg.a.64148","DOIUrl":"https://doi.org/10.1002/ajmg.a.64148","url":null,"abstract":"<p><p>Cardiac involvement in Gaucher disease (GD) is an uncommon feature, most often associated with the homozygous Asp448His (D409H) variant in GBA1 and typically presents with valvular and pericardial calcifications or myocardial infiltration. To date, approximately 132 individuals with this cardiovascular phenotype (GDIIIc) have been reported, with limited representation from the Middle East. This study reports the first cohort from Kuwait, involving five individuals from three unrelated Middle Eastern families, all with molecularly confirmed homozygous Asp448His variants. All individuals demonstrated early-onset cardiac valvular disease requiring surgical intervention, in addition to organomegaly, skeletal manifestations, and neurological symptoms. Despite corrective surgeries, four individuals died, with only one adult female currently alive and stable. Remarkably, this surviving patient is the first reported individual with GDIIIc to have successfully conceived and delivered a healthy child prior to her diagnosis, initiation of enzyme replacement therapy, or cardiac surgery. She later developed a broad spectrum of neuropsychiatric symptoms, including phobias, hallucinations, obsessive thoughts, anxiety, and delusions of persecution, as well as resting tremors and dysphagia. Brain MRI revealed granular ependymitis and cerebral microbleeds-neuroradiological features not previously described in GDIIIc-making her case uniquely informative. These findings broaden the phenotypic spectrum of GDIIIc and highlight the importance of recognizing cardiac and neuropsychiatric manifestations in individuals with the Asp448His variant. Early identification and multidisciplinary management may improve outcomes in this ultra-rare but severe disease.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64148"},"PeriodicalIF":1.7,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe Nerve Enlargement in SOS2-Related Noonan Syndrome.","authors":"Erika Leenders, Fieke Draaisma, Corrie E Erasmus, Catelijne Coppens, Lotte E R Kleimeier, Melanie Burgers, Tuula Rinne, Martin Zenker, Laura Mazzanti, Wesley Reintjes, Nens van Alfen, Jos M T Draaisma","doi":"10.1002/ajmg.a.64142","DOIUrl":"https://doi.org/10.1002/ajmg.a.64142","url":null,"abstract":"<p><p>Noonan syndrome is a genetic multisystem congenital disorder, caused by pathogenic variants in genes that encode components of the RAS/MAPK signaling pathway. Pathogenic variants in SOS2 represent less than 2% of cases with NS. The phenotype includes a particularly high prevalence (65%) of lymphatic disease. Recently, severe nerve enlargements were described in patients with a pathogenic variant in SOS2. To establish the occurrence of nerve enlargements in SOS2-related Noonan syndrome, we retrospectively analyzed the data of all six patients with SOS2-related Noonan syndrome at our center. All patients had undergone high-resolution nerve ultrasound for clinical reasons, and all had enlarged nerves, most of them severe. All of our patients and the three patients with enlarged nerves described in three published case series have an amino acid substitution at p.Met267.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64142"},"PeriodicalIF":1.7,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144224000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Memory of Jürgen W. Spranger, MD (1931-2025)","authors":"Andrea Superti-Furga MD,&nbsp;Sheila Unger MD,&nbsp;Gen Nishimura MD, PhD,&nbsp;Christine Hall MD,&nbsp;Carlos R. Ferreira MD","doi":"10.1002/ajmg.a.63750","DOIUrl":"https://doi.org/10.1002/ajmg.a.63750","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 7","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Table of Contents, Volume 197A, Number 7, July 2025","authors":"","doi":"10.1002/ajmg.a.63755","DOIUrl":"https://doi.org/10.1002/ajmg.a.63755","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 7","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.a.63755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144220160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"23andMe Declares Bankruptcy","authors":"Roxanne Nelson","doi":"10.1002/ajmg.a.63752","DOIUrl":"https://doi.org/10.1002/ajmg.a.63752","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":"197 7","pages":""},"PeriodicalIF":1.7,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144219965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}