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American Journal of Medical Genetics. Part A

Monika Gos, Robert Smigiel, Teresa Kaczan, Aleksandra Landowska, Anna Abramowicz, Malgorzata Sasiadek, Jerzy Bal
Cardio-facio-cutaneous syndrome (CFCS), a rare congenital disorder of RASopathies, displays high phenotypic variability. Complications during pregnancy and in the perinatal period are commonly reported. Polyhydramnios is observed in over half of pregnancies and might occur with fetal macrocephaly, macrosomia, and/or heart defects. Premature birth is not uncommon and any complications like respiratory insufficiency, edema, and feeding difficulties are present and might delay accurate clinical diagnosis. Besides neonatal complications, CFCS newborns and later infants have distinctive dysmorphic features usually accompanied by neurological (hypotonia with motor delay, neurocognitive delay) findings...
May 25, 2018: American Journal of Medical Genetics. Part A
Helga Rehder, Franco Laccone, Susanne G Kircher, Ralf L Schild, Christiane Rapp, Rainer Bald, Bernt Schulze, Jana Behunova, Juergen Neesen, Katharina Schoner
The Piepkorn type of lethal osteochondrodysplasia (POCD) is a rare and lethal dwarfing condition. Four cases have been reported to date. The characteristic features are distinctly shortened "flipper-like" limbs, polysyndactyly, excessive underossification, especially of the limb bones and vertebrae, and large (giant) chondrocytes in the cartilaginous bone primordia. These characteristics allowed the diagnosis of Piepkorn type of osteochondrodysplasia in four new cases, three fetuses of 15 to 22 weeks and one 106-year-old museum exhibit...
May 23, 2018: American Journal of Medical Genetics. Part A
Manar Zaghlula, Daniel G Glaze, Gregory M Enns, Lorraine Potocki, Aloysia L Schwabe, Bernhard Suter
No abstract text is available yet for this article.
May 19, 2018: American Journal of Medical Genetics. Part A
Nancy J Butcher, Erik Boot, Anthony E Lang, Danielle Andrade, Jacob Vorstman, Donna McDonald-McGinn, Anne S Bassett
Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at elevated risk of developing treatable psychiatric and neurological disorders, including anxiety disorders, schizophrenia, seizures, and movement disorders, often beginning in adolescence or early to mid-adulthood. Here, we provide an overview of neuropsychiatric features associated with 22q11.2DS in adulthood. Results of a new case series of 13 individuals with 22q11.2DS and catatonic features together with 5 previously reported cases support a potential association of this serious psychomotor phenotype with the 22q11...
May 19, 2018: American Journal of Medical Genetics. Part A
Andrea Klunder Petersen, Haley Streff, Mari Tokita, Bret L Bostwick
Pathogenic variants in CHD2 (chromodomain helicase DNA-binding protein 2) have been reported in neurodevelopmental disorders with a broad spectrum of phenotypic variability, ranging from mild intellectual disability to atonic-myoclonic epilepsy. However, given the paucity of reported cases the extent of this phenotypic spectrum is currently unknown. Furthermore, all confirmed pathogenic CHD2 variants reported to date have been de novo, preventing the study of intrafamilial phenotypic heterogeneity and creating ambiguity regarding recurrence risk, penetrance, and expressivity...
May 9, 2018: American Journal of Medical Genetics. Part A
Tomoko Uehara, Naoki Hosogaya, Nobutake Matsuo, Kenjiro Kosaki
Systemic lupus erythematosus (SLE) has been reported among patients with RASopathy. Five patients have been reported: three with SHOC2 variants, one with a PTPN11 variant, and one with a KRAS variant. SHOC2 variant might represent a relatively common predisposing factor for SLE among the RASopathy genes. However, the clinical details were only reported for two patients, while information on the remaining patient appeared only in a tabular format with minimal clinical description. Here, we report a patient with a SHOC2 variant and SLE...
May 7, 2018: American Journal of Medical Genetics. Part A
Mari Minatogawa, Fuminori Iwasaki, Takayuki Yokoi, Junichi Nagai, Satoru Sakazume, Hiroaki Goto, Kenji Kurosawa
No abstract text is available yet for this article.
May 7, 2018: American Journal of Medical Genetics. Part A
Anjali Sadhwani, Neville E Sanjana, Jennifer M Willen, Stephen N Calculator, Emily D Black, Lora J H Bean, Hong Li, Wen-Hann Tan
We present three children from two unrelated families with Angelman syndrome (AS) whose developmental skills are far more advanced than any other non-mosaic AS individual ever reported. All have normal gait and use syntactic language spontaneously to express their needs. All of them have a c.2T > C (p.Met1Thr) variant in UBE3A, which abrogates the start codon of isoform 1, but not of isoforms 2 and 3. This variant was maternally inherited in one set of siblings, but de novo in the other child from the unrelated family...
May 7, 2018: American Journal of Medical Genetics. Part A
Jamie McDonald, Whitney L Wooderchak-Donahue, Katharine Henderson, Eleri Paul, Ashley Morris, Pinar Bayrak-Toydemir
Mosaicism in hemorrhagic telangiectasia (HHT) has been previously identified when testing blood samples of HHT patients. We report the first detection of mosaicism not involving blood of a family proband, and discuss implications for genetic testing algorithms in HHT families. Sanger sequencing and large deletion/duplication analysis in a patient with HHT identified no pathogenic variant in ENG, ACVRL1, or SMAD4. Exome sequencing was then performed on this proband, as well as her affected adult child. A pathogenic ENG variant was detected in the proband's affected child, but not in DNA extracted from peripheral blood of the affected parent/proband...
May 7, 2018: American Journal of Medical Genetics. Part A
Meena Balasubramanian, Nadja Fratzl-Zelman, Rory O'Sullivan, Mary Bull, Nicola Fa Peel, Rebecca C Pollitt, Rebecca Jones, Elizabeth Milne, Kath Smith, Paul Roschger, Klaus Klaushofer, Nicholas J Bishop
BACKGROUND: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass. METHODS: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients. RESULTS: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult...
May 7, 2018: American Journal of Medical Genetics. Part A
Saud Alsahli, Stefan T Arold, Ahmed Alfares, Bader Alhaddad, Mohammed Al Balwi, Erik-Jan Kamsteeg, Waleed Al-Twaijri, Majid Alfadhel
Intellectual disability (ID) and global developmental delay are closely related; the latter is reserved for children under the age of 5 years as it is challenging to reliably assess clinical severity in this population. ID is a common condition, with up to 1%-3% of the population being affected and leading to a huge social and economic impact. ID is attributed to genetic abnormalities most of the time; however, the exact role of genetic involvement in ID is yet to be determined. Whole exome sequencing (WES) has gained popularity in the workup for ID, and multiple studies have been published examining the diagnostic yield in identification of the disease-causing variant (16%-55%), with the genetic involvement increasing as intelligence quotient decreases...
May 7, 2018: American Journal of Medical Genetics. Part A
Rika Kosaki, Hiroshi Ono, Hiroshi Terashima, Kenjiro Kosaki
Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension...
May 7, 2018: American Journal of Medical Genetics. Part A
Sharolin Boban, Helen Leonard, Kingsley Wong, Andrew Wilson, Jenny Downs
Sleep disturbances are debilitating for individuals with Rett syndrome (RTT) and their families yet the evidence base for management is poor. We investigated management strategies and their relationships with sleep problems. Data were provided by 364/461 (79%) families with a child with RTT and registered with the International RTT Phenotype Database. Logistic regression models were used to investigate relationships between impacts of sleep problems on the child and family with age group, mutation type, medication type, and sleep hygiene score...
April 28, 2018: American Journal of Medical Genetics. Part A
Sarah Geoghegan, Graham King, Jennifer Henchliffe, Simon C Ramsden, Raymond J Barry, Andrew J Green, Susan M O'Connell
Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by intellectual disability, congenital heart defects, a characteristic facial appearance, gastro-intestinal complications, ectodermal abnormalities and growth failure. The RASopathies result from germline mutations in the Ras/Mitogen-activated-protein-kinase (MAPK) pathway. CFC is associated with mutations in BRAF, KRAS, MEK1 and MEK2. CFC has been considered a "sporadic" disorder, with minimal recurrence risk to siblings. In recent years, vertical transmission of CFC has been seen in mutations involving the MEK2 and KRAS genes, but has not previously been reported with BRAF mutations...
April 28, 2018: American Journal of Medical Genetics. Part A
David Owen, Ana Töpf, Veeramani Preethish-Kumar, Paulo José Lorenzoni, Bas Vroling, Rosana Herminia Scola, Elza Dias-Tosta, Argemiro Geraldo, Kiran Polavarapu, Saraswati Nashi, Daniel Cox, Teresinha Evangelista, John Dawson, Rachel Thompson, Jan Senderek, Steven Laurie, Sergi Beltran, Marta Gut, Ivo Gut, Atchayaram Nalini, Hanns Lochmüller
Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c...
April 28, 2018: American Journal of Medical Genetics. Part A
Umakanth Katwa, Alissa M D'Gama, Anita E Qualls, Lucas M Donovan, Jody Heffernan, Jiahai Shi, Pankaj B Agrawal
Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired-like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non-polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma...
April 28, 2018: American Journal of Medical Genetics. Part A
Anaëlle Lenormand, Roman Khonsari, Pierre Corre, Jean Philippe Perrin, Cécile Boscher, Mathilde Nizon, Olivier Pichon, Albert David, Cedric Le Caignec, Helios Bertin, Bertrand Isidor
Ankyloglossia is a congenital oral anomaly characterized by the presence of a hypertrophic and short lingual frenulum. Mutations in the gene encoding the transcription factor TBX22 have been involved in isolated ankyloglossia and X-linked cleft palate. The knockout of Lgr5 in mice results in ankyloglossia. Here, we report a five-generation family including patients with severe ankyloglossia and missing lower central incisors. Two members of this family also exhibited congenital anorectal malformations. In this report, male-to-male transmission was in favor of an autosomal dominant inheritance, which allowed us to exclude the X-linked TBX22 gene...
April 28, 2018: American Journal of Medical Genetics. Part A
Shinn Young Kim, Hyun-Sun Ko, Namshin Kim, Seon-Hee Yim, Seung-Hyun Jung, Jiwoong Kim, Myung-Duk Lee, Yeun-Jun Chung
The etiology of imperforate anus, a major phenotype of anorectal malformation (ARM), is still unknown and not a single gene has been reported to be associated with it. We studied a Korean family with six affected members with imperforate anus across three generations by whole exome sequencing and identified a missense mutation in the EBF2 gene (c.215C > T; p.Ala72Val). This mutation is completely segregated with the disease phenotype in the family and is evolutionarily highly conserved among diverse vertebrates...
April 28, 2018: American Journal of Medical Genetics. Part A
Chloé Quélin, Philippe Loget, Lucile Boutaud, Nadia Elkhartoufi, Joelle Milon, Sylvie Odent, Mélanie Fradin, Florence Demurger, Laurent Pasquier, Sophie Thomas, Tania Attié-Bitach
Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c...
April 27, 2018: American Journal of Medical Genetics. Part A
Ann Swillen, Edward Moss, Sasja Duijff
The 22q11.2 deletion syndrome (22q11.2 DS) places affected individuals at an increased risk for neurodevelopmental/cognitive, behavioral and social-emotional difficulties. Poor cognitive functioning and intellectual disabilities, attention and executive functioning deficits, learning disorders, emotional dysregulation and impairments in social processing are common among individuals with 22q11.2 DS. Identifying risk and protective/resilience factors that can be detected in early life and can predict neurodevelopmental outcomes for people with 22q11...
April 25, 2018: American Journal of Medical Genetics. Part A
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