American Journal of Medical Genetics Part A最新文献

{"title":"Nonrecurrent Triplication of 5q21.3q23.3: A Case Report and Review of the Literature.","authors":"Jacob A Ginter, Sarah Beaudry, Natalya Guseva, Jaime Nagy, Aaron A Stence, Alpa Sidhu","doi":"10.1002/ajmg.a.63969","DOIUrl":"https://doi.org/10.1002/ajmg.a.63969","url":null,"abstract":"<p><p>Triplications involving 5q21.3q23.3 are rare, and a phenotype has not been established. Here, we present a 4-month-old male with dysmorphic facial features and congenital cardiac malformation. Chromosomal microarray identified a pathogenic triplication of 5q21.3q23.3 with chromosome analysis showing the extra 5q material inserted into 16q. Optical genome mapping (OGM) was performed to further characterize the triplication. We compared the clinical features of our proband with previous case reports of individuals with duplications or triplications in the region to identify a phenotype. Common features appear to include short stature, developmental delays, learning difficulties, and cardiac malformations. We discuss genes in the region with a reported role in cardiac development, hypothesize that the triplication may have resulted from microhomology-mediated break-induced replication, and discuss the utility and limitations of OGM in this case. To our knowledge, this is the first reported case of a de novo triplication of 5q21.3q23.3.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63969"},"PeriodicalIF":1.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876003","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":"Identification of a Founder GLDN Variant Associated With \"Lethal\" Arthrogryposis in Nunavik Inuit: Implications for Obstetrical and Long-Term Survivors' Management.","authors":"Alexa McAdam, Yoko A Ito, Marilyn Richard, Dan Spiegelman, Daniel Rochefort, Lan Xiong, Maryam Oskoui, David Zielinski, Guy A Rouleau, Sirui Zhou, Kym M Boykott, Isabelle De Bie","doi":"10.1002/ajmg.a.63974","DOIUrl":"https://doi.org/10.1002/ajmg.a.63974","url":null,"abstract":"<p><p>Biallelic variants in GLDN have recently been associated with lethal congenital contracture syndrome 11 (LCCS11), a form of fetal akinesia deformation sequence (FADS) with high neonatal mortality. In this report, we describe five individuals from two Canadian Inuit families originating from different communities in Nunavik all affected with FADS and harboring a rare homozygous missense variant, [NM_181789.4:c.82G >C p.(Ala28Pro)] in GLDN. Two pregnancies presented with significant obstetrical complications including placental abruption and hemorrhage. Four infants died shortly after birth, while one survived past the neonatal period. This individual, while apparently asymptomatic during infancy, then presented with progressive neuromuscular and respiratory compromise that became more evident in adolescence. Data from a Nunavik Inuit cohort demonstrated a minor allele frequency (MAF) of 0.03571 for this variant compared to 0.00001341 in the general population, suggesting a founder effect in the Nunavik Inuit population. Our findings support the presence of a founder variant associated with LCCS11 in Nunavik Inuit populations. Our data corroborate those of other reports, demonstrating that LCCS11 is not universally lethal, but long-term survivors are at risk of progressive neuromuscular compromise. We also highlight in this report the significant obstetrical complications associated with this fetal-onset condition.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63974"},"PeriodicalIF":1.7,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875997","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 Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type II.","authors":"Mackenna E Schouw, Claudia A L Ruivenkamp, Tamara T Koopmann, Gijs W E Santen, Peter G J Nikkels, Karin van der Tuin","doi":"10.1002/ajmg.a.63972","DOIUrl":"https://doi.org/10.1002/ajmg.a.63972","url":null,"abstract":"<p><p>Osteogenesis imperfecta (OI) is a rare disease, hallmarked by bone fragility, multiple fractures, and deformities, and is commonly caused by pathogenic variants in the genes encoding type I collagen. Type II OI is the most severe form and is lethal in the perinatal period. Here, we report recurrence of perinatal lethal OI in two fetuses due to parental mosaicism for a deep intronic pathogenic variant at c.2451 + 77C > T in intron 35 of COL1A1, which resulted in aberrant splicing and the in-frame addition of 75 nucleotides into the mRNA. These patients highlight the importance of considering deep intronic variants in type 1 collagen genes in patients with high suspicion of OI, which may be missed with conventional genetic analysis.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63972"},"PeriodicalIF":1.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875977","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":"Familial RPL26 Variant Causing Congenital Anomalies Without Hematological Features of Diamond Blackfan Anemia.","authors":"Lisa M Karger, Bryn D Webb, Lisa Edelmann, Jun Liao, Lakshmi Mehta","doi":"10.1002/ajmg.a.63954","DOIUrl":"https://doi.org/10.1002/ajmg.a.63954","url":null,"abstract":"<p><p>Diamond Blackfan anemia (DBA) is an autosomal dominant disorder with a heterogeneous clinical presentation which may include macrocytic anemia typically presenting in the first year of life, growth retardation, and congenital malformations in 30%-50% of patients. This phenotypic variability is partially explained by genotype-phenotype correlations, with several ribosomal protein genes implicated in this disorder. Most cases are due to de novo variants, but familial occurrences highlight variable expressivity and reduced penetrance. To date, one case has been previously reported with a pathogenic variant in the RPL26 gene: a 3.5-year-old female with multiple congenital anomalies and typical hematological features of DBA. Here, we report a novel frameshift variant in RPL26 identified in a proband and his brother with limb malformations without anemia. Decreased RPL26 protein levels were detected in the proband's lymphoblasts. Subsequent clinical workup revealed high erythrocyte adenosine deaminase activity (eADA) in the proband, without anemia. This family represents the second report of RPL26-associated congenital anomalies in the DBA spectrum and further illustrates the non-hematological presentation of Diamond Blackfan \"anemia\".</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63954"},"PeriodicalIF":1.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142875982","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":"Prenatal Diagnosis of Proteus Syndrome: About a Case.","authors":"Luana Giovannangeli, Virginie Magry, Florence Jobic, Kahia Messaoudi, Walaa Darwiche, Marianne Perriere, Alexis Billes, Ségolène Delmas Lanta, Alice Masurel, Gilles Morin, Guillaume Jedraszak","doi":"10.1002/ajmg.a.63968","DOIUrl":"https://doi.org/10.1002/ajmg.a.63968","url":null,"abstract":"<p><p>Proteus syndrome (PS) is a rare disorder (< 1/1000000), marked by progressive overgrowth commonly impacting the skeleton, skin, adipose tissue, and central nervous system. Clinical criteria were established in 2019. PS arises from a somatic activating variation in the AKT1 gene. We report the second case of PS diagnosed prenatally using whole exome sequencing (WES). A 34-year-old woman was referred for nonvisualized anterior brain structures and genital anomalies. At 21 weeks of gestation (WG), ultrasonography confirmed brain anomalies, genital anomalies, and macrosomia. Array-CGH revealed no pathogenic imbalances (arr(X,1-22)×2). Follow-up ultrasound (25 WG) and MRI (27 WG) also showed a megalencephaly, leading to WES on amniocytes. The reported mosaic variation in AKT1 was identified. Medical termination of pregnancy occurred at 30 + 1 WG. We present a case of PS confirmed prenatally via WES. To date, six cases of prenatal PS suspicion have been reported, four of which lacked molecular diagnosis. Calculating prenatal clinical scores indicate PS could not be definitively diagnosed without molecular confirmation. Certain features, such as limb malformation and gray matter heterotopia, seem to be significant in prenatal diagnosis. WES, with an average coverage depth of 130X, is valuable for diagnosing suspected PS.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63968"},"PeriodicalIF":1.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862750","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 Digital Anomalies, Hippocampal Atrophy, and Mutations Expand the Genotypic and Phenotypic Spectra of CNKSR2 in the Houge Type of X-Linked Syndromic Intellectual Development Disorder (MRXSHG).","authors":"Mohammad-Reza Ghasemi, Sahand Tehrani Fateh, Afif Ben-Mahmoud, Vijay Gupta, Lara G Stühn, Gaetan Lesca, Nicolas Chatron, Konrad Platzer, Patrick Edery, Hossein Sadeghi, Bertrand Isidor, Benjamin Cogné, Heidi L Schulz, Ilona Krauspe-Stübecke, Radhakrishnan Periyasamy, Sheela Nampoothiri, Reza Mirfakhraie, Sahar Alijanpour, Steffen Syrbe, Ulrich Pfeifer, Stephanie Spranger, Kathrin Grundmann-Hauser, Tobias B Haack, Maria T Papadopoulou, Tayrine da Silva Gonçalves, Eleni Panagiotakaki, Alexis Arzimanoglou, Seyed Hassan Tonekaboni, Massimiliano Rossi, G Christoph Korenke, Yves Lacassie, Mi-Hyeon Jang, Lawrence C Layman, Mohammad Miryounesi, Hyung-Goo Kim","doi":"10.1002/ajmg.a.63963","DOIUrl":"https://doi.org/10.1002/ajmg.a.63963","url":null,"abstract":"<p><p>The Houge type of X-linked syndromic intellectual developmental disorder (MRXSHG) encompasses a spectrum of neurodevelopmental disorders characterized by intellectual disability (ID), language/speech delay, attention issues, and epilepsy. These conditions arise from hemizygous or heterozygous deletions, along with point mutations, affecting CNKSR2, a gene located at Xp22.12. CNKSR2, also known as CNK2 or MAGUIN, functions as a synaptic scaffolding molecule within the neuronal postsynaptic density (PSD) of the central nervous system. It acts as a link connecting postsynaptic structural proteins, such as PSD95 and S-SCAM, by employing multiple functional domains crucial for synaptic signaling and protein-protein interactions. Predominantly expressed in dendrites, CNKSR2 is vital for dendritic spine morphogenesis in hippocampal neurons. Its loss-of-function variants result in reduced PSD size and impaired hippocampal development, affecting processes including neuronal proliferation, migration, and synaptogenesis. We present 15 patients including three from the MENA (Middle East and North Africa), a region with no documented mutations in CNKSR2. Each individual displays unique clinical presentations that encompass developmental delay, ID, language/speech delay, epilepsy, and autism. Genetic analyses revealed 14 distinct variants in CNKSR2, comprising five nonsense, three frameshift, two splice, and four missense variants, of which 13 are novel. The ACMG guidelines unanimously interpreted these 14 variants in 15 individuals as pathogenic, highlighting the detrimental impact of these CNKSR2 genetic alterations and confirming the molecular diagnosis of MRXSHG. Importantly, variants Ser767Phe and Ala827Pro may lead to proteasomal degradation or reduced PSD size, contributing to the neurodevelopmental phenotype. Furthermore, these two amino acids, along with another two affected by four missense variants, exhibit complete conservation in nine vertebrate species, illuminating their crucial role in the gene's functionality. Our study revealed unique new digital and brain phenotype, including pointed fingertips (fetal pads of fingertips), syndactyly, tapering fingers, and hippocampal atrophy. These novel clinical features in MRXSHG, combined with 13 novel variants, expand the phenotypic and genotypic spectra of MRXSHG associated with CNKSR2 mutations.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63963"},"PeriodicalIF":1.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142870747","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":"Sodium Oxybate-Treated Familial Myoclonus-Dystonia Syndrome Due to Novel SGCE Variant.","authors":"Malak Ali Alghamdi, Muddathir H Hamad, Isra Alghamdi, Ghiada Alghamdi, Muneera Al-Jelaify, Sohaila Alshimemeri, Hebattalah Hamed, Nouran Adly, Mustafa A Salih, Naif A Almontashiri, Fahad A Bashiri","doi":"10.1002/ajmg.a.63964","DOIUrl":"https://doi.org/10.1002/ajmg.a.63964","url":null,"abstract":"<p><p>Myoclonus-dystonia syndrome (MDS, OMIM #159900) is an autosomal-dominant movement disorder caused by heterozygous variants in the epsilon sarcoglycan gene (SGCE) and characterized by a combination of myoclonic jerks, dystonia, and psychiatric comorbidities. Patients with MDS have a normal life expectancy with markedly reduced quality of life. Here, we report four family members diagnosed with MDS of variable severity due to a novel heterozygous splicing variant in SGCE (c.341-2A>G), including a 13-year-old female who presented with disabling dystonic spasms, myoclonic jerks, and psychiatric symptoms. She had shown little or no response to several conventional MDS treatments. However, disabling axial dystonia was significantly improved by sodium oxybate (1 g, twice daily). Although there was less effect on myoclonus, sodium oxybate treatment significantly improved the overall quality of life at the 3-years follow-up. Clinical trials are warranted to assess the clinical efficacy and safety of sodium oxybate for MDS-associated dystonia.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63964"},"PeriodicalIF":1.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862760","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":"Expansion of the Phenotype of You-Hoover-Fong Syndrome and Possible Increased Risk of Cancer.","authors":"Alessandro De Falco, Fabiola De Gregorio, Massimo Eraldo Abate, Chiara Paolella, Vincenzo Nigro, Iris Scala, Nicola Brunetti-Pierri","doi":"10.1002/ajmg.a.63966","DOIUrl":"https://doi.org/10.1002/ajmg.a.63966","url":null,"abstract":"<p><p>You-Hoover-Fong syndrome (YHFS) is a rare autosomal recessive disorder characterized by global developmental delay, microcephaly, dysmorphic facial features, and a spectrum of neurodevelopmental abnormalities. YHFS is caused by pathogenic variants in TELO2, a gene involved in regulation of the cell cycle. To date, 29 individuals with YHFS have been reported and none of them has been reported to develop tumors. We describe two siblings with YHFS both presenting with bilateral acoustic nerve agenesis, microcephaly, and dysmorphic features. Notably, one sibling developed hepatoblastoma at the age of 7.5 years. Clinical exome sequencing revealed in both siblings compound heterozygous variants in the TELO2 gene. Although the development of hepatoblastoma might be coincidental, given the role of TELO2 in cell cycle, we suspect YHFS might be associated with an increased cancer susceptibility. Further cases are needed to confirm whether YHFS is associated with an increased risk of cancer.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63966"},"PeriodicalIF":1.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862746","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":"Recurrent FLNA p.Gly1554Arg Variant Associated With Familial Ebstein Anomaly and Joint Stiffness.","authors":"Yukiko Kuroda, Koki Nagai, Yasuhiro Kawai, Takuya Wakamiya, Takuya Naruto, Kenji Kurosawa","doi":"10.1002/ajmg.a.63973","DOIUrl":"https://doi.org/10.1002/ajmg.a.63973","url":null,"abstract":"","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63973"},"PeriodicalIF":1.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862758","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 Homozygous MYH1 Variant Underlies Autosomal Recessive Isolated Recurrent Rhabdomyolysis.","authors":"Eyyup Uctepe, Hanifenur Mancılar, Fatma Nisa Esen, Gokcen Gundogdu Unverengil, Barbara Vona, Ahmet Yesilyurt","doi":"10.1002/ajmg.a.63952","DOIUrl":"https://doi.org/10.1002/ajmg.a.63952","url":null,"abstract":"<p><p>Rhabdomyolysis is a severe condition involving the breakdown of skeletal muscle fibers, leading to the release of muscle components into the bloodstream, which can lead to potential complications such as acute kidney injury and electrolyte imbalances. The etiology of rhabdomyolysis is multifactorial, encompassing traumatic, exertional, metabolic, infectious, toxic, and genetic causes. Genetic causes, including variants in LPIN1, RYR1, and CACNA1S, are increasingly recognized as significant contributors to recurrent rhabdomyolysis. MYH1 has recently been identified as a candidate gene for recurrent rhabdomyolysis with limited evidence originating from a single patient. In this report, we describe a 35-year-old male, born to consanguineous parents, who presented with recurrent rhabdomyolysis attacks, beginning at age 28, characterized by muscle pain, weakness, and episodes of acute kidney injury requiring dialysis. During attacks, the patient exhibited remarkably elevated markers of muscle breakdown and mildly elevated creatine kinase levels between episodes. A muscle biopsy revealed non-specific myopathic changes. Exome sequencing analysis was carried out and revealed a novel homozygous variant (NM_005963.4: c.1825G>A [p.Val609Met]) in MYH1 segregating in a manner compatible with an autosomal recessive pattern. In summary, this case provides confirmatory support for the role of pathogenic MYH1 variants in the pathogenesis of recurrent rhabdomyolysis and emphasizes the importance of comprehensive genetic testing in patients with unexplained recurrent episodes of muscle breakdown. Further cases are necessary to fully elucidate the genotypic and phenotypic spectrum of MYH1-related muscle disorders.</p>","PeriodicalId":7507,"journal":{"name":"American Journal of Medical Genetics Part A","volume":" ","pages":"e63952"},"PeriodicalIF":1.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142833308","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}