American Journal of Medical Genetics Part A最新文献

{"title":"Growth Hormone Treatment in Patients With KBG Syndrome: Novel Insights, Challenges and Recommendations From Six New Patients and Literature Review.","authors":"Sietse M Aukema, Kim Vandenput, Emanuela Scarano, Himanshu Goel, Lily Guo, Michiel Vanneste, Koen Devriendt, Nitash Zwaveling-Soonawala, Cordula Kiewert, Alma Kuechler, Ilaria Parenti, Eleonora Orlandini, Elke de Boer, Siddharth Banka, Elizabeth Wall, Gholson J Lyon, Karen J Low, Joyce M Geelen, Yvonne G van der Zwan, Charlotte W Ockeloen","doi":"10.1002/ajmg.a.64168","DOIUrl":"https://doi.org/10.1002/ajmg.a.64168","url":null,"abstract":"<p><p>KBG syndrome is one of the most frequent neurodevelopmental disorders and is caused by ANKRD11 variants. Postnatal short stature is observed in ~50% of patients. Recombinant human growth hormone (rhGH) has become a valuable treatment for patients with growth hormone deficiency (GHD) along with Prader-Willi and Turner syndrome. Limited evidence suggests benefits for some patients with KBG syndrome, but systematic analysis and detailed phenotyping are lacking. In this study, we include six unpublished patients with KBG syndrome treated with rhGH and 22 patients from the literature. At treatment start, 43% had GHD. Median height before treatment was -2.9 standard deviation score (SDS) which increased to -1.8 SDS at the latest measurement. Moreover, half of the patients showed height gains of ≥ 1 SDS and 10/18 patients with short stature before treatment achieved heights within normal ranges following treatment or at the latest available measurement. Of interest, the difference between pre-treatment height SDS and that at the latest measurement (∆HSDS) was comparable for patients with and without GHD. This study represents the largest group of patients with KBG syndrome treated with rhGH so far and suggests that rhGH treatment has a positive impact on height, as indicated by ∆HSDS, in a subset of patients.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64168"},"PeriodicalIF":1.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648271","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":"Abdominal Compression Syndromes in the Hypermobile Ehlers-Danlos Syndrome.","authors":"Aubrey Milunsky, Jeff M Milunsky, Richard Hsu","doi":"10.1002/ajmg.a.64182","DOIUrl":"https://doi.org/10.1002/ajmg.a.64182","url":null,"abstract":"<p><p>The median arcuate ligament syndrome (MALS) is the main cause of abdominal compression syndromes (ACS). Diagnosis is frequently missed for many years despite the unremitting epigastric and left upper abdominal quadrant pain, postprandial pain, postural relief, sitophobia, and weight loss. If MALS occurs in patients with hypermobile Ehlers-Danlos syndrome (hEDS) in which gastrointestinal symptoms are common, diagnosis is even more difficult. This study, based on an extensive experience (~8000) with various connective tissue disorders (CTD) and a review of our patients' records, revealed striking concurrence of MALS and hEDS in 45 patients. 80% had analyses of 5-37 CTD genes (COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PMEPA1, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2, FBN1), and up to 19 aneurysm genes. Clinical diagnoses of MALS were confirmed by abdominal CT scan, CTA, or MRA with duplex ultrasound assessment of celiac artery peak systolic and diastolic velocities. We found 93.3% were female, all had unremitting abdominal pain for < 1-35 years, 62.2% were 20-40 years of age, 93.3% reported postural relief, 95.5% had postprandial pain, weight loss > 25 lbs in 35.6%. We report for the first time that 11/45 patients with hEDS had May-Thurner syndrome, 4 having concurrent MALS. Total pain relief followed MALS resection and celiac plexus neurectomy in 28 patients thus far.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64182"},"PeriodicalIF":1.7,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144625207","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":"Correction to \"Clinical Characteristics of Patients With Kabuki Syndrome at a Single Tertiary Children's Hospital\".","authors":"","doi":"10.1002/ajmg.a.64162","DOIUrl":"https://doi.org/10.1002/ajmg.a.64162","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64162"},"PeriodicalIF":1.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599140","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":"First Report of BAP1-Associated Polyposis.","authors":"Angela L Jacobson, Maegan E Roberts, Lindsey Byrne, Jenna Wolfe, Peter P Stanich, Mohamed H Abdel-Rahman, Colin C Pritchard, Eric Q Konnick","doi":"10.1002/ajmg.a.64176","DOIUrl":"https://doi.org/10.1002/ajmg.a.64176","url":null,"abstract":"<p><p>BAP1 Tumor Predisposition Syndrome (BAP1-TPDS) is caused by germline pathogenic variants in the BAP1 gene and has been associated with uveal melanoma, mesothelioma, cutaneous melanoma, renal cell carcinoma, and other benign cutaneous lesions. Adenomatous colon polyposis has not previously been reported as part of BAP1-TPDS. We report two patients with unexplained adenomatous oligopolyposis and germline BAP1 pathogenic variants. To determine if BAP1 had a role in polypogenesis, we performed somatic mutational analysis on multiple polyps from both patients (n = 8 total polyps tested). In every polyp tested, we found evidence of second BAP1 allele inactivation, including second somatic BAP1 mutations. Further, we did not detect any mutations in the commonly identified adenomatous polyposis pathway drivers, APC, CTNNB1, or other WNT/β-catenin. We did not detect somatic BAP1 mutations in any adenomatous polyps from patients without germline BAP1 pathogenic variants (n = 151 patients), highlighting the specificity of somatic BAP1 second hit mutations in BAP1 germline carrier polyps. Our findings strongly support that the polyps in these patients were caused by BAP1, and that adenomatous oligopolyposis is a part of the BAP1-TPDS tumor spectrum. Further work is needed to characterize the penetrance of this new BAP1-associated phenotype.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64176"},"PeriodicalIF":1.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599142","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":"A Rare Molecular Diagnosis in a Patient With Hepatocerebral Syndrome Contributes to the Expansion of the Phenotypic Spectrum of POLG2-Related Mitochondrial Disorder.","authors":"Vittoria Rossi, Dan Brooks, Hongzheng Dai, Elizabeth Mizerik, Karla Salazar, Daniel Davila-Williams, Yishay Ben-Moshe, Seema R Lalani, Sarah H Elsea, Charul Gijavanekar, Daryl A Scott, Keren Machol, Mir Reza Bekheirnia, Fernando Scaglia","doi":"10.1002/ajmg.a.64177","DOIUrl":"https://doi.org/10.1002/ajmg.a.64177","url":null,"abstract":"<p><p>POLG2 encodes an accessory subunit in DNA polymerase gamma that is required for mitochondrial DNA synthesis. Monoallelic pathogenic variants in POLG2 are associated primarily with progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant type 4 (PEOA4, MIM #610131). We report a rare case of severe infantile hepatocerebral syndrome associated with biallelic variants in POLG2. The proband, a 5-week-old female infant, presented with seizures and acute liver failure. Extensive metabolic workup, including untargeted metabolomics analysis and elevated plasma growth differentiation factor 15, was suggestive of mitochondrial dysfunction. Rapid trio genome sequencing identified compound heterozygous variants, a likely pathogenic variant and a variant of uncertain significance in POLG2. This case expands the clinical phenotype associated with POLG2-related mitochondrial disease to include a severe hepatocerebral syndrome manifesting in early childhood. This case underscores the utility of integrated genomic and metabolomic analyses in diagnosing rare and complex mitochondrial disorders. These findings also emphasize the importance of considering POLG2-related mitochondrial disease in the differential diagnosis of infants presenting with liver failure and neurological symptoms and enhance our understanding of the phenotypic spectrum associated with this disorder.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64177"},"PeriodicalIF":1.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590251","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":"Early Enzyme Replacement Therapy Does Not Prevent the Protein Losing Enteropathy Syndrome in Neurovisceral Gaucher Disease.","authors":"Vincenza Gragnaniello, Mara Cananzi, Annachiara Cavaliere, Christian Loro, Chiara Cazzorla, Daniela Gueraldi, Andrea Puma, Alberto B Burlina","doi":"10.1002/ajmg.a.64184","DOIUrl":"https://doi.org/10.1002/ajmg.a.64184","url":null,"abstract":"<p><p>Gaucher disease (GD) is a rare lysosomal storage disorder characterized by multisystemic involvement. With the advent of enzyme replacement therapy (ERT), patient survival has improved, revealing new long-term complications. We report a case of a 4-year-old male with severe neurovisceral GD who developed protein-losing enteropathy (PLE) secondary to mesenteric lymphadenopathy, despite ERT starting in the neonatal period. Furthermore, we review the literature related to this rare complication. The patient presented with severe recurrent diarrhea, abdominal distension, weight loss, and malnutrition. Abdominal CT revealed multiple enlarged mesenteric lymph nodes with calcification. Laboratory findings showed lymphopenia and increased fecal alpha-1-antitrypsin. Other causes of diarrhea were excluded. Treatment with a specific diet (high-protein, MCT-enriched) and a course of budesonide resulted in persistent clinical improvement and normalization of laboratory parameters. This case highlights the emergence of gastrointestinal complications in patients with neurovisceral GD on long-term ERT, particularly the development of PLE due to mesenteric lymphadenopathy. It underscores the need for vigilance in monitoring GD patients for such complications and demonstrates the potential efficacy of dietary interventions and anti-inflammatory therapy in managing PLE in this context. The case also emphasizes the limitations of current ERT in addressing all aspects of GD, particularly in sequestered sites like lymph nodes, and calls for new therapeutic strategies to address these challenges.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64184"},"PeriodicalIF":1.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144599141","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":"Novel Homozygous Full Gene Deletion of SLC12A5 in a Newborn With Refractory Seizures.","authors":"Lauren M Wainman, Dana L Wright, Nidhi D Shah, Wahab A Khan, Gregory J Tsongalis, Joel A Lefferts","doi":"10.1002/ajmg.a.64180","DOIUrl":"https://doi.org/10.1002/ajmg.a.64180","url":null,"abstract":"<p><p>SLC12A5 codes for a protein that mediates electroneutral potassium-chloride cotransport in mature neurons and is required to maintain chloride homeostasis in neurons. Pathogenic missense or truncating variants in SLC12A5 are associated with seizures and severe developmental impairment. Here, we describe a novel homozygous deletion (at least 50.3 kb) of SLC12A5 and NCOA5 genes in a neonate with refractory seizures identified by exome sequencing (ES). The proband was born at 30 weeks 4 days of gestation with a very low birth weight (1320 g), hypotonia, intractable refractory status epilepticus consistent with early infantile epileptiform encephalopathy, respiratory distress, multiple limb contractures, and dysmorphic facies. Confirmatory chromosome microarray analysis identified a ~86 kb homozygous deletion within a ~3 Mb long continuous stretch of homozygosity. The patient died at 5 days of age due to multiorgan failure subsequent to intractable status epilepticus. This is the first reported case of homozygous deletion of SLC12A5 that resulted in a live birth and demonstrates that SLC12A5 serves a critical role in muscle development, lung function, and neuronal function.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64180"},"PeriodicalIF":1.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590253","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":"Exploring Pediatricians' Implicit Bias Related to Newborns' Intellectual Disability Risk: Merged Vignette and Implicit Association Test (IAT) Results.","authors":"Robin L Treptow, Joy V Browne, Joshua Feder, Ira Glovinsky, Brian G Skotko","doi":"10.1002/ajmg.a.64166","DOIUrl":"https://doi.org/10.1002/ajmg.a.64166","url":null,"abstract":"<p><p>This pilot study was designed to assess pediatricians' bias about intellectual disability (ID); whether symptoms suggesting Down syndrome (DS), meconium aspiration syndrome (MAS), cerebral palsy (CP), and fetal alcohol effects (FAE) predict lower ratings of infant potential versus controls; and whether proposed advice to parents of a likely DS diagnosis versus another diagnosis (such as meconium aspiration syndrome) would be more negative. Pediatricians (N = 56) completed an implicit association test (IAT) for intellectual disability (ID) plus an experimental vignette survey about a few days' old infant with apparent DS, MAS, FAE, or CP in Qualtrics. Measured outcomes were bias about ID, ratings of expected development, and advice for parents. Data were assessed using d-score frequencies, ANOVAs, and Tukey's HSD plus Cohen's d, and narrative analysis. Pediatricians (93%; n = 52) had high negative bias about persons with ID (d-scores < = -0.36). For DS versus MAS, pediatricians expected ID to be higher (p < 0.001, d_Cohen = 3.05) and childhood, adolescent, and adult daily living skills to be lower (p < 0.05, d_Cohen = 1.64; p < 0.05, d_Cohen = 2.47; p < 0.05, d_Cohen = 1.70). For DS versus CP, pediatricians expected early developmental skills quality to be higher (p = 0.012, d_Cohen = 1.14); later developmental skills quality did not differ between groups. Less reassuring advice was considered for parents of the infants with DS versus MAS. In this pilot study, pediatricians generally exhibited a negative bias for infants with ID, and their perceptions about the infant's ability, as well as their associated advice for parents, were related to the postnatal diagnosis. Future research can expand and more extensively explore the use of IAT for intellectual disabilities within obstetric and pediatric practices.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64166"},"PeriodicalIF":1.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582825","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":"Genetic Diseases Mimicking Rheumatic Disorders: Insights From Southeastern Turkey.","authors":"Akçahan Akalın, Hatice Dilara Karakaş, Canan Çelebi, Hülya Köse, Enise Avcı Durmuşalioğlu, Gizem Ürel-Demir, Ruken Yıldırım, Esra Işık, Pelin Ozlem Simsek Kiper","doi":"10.1002/ajmg.a.64174","DOIUrl":"https://doi.org/10.1002/ajmg.a.64174","url":null,"abstract":"<p><p>A subset of genetic conditions, particularly skeletal dysplasias, comprises a heterogeneous group of inherited disorders characterized by abnormal bone development, joint stiffness, and short stature. Their musculoskeletal manifestations frequently mimic those of rheumatic diseases, especially Juvenile Idiopathic Arthritis (JIA), complicating accurate diagnosis. We conducted a comprehensive clinical, radiological, and molecular evaluation of 47 individuals (23 males, 24 females) from 22 distinct families who presented primarily with non-inflammatory musculoskeletal complaints. Genomic investigations included targeted next-generation sequencing panels, chromosomal microarray analysis, and multiplex ligation-dependent probe amplification. Pathogenic or likely pathogenic variants were identified in all cases, establishing the following diagnoses: Hereditary Multiple Exostoses (n = 9), Camptodactyly-Arthropathy-Coxa Vara-Pericarditis syndrome (n = 12), Progressive Pseudorheumatoid Dysplasia (n = 7), Trichorhinophalangeal Syndrome types I/II (n = 5), Spondyloenchondrodysplasia with Immune Dysregulation (n = 6), Pseudoachondroplasia (n = 3), Primary Hypertrophic Osteoarthropathy type 1 (n = 1), Ehlers-Danlos Syndrome (n = 2), Multicentric Osteolysis-Nodulosis-Arthropathy (n = 1), and Mucopolysaccharidosis type VI (n = 1). Certain genetic disorders may present with musculoskeletal manifestations that closely resemble those of rheumatic diseases. Therefore, a comprehensive evaluation for underlying genetic causes is essential in patients with non-inflammatory skeletal findings, as it improves diagnostic precision and guides appropriate management strategies. This study aims to investigate the clinical and molecular features of patients with non-inflammatory musculoskeletal involvement, with a particular focus on the phenotypic overlap between genetic disorders and rheumatic diseases. Furthermore, seven novel variants were identified, expanding the mutational spectrum associated with these rare conditions and contributing new insights to the existing literature.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64174"},"PeriodicalIF":1.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582826","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":"Neuroaxonal Dystrophy With Osteopetrosis Associated With a Novel Biallelic Nonsense Homozygous Variant in BORCS5.","authors":"Yael Fisher, Orli Greenberg, Patrick Shannon, Andrea Staines, Bobbi McGivern, Melanie Patricia Napier, David Chitayat","doi":"10.1002/ajmg.a.64164","DOIUrl":"https://doi.org/10.1002/ajmg.a.64164","url":null,"abstract":"<p><p>Neuroaxonal dystrophy (NAD) with osteopetrosis syndrome (OMIM # 600329) was first reported in a consanguineous Moroccan Jewish family. However, to date, no genetic variant has been linked to this disease. We report on sibs, born to consanguineous Pakistani parents identified prenatally with cerebral ventriculomegaly and agenesis of the corpus callosum, and autopsies done on both showed similar abnormalities, including facial dysmorphism, osteopetrosis, and neuropathologic findings consistent with NAD. Trio exome sequencing identified a homozygous c.283 C>T; p.(Arg95Ter) variant in exon 3 of the BORCS5 gene (NM_058169.4) in each of the couple's fetuses, and each of the parents was heterozygous for this variant. Interestingly, one of the affected fetuses was also homozygous for a biallelic missense VUS variant in SCYL2 (NM_017988.5) c.902G>A; p. Arg301His, heterozygous in parents. However, the autopsy findings on the two sibs were identical, raising the possibility that this SCYL2 homozygote variant did not contribute to the phenotype.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e64164"},"PeriodicalIF":1.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574718","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}