Journals American Journal of Medical Ge...

American Journal of Medical Genetics. Part A
Elizabeth K Baker, Faris N Al Gharaibeh, Kevin Bove, Maria A Calvo-Garcia, Amelle Shillington, Katherine VandenHeuvel, DonnaMaria E Cortezzo
Ryanodine receptor type 1-related disorder (RYR1-RD) is the most common subgroup of congenital myopathies with a wide phenotypic spectrum ranging from mild hypotonia to lethal fetal akinesia. Genetic testing for myopathies is imperative as the diagnosis informs counseling regarding prognosis and recurrence risk, treatment options, monitoring, and clinical management. However, diagnostic challenges exist as current options are limited to clinical suspicion prompting testing including: single gene sequencing or familial variant testing, multi-gene panels, exome, genome sequencing, and invasive testing including muscle biopsy...
March 25, 2023: American Journal of Medical Genetics. Part A
Ozlem Gorukmez, Orhan Gorukmez, Ali Topak
Clinical exome sequencing (CES) is important for the diagnosis of Mendelian diseases, which are clinically and etiologically heterogeneous. Sharing of large amounts of CES data associated with clinical findings will increase the accuracy of variant interpretation. We performed a retrospective study to state the diagnostic yield of CES in 1589 patients with a wide phenotypic spectrum. CES was performed using the Sophia Clinical Exome Sequencing Kit with 4493 genes, followed by sequencing on a NextSeq 500 system...
March 25, 2023: American Journal of Medical Genetics. Part A
Careni Spencer, George Comitis, John Lawrenson, Karen Fieggen
Congenital heart defects and skeletal malformations syndrome (CHDSKM; OMIM #617602) is a rare syndrome characterized by distinctive facial features, congenital cardiac lesions, failure to thrive, and skeletal abnormalities. Hearing impairment, renal, and ophthalmological abnormalities have also recently been reported. We report here the clinical and molecular phenotype of an adolescent male who presented with multisystem involvement suggestive of a connective tissue disorder. The proband presented with the typical dysmorphic, skeletal, and skin findings of CHDSKM...
March 22, 2023: American Journal of Medical Genetics. Part A
Pagna Sok, Aniko Sabo, Lynn M Almli, Mary M Jenkins, Wendy N Nembhard, A J Agopian, Michael J Bamshad, Elizabeth E Blue, Lawrence C Brody, Austin L Brown, Marilyn L Browne, Mark A Canfield, Suzan L Carmichael, Jessica X Chong, Shannon Dugan-Perez, Marcia L Feldkamp, Richard H Finnell, Richard A Gibbs, Denise M Kay, Yunping Lei, Qingchang Meng, Cynthia A Moore, James C Mullikin, Donna Muzny, Andrew F Olshan, Faith Pangilinan, Jennita Reefhuis, Paul A Romitti, Jeremy M Schraw, Gary M Shaw, Martha M Werler, Sanjiv Harpavat, Philip J Lupo
The etiology of biliary atresia (BA) is unknown, but recent studies suggest a role for rare protein-altering variants (PAVs). Exome sequencing data from the National Birth Defects Prevention Study on 54 child-parent trios, one child-mother duo, and 1513 parents of children with other birth defects were analyzed. Most (91%) cases were isolated BA. We performed (1) a trio-based analysis to identify rare de novo, homozygous, and compound heterozygous PAVs and (2) a case-control analysis using a sequence kernel-based association test to identify genes enriched with rare PAVs...
March 21, 2023: American Journal of Medical Genetics. Part A
Rachel Youjin Oh, Kathy Chun, Paul E Kowalski, David Chitayat
Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2. It is characterized by bitemporal atrophic skin lesions and distinctive facial features. Individuals with de novo or inherited duplication or triplication of the chromosomal region 1p36.22p36.21 have also been reported to have the SS phenotype with additional neurodevelopmental challenges (rarely seen in individuals with TWIST2 mutations) and variable expressivity and penetrance...
March 21, 2023: American Journal of Medical Genetics. Part A
Hong Le, Eva Jin, Ann Jewell, Colleen Jackson-Cook, Gloria T Haskell, Natario Couser
The 6p25 deletion syndrome is a rare genetic disorder characterized by a wide spectrum of congenital anomalies. Ophthalmic abnormalities appear to be highly associated with the syndrome, although this relationship has not been well characterized to date. We conducted a systematic literature review to highlight the ocular features in patients with this deletion syndrome and describe a 7-month-old female who has a 6.07 MB 6p25.1p25.3 deletion and a 4.25 MB 17q25.3 duplication. Our patient presented with multiple congenital anomalies, including macrocephaly, frontal bossing, low set ears, tent-shaped mouth, saddle nose, flat midface, and hearing impairment...
March 20, 2023: American Journal of Medical Genetics. Part A
Jorge Román Corona-Rivera, Felipe de Jesús Bustos Rodríguez, Laura Leticia Vega-Silva, Fernando Hernández-Camarena, Christian Peña-Padilla, Katia Alejandra Castillo-Reyes, Jessica Paola Cruz-Cruz, Lucina Bobadilla-Morales, Alfredo Corona-Rivera
Cutis verticis gyrata (CVG) is classified as primary or secondary according to the absence or presence of underlying soft tissue abnormalities. We report an infant with Turner syndrome (TS) who in addition presented with CVG on the scalp. The skin biopsy revealed a hamartoma-like lesion. We reviewed the clinical and histopathological findings of the 13 reported cases of congenital CVG in patients with TS, including ours. In 11 of them, CVG was localized on the skin of the scalp, mainly on the parietal region, and in two, on the forehead...
March 18, 2023: American Journal of Medical Genetics. Part A
Rameen Shah, Christin Johnsen, Beth A Pletcher, Andrew C Edmondson, Tamas Kozicz, Eva Morava
ALG13-CDG is a rare X-linked disorder of N-linked glycosylation. Given the lack of long-term outcome data in ALG13-CDG, we collected natural history data and reviewed individuals surviving to young adulthood with confirmed pathogenic variants in ALG13 in our own cohort and in the literature. From the 14 ALG13-CDG patients enrolled into our Frontiers of Congenital Disorders of Glycosylation Consortium natural history study only two patients were older than 16 years; one of these two females is so far unreported...
March 17, 2023: American Journal of Medical Genetics. Part A
Patricia V Hernandez, Katherine A King, Michael J Evenson, Meagan M Corliss, Molly C Schroeder, Jonathan W Heusel, Julie A Neidich, Yang Cao
Arteriovenous malformations (AVMs) are vascular lesions in which an overgrowth of blood vessels of varying sizes develops with one or more direct connections between the arterial and venous circulation. We performed a retrospective review of a cohort of 54 patients with AVMs referred to our clinical genomic laboratory for high-depth next-generation sequencing (NGS) panel of Disorders of Somatic Mosaicism (DoSM). Thirty-seven of 54 patients were female (68.5%). Among the 54 cases, 37 (68.5%) cases had pathogenic and/or likely pathogenic (P/LP) variants identified, two cases (3...
March 16, 2023: American Journal of Medical Genetics. Part A
Aylin Yüksel Ülker, Dilek Uludağ Alkaya, Ahmet Okay Çağlayan, Esra Usluer, Ayça Aykut, Ayça Aslanger, Mehmet Vural, Beyhan Tüysüz
Overgrowth-intellectual disability (OGID) syndromes are clinically and genetically heterogeneous group of disorders. The aim of this study was to examine the molecular etiology and long-term follow-up findings of Turkish OGID cohort. Thirty-five children with OGID were included in the study. Single gene sequencing, clinical exome analysis, chromosomal microarray analysis and whole exome sequencing were performed. Five pathogenic copy number variants were detected in the patients; three of them located on chromosome 5q35...
March 15, 2023: American Journal of Medical Genetics. Part A
Bailey A Martin-Giacalone, Angela E Lin, Sonja A Rasmussen, Russell S Kirby, Eirini Nestoridi, Rebecca F Liberman, A J Agopian, John C Carey, Janet D Cragan, Nina Forestieri, Vinita Leedom, Aubree Boyce, Wendy N Nembhard, Monika Piccardi, Theresa Sandidge, Xiaoyi Shan, Charles J Shumate, Erin B Stallings, Roger Stevenson, Philip J Lupo
The lack of United States population-based data on Turner syndrome limits assessments of prevalence and associated characteristics for this sex chromosome abnormality. Therefore, we collated 2000-2017 data from seven birth defects surveillance programs within the National Birth Defects Prevention Network. We estimated the prevalence of karyotype-confirmed Turner syndrome diagnosed within the first year of life. We also calculated the proportion of cases with commonly ascertained birth defects, assessed associations with maternal and infant characteristics using prevalence ratios (PR) with 95% confidence intervals (CI), and estimated survival probability...
March 15, 2023: American Journal of Medical Genetics. Part A
Takeaki Tamura, Keiko Shimojima Yamamoto, Taichi Imaizumi, Hisako Yamamoto, Yusaku Miyamoto, Hiroshi Yagasaki, Ichiro Morioka, Hitoshi Kanno, Toshiyuki Yamamoto
Many disease-causing genes have been identified by determining the breakpoints of balanced chromosomal translocations. Recent progress in genomic analysis has accelerated the analysis of chromosomal translocation-breakpoints at the nucleotide level. Using a long-read whole-genome sequence, we analyzed the breakpoints of the cytogenetically balanced chromosomal translocation t(5;15)(q21;26.3), which was confirmed to be of de novo origin, in a patient with a neurodevelopmental disorder. The results showed complex rearrangements with seven fragments consisting of five breakpoint-junctions (BJs)...
March 14, 2023: American Journal of Medical Genetics. Part A
Beryl Royer-Bertrand, Sébastien Lebon, Ailsa Craig, Johanna Maeder, Laureane Mittaz-Crettol, Heidi Fodstad, Andrea Superti-Furga, Jean-Marc Good
No abstract text is available yet for this article.
March 10, 2023: American Journal of Medical Genetics. Part A
Melina L Corriveau, Sabrina I Amaya, Mary Clare Koebel, Vanesa C Lerma, Sydney L Michener, Alicia Turner, Rebecca J Schultz, Elaine S Seto, Gloria E Diaz-Medina, William J Craigen, John W Swann, Mingshan Xue, Hsiao-Tuan Chao
The p-21-activated kinase 1 (PAK1) protein, encoded by the PAK1 gene, is an evolutionarily conserved serine/threonine-protein kinase that regulates key cellular developmental processes. To date, seven de novo PAK1 variants have been reported to cause the Intellectual Developmental Disorder with Macrocephaly, Seizures, and Speech Delay (IDDMSSD). In addition to the namesake features, other common characteristics include structural brain anomalies, delayed development, hypotonia, and dysmorphic features. Here, we report a de novo PAK1 NM_002576...
March 10, 2023: American Journal of Medical Genetics. Part A
Sharmila Kiss, John Christodoulou, David R Thorburn, Jeremy L Freeman, Andrew J Kornberg, Simone Mandelstam, Alison G Compton, Beryl Cummings, Lynn Pais, Joy Yaplito-Lee, Susan M White
Mitochondrial respiratory chain disorders (MRC) are amongst the most common group of inborn errors of metabolism. MRC, of which complex I deficiency accounts for approximately a quarter, are very diverse, causing a wide range of clinical problems and can be difficult to diagnose. We report an illustrative MRC case whose diagnosis was elusive. Clinical signs included failure to thrive caused by recurrent vomiting, hypotonia and progressive loss of motor milestones. Initial brain imaging suggested Leigh syndrome but without expected diffusion restriction...
March 9, 2023: American Journal of Medical Genetics. Part A
Hagit Daum, Joël Zlotogora
No abstract text is available yet for this article.
March 9, 2023: American Journal of Medical Genetics. Part A
Daniel T Kashima, Christina M Sloan-Heggen, Rachel J Gottlieb-Smith, Amanda Barone Pritchard
Ethylmalonic encephalopathy (EE) is a rare, severe, autosomal recessive condition caused by pathogenic variants in ETHE1 leading to progressive encephalopathy, hypotonia evolving to dystonia, petechiae, orthostatic acrocyanosis, diarrhea, and elevated ethylmalonic acid in urine. In this case report, we describe a patient with only mild speech and gross motor delays, subtle biochemical abnormalities, and normal brain imaging found to be homozygous for a pathogenic ETHE1 variant (c.586G>A) via whole exome sequencing...
March 9, 2023: American Journal of Medical Genetics. Part A
Suraj S Shah, Anne Fulton, Mireille Jabroun, Diana Brightman, Brittany N Simpson, Olaf A Bodamer
We aim to assess if genotype-phenotype correlations are present within ocular manifestations of Kabuki syndrome (KS) among a large multicenter cohort. We conducted a retrospective, medical record review including clinical history and comprehensive ophthalmological examinations of a total of 47 individuals with molecularly confirmed KS and ocular manifestations at Boston Children's Hospital and Cincinnati Children's Hospital Medical Center. We assessed information regarding ocular structural, functional, and adnexal elements as well as pertinent associated phenotypic features associated with KS...
March 9, 2023: American Journal of Medical Genetics. Part A
Christina G Tise, Courtney P Verscaj, Bryce A Mendelsohn, Jeremy Woods, Chung U Lee, Gregory M Enns, Zinandré Stander, Patricia L Hall, Tina M Cowan, Kristina P Cusmano-Ozog
Although decreased citrulline is used as a newborn screening (NBS) marker to identify proximal urea cycle disorders (UCDs), it is also a feature of some mitochondrial diseases, including MT-ATP6 mitochondrial disease. Here we describe biochemical and clinical features of 11 children born to eight mothers from seven separate families who were identified with low citrulline by NBS (range 3-5 μM; screening cutoff >5) and ultimately diagnosed with MT-ATP6 mitochondrial disease. Follow-up testing revealed a pattern of hypocitrullinemia together with elevated propionyl-(C3) and 3-hydroxyisovaleryl-(C5-OH) acylcarnitines, and a homoplasmic pathogenic variant in MT-ATP6 in all cases...
March 8, 2023: American Journal of Medical Genetics. Part A
Célia Azevedo Soares, Manuela Ferreira Almeida, Gabriela Soares, Natália Tkachenko, Ana Maria Fortuna, Carla Carmona
In phenylketonuria (PKU), high phenylalanine (Phe) levels hamper neurodevelopment impairing executive function later in life. While the second has been more studied, fewer data exist on predictors of PKU patients' development in specific populations. To contribute to the field, we performed a retrospective analysis of predictors of neurodevelopment in PKU patients in a Portuguese cohort. We analyzed the retrospective data on the metabolic control of 89 patients, as their health and familial features. Griffith's Mental Development Scale performance at age 6 (GMDS6) was used to assess neurodevelopment...
March 5, 2023: American Journal of Medical Genetics. Part A
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