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A novel GRK2 variant in a patient with Jeune asphyxiating thoracic dysplasia accompanied by Morgagni hernia Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-22 Pelin Özlem Şimşek‐Kiper, Beren Karaosmanoğlu, Ekim Zihni Taşkıran, Özlem Boybeyi Türer, Gülen Eda Utine, Tutku Soyer
Skeletal ciliopathies constitute a subgroup of ciliopathies characterized by various skeletal anomalies arising from mutations in genes impacting cilia, ciliogenesis, intraflagellar transport process, or various signaling pathways. Short‐rib thoracic dysplasias, previously known as Jeune asphyxiating thoracic dysplasia (ATD), stand out as the most prevalent and prototypical form of skeletal ciliopathies
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Phenotypic consequences of GBA1 pathological variant R463C (p.R502C) Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-22 Emory Ryan, Samantha Nishimura, Grisel Lopez, Nahid Tayebi, Ellen Sidransky
Gaucher disease (GD) is an autosomal recessively inherited lysosomal storage disorder caused by biallelic pathological variants in the GBA1 gene. Patients present along a broad clinical spectrum, and phenotypes are often difficult to predict based on genotype alone. The variant R463C (p.Arg502Cys) exemplifies this challenge. To better characterize its different clinical presentations, we examined the
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Identification of a de novo PUF60 variant associated with craniofacial microsomia Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-22 Takuya Ogawa, Jingyi Xue, Long Guo, Maristela Sayuri Inoue‐Arai, Siulan Vendramini‐Pittoli, Roseli Maria Zechi‐Ceide, Rosana Maria Candido‐Souza, Cristiano Tonello, Michele Madeira Brandão, Terumi Okada Ozawa, Adriano Porto Peixoto, Daniela Maria Cury Ferreira Ruiz, Tomoki Nakashima, Shiro Ikegawa, Keiji Moriyama, Nancy Mizue Kokitsu‐Nakata
Craniofacial microsomia (CFM), also known as the oculo‐auriculo‐vertebral spectrum, is a congenital disorder characterized by hypoplasia of the mandible and external ear due to tissue malformations originating from the first and second branchial arches. However, distinguishing it from other syndromes of branchial arch abnormalities is difficult, and causal variants remain unidentified in many cases
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Clinical case report of intractable paroxysmal sympathetic hyperactivity in TANGO2 deficiency disorder Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-18 Kaitlin Morrison, Hitoshi Koshiya, Robert Safier, Amanda Brown, Carol May, Jerry Vockley, Lina Ghaloul‐Gonzalez
TANGO2 deficiency disorder (TDD) is a neurodegenerative disease characterized by a broad and variable spectrum of clinical manifestations, even among individuals sharing the same pathogenic variants. Here, we report a severely affected individual with TDD presenting with intractable paroxysmal sympathetic hyperactivity (PSH). While progressive brain atrophy has been observed in TDD, PSH has not been
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Further characterization of ARSK‐related mucopolysaccharidosis type 10 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-18 Dilek Uludağ Alkaya, Hasan Emir Taner, Timur Yıldırım, Evren Akpınar, Beyhan Tüysüz
Mucopolysaccharidosis type 10 is caused by biallelic variants in ARSK, which encodes for a lysosomal sulfatase. To date, seven patients with a mild phenotype resembling spondyloepiphyseal dysplasia or multiple epiphyseal dysplasia have been described. In this report, we present two novel ARSK variants and report clinical and radiological findings of three patients. The patients' initial complaints
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Parents of children with Down syndrome reflect on their postnatal diagnoses, 2003–2022 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-15 Jonathan M. Artal, Lindsey Randall, Sabina Rubeck, Megan Allyse, Marsha Michie, Kirsten A. Riggan, Stephanie Meredith, Brian G. Skotko
A 2003 survey revealed the scope of mothers' dissatisfaction with their postnatal support following a diagnosis of Down syndrome (DS). Substantial proportions of mothers reported that providers conveyed diagnoses with pity, emphasized negative aspects of DS, and neglected to provide adequate materials explaining DS. This study follows up on the 2003 survey by assessing whether parents' experiences
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Similarity of aortic events between siblings with heritable thoracic aortic diseases: Clinical analysis focusing on identical twins and same‐sex siblings Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-15 Takeshi Yagyu, Kazufumi Ida, Teruo Noguchi
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Laryngeal clefts in Prader–Willi syndrome: Feeding difficulties and aspiration not always caused by hypotonia Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-15 Minna L. Rodrigo, Christine Heubi, Eric Chiou, Ann Scheimann
Feeding difficulties, aspiration, and failure to thrive in infancy are commonly seen in patients with Prader–Willi Syndrome (PWS) and attributed to hypotonia. Patients with PWS and laryngeal clefts were identified by review of medical records at three tertiary care children's hospitals between 2017 and 2022. We present three patients with PWS with feeding difficulties who were also found to have laryngeal
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Immunological and hematological findings as major features in a patient with a new germline pathogenic CBL variant Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-12 Emilia Stellacci, Jennefer N. Carter, Luca Pannone, David Stevenson, Dorsa Moslehi, Serenella Venanzi, , Jonathan A. Bernstein, Marco Tartaglia, Simone Martinelli
Casitas B-lineage lymphoma (CBL) encodes an adaptor protein with E3-ligase activity negatively controlling intracellular signaling downstream of receptor tyrosine kinases. Somatic CBL mutations play a driver role in a variety of cancers, particularly myeloid malignancies, whereas germline defects in the same gene underlie a RASopathy having clinical overlap with Noonan syndrome (NS) and predisposing
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Novel Alu insertion in the ZEB2 gene causing Mowat‐Wilson syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-11 Maria Barington, Mads Bak, Kristín Rós Kjartansdóttir, Thomas van Overeem Hansen, Ulf Birkedal, Elsebet Østergaard, Hanne Buciek Hove
Alu elements are short, interspersed elements located throughout the genome, playing a role in human diversity, and occasionally causing genetic diseases. Here, we report a novel Alu insertion causing Mowat‐Wilson syndrome, a rare neurodevelopmental disorder, in an 8‐year‐old boy displaying the typical clinical features for Mowat‐Wilson syndrome. The variant was not initially detected in genome sequencing
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“Why did I choose genetics?”: A survey of current and recent medical genetics and genomics residents provides insight into recruitment efforts Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-11 Jennifer Cassady Hayek, Miriam G. Blitzer, Nathaniel H. Robin
There is a shortage of clinical geneticists, even with concerted recruitment efforts. Previously, no data had been collected about why young career geneticists chose this specialty. To investigate this question, we carried out a survey of current and recent medical genetics and genomics residents. The goal of this survey was to understand their reasons for pursuing medical genetics and genomics as
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Ocular manifestations of CHARGE syndrome in a pediatric cohort with genotype/phenotype analysis Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-10 Kunal Kanwar, Saffiya Bashey, Brenda L. Bohnsack, Andy Drackley, Alexander Ing, Safa Rahmani, Hantamalala Ralay Ranaivo, Patrick McMullen, Andrew Skol, Kailee Yap, Valerie Allegretti, Jennifer L. Rossen
CHARGE syndrome is a rare multi‐system condition associated with CHD7 variants. However, ocular manifestations and particularly ophthalmic genotype–phenotype associations, are not well‐studied. This study evaluated ocular manifestations and genotype–phenotype associations in pediatric patients with CHARGE syndrome. A retrospective chart review included pediatric patients under 20 years‐old with clinical
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Table of Contents, Volume 194A, Number 5, May 2024 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-09
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In Memoriam: Ishwar Chander Verma, MD (1936‐2024) Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-09
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Alphamissense Predictive of Pathogenic Protein Variants Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-09
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Identification of a novel phenotype of external ear deformity related to Coffin–Siris syndrome‐9 and literature review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-09 Ruohao Wu, Wenting Tang, Pinggan Li, Zhe Meng, Xiaojuan Li, Liyang Liang
De novo germline variants of the SRY‐related HMG‐box 11 gene (SOX11) have been reported to cause Coffin–Siris syndrome‐9 (CSS‐9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies
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Cover Image, Volume 194A, Number 5, May 2024 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-09
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Homozygosity for disease‐causing variants in AMT and GLDC in a patient with severe nonketotic hyperglycinemia Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-04 Andy Drackley, Merlene Peter, Pamela Rathbun, Alexander Ing, Carlos E. Prada, Kai Lee Yap
Nonketotic hyperglycinemia (NKH) is a relatively well‐characterized inborn error of metabolism that results in a combination of lethargy, hypotonia, seizures, developmental arrest, and, in severe cases, death early in life. Three genes encoding components of the glycine cleavage enzyme system—GLDC, AMT, and GCSH—are independently associated with NKH. We report on a patient with severe NKH in whom the
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ECEL1 related distal arthrogryposis 5D in an Indian cohort—Report of recognizable musculoskeletal phenotype and a possible founder variant Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-03 Mounika Endrakanti, Jyoti Sharma, Abdul S. Ethayathulla, Punit Kaur, Shah Alam Khan, Madhulika Kabra, Neerja Gupta
Distal arthrogryposis type 5D (DA5D) is clinically characterized by knee extension contractures, distal joint contractures, clubfoot, micrognathia, ptosis, and scoliosis. We report nine affected individuals from eight unrelated Indian families with DA5D. Although the overall musculoskeletal phenotype is not very distinct from other distal arthrogryposis, the presence of fixed knee extension contractures
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A novel 3q interstitial deletion including GATA2 and ZNF148: A case report Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-03 Elizabeth Martin, Elizabeth A. VanSickle, Linda Z. Rossetti
GATA2 and ZNF148 have both been mapped to chromosome 3q. Pathogenic variants in GATA2 have been associated with immunodeficiency and high risk for myelodysplasia, acute myeloid leukemia, and chronic myelomonocytic leukemia. Gain‐of‐function variants in ZNF148 have previously been suggested as a mechanism for agenesis of the corpus callosum (ACC). Here, we report a novel 10.4 Mb interstitial deletion
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Neurodevelopmental disorder in a patient with HMBS and SCN3A variants—A possibly blended phenotype further delineating autosomal recessive HMBS related disease Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-03 Kłaniewska M, Rydzanicz M, Bladowska J, Borys ‐ Iwanicka A, Iwanicka ‐ Pronicka K, Wasilewski R, Odnoczko E, Zubkiewicz‐Kucharska A, Smigiel R, Ploski R
Monoallelic pathogenic HMBS variants are a well‐established cause of acute intermittent porphyria (AIP), whereas biallelic pathogenic variants may cause HMBS‐related leukoencephalopathy which remains a poorly characterized disorder. We describe an 8‐year‐old girl with hypotonia, hearing impairment, horizontal nystagmus, bilateral strabismus, impaired visual acuity, and optic nerve atrophy. She had
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Two sisters with RSPRY1‐related spondyloepimetaphyseal dysplasia Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-02 Swati Singh, Hitesh Shah, Ashwin Dalal, Anju Shukla, Gandham SriLakshmi Bhavani, Katta M. Girisha
Biallelic variants in RSPRY1 have been found to result in spondyloepimetaphyseal dysplasia. Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene. The phenotype in our patients resembles s
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The society for craniofacial genetics and developmental biology 46th annual meeting Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-02 Samantha A. Brugmann, David E. Clouthier, Katherine A. Fantauzzo, Matthew P. Harris, Juhee Jeong, Jean‐Pierre Saint‐Jeannet, Rolf W. Stottmann, Amy E. Merrill
The Society for Craniofacial Genetics and Developmental Biology (SCGDB) held its 46th Annual Meeting at Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio on October 10th–12th, 2023. On the first day of the meeting, Drs. Sally Moody and Justin Cotney were each honored with the SCGDB Distinguished Scientist Awards for their exceptional contributions to the field of craniofacial biology
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SYNGAP1‐related developmental and epileptic encephalopathy: Genotypic and phenotypic characteristics and longitudinal insights Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-02 Hye Jin Kim, Minhye Kim, Seoyun Jang, Jae So Cho, Soo Yeon Kim, Anna Cho, Hunmin Kim, Byung Chan Lim, Jong‐Hee Chae, Jieun Choi, Ki Joong Kim, WooJoong Kim
The clinical and genetic characteristics of SYNGAP1 mutations in Korean pediatric patients are not well understood. We retrospectively analyzed 13 individuals with SYNGAP1 mutations from a longitudinal aspect. Clinical data, genetic profiles, and electroencephalography (EEG) patterns were examined. Genotypic analyses included gene panels and whole‐exome sequencing. All patients exhibited global developmental
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Truncating variants of the sterol recognition region of SHH cause hypertelorism phenotype rather than hypotelorism‐holoprosencephaly Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-04-02 Mamiko Yamada, Seiji Mizuno, Mie Inaba, Tomoko Uehara, Hidehito Inagaki, Hisato Suzuki, Fuyuki Miya, Toshiki Takenouchi, Hiroki Kurahashi, Kenjiro Kosaki
Sonic hedgehog signaling molecule (SHH) is a key molecule in the cilia‐mediated signaling pathway and a critical morphogen in embryogenesis. The association between loss‐of‐function variants of SHH and holoprosencephaly is well established. In mice experiments, reduced or increased signaling of SHH have been shown to be associated with narrowing or excessive expansion of the facial midline, respectively
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Clinical outcomes and medical management of achondroplasia in Japanese children: A retrospective medical record review of clinical data Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-30 Hiroyuki Saitou, Taichi Kitaoka, Takuo Kubota, Junko Kanno, Hiroshi Mochizuki, Toshimi Michigami, Kosei Hasegawa, Ikuma Fujiwara, Takashi Hamajima, Daisuke Harada, Yuko Seki, Keisuke Nagasaki, Sumito Dateki, Noriyuki Namba, Hirofumi Tokuoka, Jeanne M. Pimenta, Shelda Cohen, Keiichi Ozono
Achondroplasia (ACH) is a rare, autosomal dominant skeletal dysplasia characterized by short stature, characteristic facial configuration, and trident hands. Before vosoritide approval in Japan, patients with ACH could start growth hormone (GH) treatment at age 3 years. However, ACH and its treatment in young Japanese children have not been studied. This retrospective, longitudinal, medical records‐based
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Prenatal findings in 11 cases with craniofacial microsomia using the Alberta Congenital Anomalies Surveillance System, 1997–2019 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-30 Mary Ann Thomas, Tanya Bedard, Susan Crawford, R. Brian Lowry
Craniofacial microsomia (CFM) primarily includes specific head and neck anomalies that co‐occur more frequently than expected. The anomalies are usually asymmetric and affect craniofacial features; however, there are frequently additional anomalies of variable severity. Published prenatal findings for CFM are limited. This study contributes 11 cases with CFM and their anomalies identified prenatally
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Importance of the biochemical investigations for the functional characterization of a NPC1 variant identified by exome sequencing Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-29 Nihal Almenabawy, Clara Hung, Iveta Sosova, Saadet Mercimek‐Andrews
Niemann–Pick disease type C (NPC) is one of the lysosomal storage disorders. It is caused by biallelic pathogenic variants in NPC1 or NPC2, which results in a defective cholesterol trafficking inside the late endosome and lysosome. There is a high clinical variability in the age of presentation and the phenotype of this disorder making the diagnosis challenging. Here, we report a patient with an infantile
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A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-29 Jennifer Yee‐ming Li, Fanny Tsz‐wai Ho, Mianne Lee, Joyce Chan, Brian Hon‐yin Chung, Joanna Yuet‐ling Tung, Alison Lap‐tak Ma
Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO
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Novel biallelic ZNF335 variant causing primary microcephaly: A case report and radiological review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-29 Dhrumil Deveshkumar Patel, Karen W. Gripp, Erin Wadman, Ishita Mishra, Vinay Kandula
Biallelic pathogenic variants in ZNF335 are one of the genetic causes of microcephaly, reported only in the past decade. It regulates neural progenitor proliferation and neurogenesis by interacting with a H3K4 methyltransferase complex. Biallelic pathogenic ZNF335 variants predispose to neuronal cell death and aberrant differentiation, thus causing secondary microcephaly. These neurodevelopmental anomalies
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Patient experiences of receiving a diagnosis of hypermobile Ehlers–Danlos syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-28 Yun‐Ting Wang, Shiva Jahani, Dayna Morel‐Swols, Angelica Kapely, Ami Rosen, Irman Forghani
Hypermobile Ehlers–Danlos syndrome (hEDS) presents with a wide range of clinical symptoms and comorbidities that impact quality of life. The diagnosis is challenging and often delayed due to the heterogeneity of the disease and lack of diagnostic biomarkers, which adds to the disease burden by affecting patients' psychosocial adaptation and overall well‐being. Previous studies have revealed that healthcare
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Developmental and behavioral phenotypes of pediatric patients with PTEN hamartoma tumor syndrome Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-28 Suzanne P. MacFarland, Melani Duvall, Raissa Tchetcho Kemajou, Sarah E. Baldino, Kristin Zelley, Chelsea Black, Allison Thomas, Nina H. Thomas, Melanie Ruffner, Yimei Li, Judith S. Miller, Garrett M. Brodeur, Emily Shabason
Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life‐impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD)
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RNA analysis and computer-aided facial phenotyping help to classify a novel TRIO splice site variant Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-22 Sarina Schwartzmann, Max Zhao, Henrike Lisa Sczakiel, Gabriele Hildebrand, Nadja Ehmke, Denise Horn, Martin A. Mensah, Felix Boschann
Pathogenic variants in TRIO, encoding the guanine nucleotide exchange factor, are associated with two distinct neurodevelopmental delay phenotypes: gain-of-function missense mutations within the spectrin repeats are causative for a severe developmental delay with macrocephaly (MIM: 618825), whereas loss-of-function missense variants in the GEF1 domain and truncating variants throughout the gene lead
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Diagnostic findings and yield of investigations for children with developmental regression Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-27 Kirsten Furley, Matthew F. Hunter, Michael Fahey, Katrina Williams
Childhood conditions that feature developmental regression are poorly understood. Phenotype–genotype characterization and diagnostic yield data are needed to inform clinical decision‐making. The aim of this study was to report the conditions featuring developmental regression and assess diagnostic yields of investigations. A retrospective chart review of children presenting with developmental regression
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Familial recurrence of incontinentia pigmenti due to de novo pathogenic variants in the IKBKG gene Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-27 Julie Steffann, Judite De Oliveira Santos, Anne‐Laure Zelbin, Smail Hadj‐Rabia, Fabienne Charbit‐Henrion, Florence Petit
Incontinentia pigmenti (IP, Bloch‐Sulzberger syndrome) is a multisystem disorder which associates specific skin lesions that evolves in four stages, and occasionally, central nervous system, eye, hair, and teeth involvement. Familial (35%) and sporadic (65%) cases are caused by pathogenic variants in the IKBKG gene. Here we report an unusual family, where, in two half‐sisters affected by typical IP
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When rare meets common: Treatable genetic diseases are enriched in the general psychiatric population Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-27 Venuja Sriretnakumar, Ricardo Harripaul, James L. Kennedy, Joyce So
Mental illnesses are one of the biggest contributors to the global disease burden. Despite the increased recognition, diagnosis and ongoing research of mental health disorders, the etiology and underlying molecular mechanisms of these disorders are yet to be fully elucidated. Moreover, despite many treatment options available, a large subset of the psychiatric patient population is nonresponsive to
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Anxiety in Turner syndrome: Engaging community to address barriers and facilitators to diagnosis and care Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-26 Alexandra Carl, Marybel Good, Erica Haag, Christa Hutaff‐Lee, Deanna Swain, Nicole Tartaglia, Casey Sakamoto, Shanlee Davis, Talia Thompson
Turner syndrome (TS), caused by complete or partial loss of the second sex chromosome, is associated with complex medical manifestations. The TS community identifies anxiety as a major contributor to reduced quality of life. The study aimed to improve understanding of anxiety symptomatology, diagnosis, and care in individuals with TS. A mixed methods design integrated community engagement, including
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A de novo frameshift variant in MED13 gene in a patient with autism spectrum disorder and magnetic resonance imaging abnormalities mimicking tuberous sclerosis Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-26 Gloria Pantalone, Maria Margherita Mancardi, Andrea Rossi, Roberta Romanelli, Elena Marasco, Marini Carla
The mediator complex subunit 13 (MED13) gene is implicated in neurodevelopmental disorders including autism spectrum disorder (ASD), intellectual disability, and speech delay with varying severity and course. Additional, extra central nervous system, features include eye or vision problems, hypotonia, congenital heart abnormalities, and dysmorphisms. We describe a 7‐year‐ and 4‐month‐old girl evaluated
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Medical findings and congenital anomalies in Vermeer's paintings Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-22 Diana W. Bianchi, Sicco A. Scherjon
The 17th century was a time of scientific discovery in Europe. Leading academic centers provided the general population with an opportunity to view anatomic dissections of human bodies. Rather than portray idealized versions of individuals, Dutch painters were committed to accurately representing their models. This was true for Johannes Vermeer. The 2023 exhibition of Vermeer's paintings at the Rijksmuseum
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Resolution of severe neurobehavioral difficulties in an individual with Primrose syndrome with sertraline Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-22 Young Min Moon, Sa Eun Park, Constance Smith‐Hicks, Aaron Hauptman
Primrose syndrome (PS) is a rare genetic disease characterized by developmental delay, intellectual disability, sensorineural hearing loss, and dysmorphic features. PS is caused by de novo pathogenic variants in the ZBTB20 gene, which encodes a transcription factor modulating neurogenesis. We describe resolution with sertraline of neurobehavioral difficulties in a 17‐year‐old Hispanic male with PS
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ELMO2 biallelic pathogenic variants in a patient with gingival hypertrophy and cherubism phenotype: Case report and molecular review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-22 Eduardo Perrone, Antonio Victor Campos Coelho, Luiza do Amaral Virmond, Jessica Grasiela de Araujo Espolaor, João Bosco de Oliveira Filho, Amanda Thamires Batista do Nascimento, Marina Cadena da Matta, Joanna Goes Castro Meira, Laércio Moreira Cardoso—Júnior, Ana Camila Mendes Andrade, Ricardo Zantieff Topolski Chaves, Angelina Xavier Acosta
Ramon syndrome (OMIM #266270) was first described in a patient with cherubism, gingival fibromatosis, epilepsy, intellectual disability, hypertrichosis, and stunted growth. In 2018, Mehawej et al. described a patient with Ramon syndrome in whom a homozygous variant in ELMO2 was identified, suggesting that this gene may be the causative for this syndrome. ELMO2 biallelic pathogenic variants were also
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Undiagnosed Disease Network collaborative approach in diagnosing rare disease in a patient with a mosaic CACNA1D variant Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-21 Kimberly M. Ezell, Rory J. Tinker, Yutaka Furuta, Alican Gulsevin, Lisa Bastarache, Rizwan Hamid, Joy D. Cogan, Lynette Rives, Serena Neumann, Brian Corner, Mary Kozuria, John A. Phillips
The Undiagnosed Disease Network (UDN) is comprised of clinical and research experts collaborating to diagnose rare disease. The UDN is funded by the National Institutes of Health and includes 12 different clinical sites (About Us, 2022). Here we highlight the success of collaborative efforts within the UDN Clinical Site at Vanderbilt University Medical Center (VUMC) in utilizing a cohort of experts
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Early‐onset West syndrome with developmental delay associated with a novel KLHL20 variant Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-21 Yukiko Kuroda, Azusa Ikeda, Takuya Naruto, Kenji Kurosawa
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14q22.3 duplication including OTX2 in a girl with medulloblastoma: A case report with literature review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-21 Claire Blake, Kimmie Widmeyer, Kristen DAquila, Aaron Mochizuki, Teresa A. Smolarek, Natasha Pillay‐Smiley, Sun Young Kim
Orthodenticle homeobox 2 (OTX2) is a known oncogenic driver of medulloblastoma. Germline duplication of 14q22.3 including OTX2 is a rare condition reported in patients with combined pituitary hormone deficiency, oculo‐auriculo‐vertebral spectrum, and hemifacial microsomia. There has been one previously published case of a patient carrying a 14q22.3 duplication that included OTX2 with hemifacial microsomia
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A further case of chondrodysplasia with growth failure occurring after hematopoietic stem cell transplantation (HSCT) Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-21 K. Kavanagh, J. Coleman, S. M. O'Connell, C. Ní Fhoghlú, D. P. Moore, C. Brenner, S. A. Lynch
There is an emerging body of evidence showing that young patients, post haematopoietic stem cell transplantation (HSCT), can develop skeletal changes that mimic an osteochondrodysplasia process. The key discriminator is that these children have had otherwise normal growth and skeletal development before the therapeutic intervention (HSCT), typically for a haematological malignancy. Herein we present
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Clinical and molecular cytogenetic studies of five new patients with 20q11q12 deletion and review of the literature: Proposition of two critical regions Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-21 Souad Bensaid, Malika Bendahmane, Sara Loddo, Gemma Poke, Louis Januel, Romain Nicolle, Valérie Malan, Nicolas Chatron, Silvia Ottombrino, Maria Lisa Dentici, Antonio Novelli, Maria Cristina Digilio, Damien Sanlaville
Deletions of the long arm of chromosome 20 (20q) are rare, with only 16 reported patients displaying a proximal interstitial 20q deletion. A 1.62 Mb minimal critical region at 20q11.2, encompassing three genes GDF5, EPB41L1, and SAMHD1, is proposed to be responsible for this syndrome. The leading clinical features include growth retardation, intractable feeding difficulties with gastroesophageal reflux
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Novel biallelic SASS6 variants associated with primary microcephaly and fetal growth restriction Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-19 Xiangtian Kong, Jian Xu, Honggang Yin, Hongru Jiang, Xian Cao, Aimin Cui, Xueqian Wang
Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age‐, ethnic‐, and sex‐specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic
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Next generation sequencing reveals novel compound heterozygous deletions in NDUFAF2 in a child with mitochondrial complex I deficiency, nuclear type 10 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-13 Aren E. Marshall, Lauren Brady, Ed Yeh, Alan J. Mears, Melanie Lacaria, Pranesh Chakraborty, Mark A. Tarnopolsky, Kristin D. Kernohan
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Intracranial calcifications simulating Aicardi‐Goutières syndrome in PARS2‐related mitochondrial disease Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-12 Amanda Gerard, Elizabeth Mizerik, Carrie A. Mohila, Sarah AlAwami, Jill V. Hunter, Debra L. Kearney, Seema R. Lalani, Fernando Scaglia
PARS2 encodes an aminoacyl‐tRNA synthetase that catalyzes the ligation of proline to mitochondrial prolyl‐tRNA molecules. Diseases associated with PARS2 primarily affect the central nervous system, causing early infantile developmental epileptic encephalopathies (EIDEE; DEE75; MIM #618437) with infantile‐onset neurodegeneration. Dilated cardiomyopathy has also been reported in the affected individuals
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Table of Contents, Volume 194A, Number 4, April 2024 Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09
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Three Genes Associated with Neurodevelopmental Disorders Identified Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09
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First Gene Therapies Approved for Sickle Cell Disease Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09
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Estimation of carrier frequencies utilizing the gnomAD database for ACMG recommended carrier screening and Finnish disease heritage conditions in non‐Finnish European, Finnish, and Ashkenazi Jewish populations Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09 Miska Kandolin, Minna Pöyhönen, Eveliina Jakkula
American College of Medical Genetics and Genomics (ACMG) recommends offering Tier 3 carrier screening to pregnant patients and those planning a pregnancy for conditions with a carrier frequency of ≥1/200 (96 genes for autosomal recessive [AR] conditions). Certain AR conditions referred to as Finnish disease heritage (FINDIS) have a higher prevalence in Finland than elsewhere. Data from gnomAD v2.1
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Megalencephaly secondary to a novel germline missense variant p.Asp322Tyr in AKT3 associated with growth hormone deficiency and central hypothyroidism: A case report Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-09 E. Renard, C. Bonnet, M. Di Patrizio, E. Schmitt, A. C. Madkaud, C. Chabot, M. Kuchenbuch, L. Lambert
Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of
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LUMBAR syndrome–OEIS complex overlap: A case series and review Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-07 L. Barrios, S. Chamlin, Kim M. Keppler‐Noreuil, K. L. Rialon, Paul Austin, A. Alhajjat, D. Bowen, Denise W. Metry, D. H. Siegel
We present three new and six published infants with overlapping features of LUMBAR syndrome (lower body hemangioma, urogenital anomalies, spinal cord malformations, bony deformities, anorectal/arterial anomalies and renal anomalies) and OEIS complex (omphalocele, exstrophy, imperforate anus, and spinal defects), also known as cloacal exstrophy. OEIS is included under the recently proposed umbrella
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Taking the risk. A systematic review of ethical reasons and moral arguments in the clinical use of polygenic risk scores Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-07 Lara Andreoli, Hilde Peeters, Kristel Van Steen, Kris Dierickx
Debates about the prospective clinical use of polygenic risk scores (PRS) have grown considerably in the last years. The potential benefits of PRS to improve patient care at individual and population levels have been extensively underlined. Nonetheless, the use of PRS in clinical contexts presents a number of unresolved ethical challenges and consequent normative gaps that hinder their optimal implementation
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TECPR2‐related hereditary sensory and autonomic neuropathy in two siblings from Palestine Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-04 Reham Khalaf‐Nazzal, Imad Dweikat, Nishanka Ubeyratna, James Fasham, Maysa Alawneh, Joseph Leslie, Mosab Maree, Adam Gunning, Deyala Z. Zayed, Nikol Voutsina, Lucy McGavin, Reem Sawafta, Martina Owens, Wisam Baker, Peter Turnpenny, Fida’ Al‐Hijawi, Emma L. Baple, Andrew H. Crosby, Lettie E. Rawlins
Due to the majority of currently available genome data deriving from individuals of European ancestry, the clinical interpretation of genomic variants in individuals from diverse ethnic backgrounds remains a major diagnostic challenge. Here, we investigated the genetic cause of a complex neurodevelopmental phenotype in two Palestinian siblings. Whole exome sequencing identified a homozygous missense
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Unraveling a history of overlap: A phenotypic comparison of RBCK1‐related disease and glycogen storage disease type IV Am. J. Med. Genet. Part A (IF 2.0) Pub Date : 2024-03-04 Haley M. Crane, Stephanie Asher, Laura Conway, Theodore G. Drivas, Staci Kallish
RBCK1‐related disease is a rare, multisystemic disorder for which our current understanding of the natural history is limited. A number of individuals initially carried clinical diagnoses of glycogen storage disease IV (GSD IV), but were later found to harbor RBCK1 pathogenic variants, demonstrating challenges of correctly diagnosing RBCK1‐related disease. This study carried out a phenotypic comparison