Journals American Journal of Medical Ge...

American Journal of Medical Genetics. Part A
Fadi I Musfee, Goo Jun, Laura E Mitchell, Han Chen, Dongchuan Guo, Siddharth K Prakash, Shaunak Sanjay Adkar, Megan L Grove, Ryan Bohyun Choi, Derek Klarin, Eric Boerwinkle, Dianna M Milewicz
The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF <0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios...
April 30, 2024: American Journal of Medical Genetics. Part A
Laura T Forero, Riley Henderson, Carolina Galarreta, Steven Swee, Lynne M Bird
Genital anomalies have been reported with VACTERL association but not considered a core feature. Acute and chronic complications stemming from unrecognized genital anomalies have been reported in adolescents and young adults with VACTERL association. We sought to determine the frequency and severity of genital anomalies in VACTERL patients and identify which core features were more frequently associated with genital anomalies. A retrospective chart review from January 2010 to October 2021 identified 211 patients with two or more core VACTERL features, 34% of whom had a genital anomaly...
April 30, 2024: American Journal of Medical Genetics. Part A
Saisuda Noojarern, Thipwimol Tim-Aroon, Kingthong Anurat, Tim Phetthong, Arthaporn Khongkraparn, Duangrurdee Wattanasirichaigoon
Pettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein...
April 29, 2024: American Journal of Medical Genetics. Part A
Nadia Falah, Surekha Pendyal, Cina Sasannejad, Allison Gibson, Yu Lin Lee, Marie McDonald, Dwight Koeberl
Significant progress has been achieved in enhancing early outcomes for individuals with maple syrup urine disease (MSUD), a rare metabolic disorder that leads to the accumulation of branched-chain amino acids leucine, isoleucine, and valine, where leucine is known as the primary neurotoxic metabolite. Newborn screening is helpful in early diagnosis and implementation of dietary treatment, thus reducing neurological deterioration and complications in young children. However, patients face the life-long challenge of maintaining metabolic control through adherence to a strict low-leucine diet to avoid long-term consequences of chronic hyperleucinemia, which include cognitive deficits, mood disorders, and movement disorders...
April 29, 2024: American Journal of Medical Genetics. Part A
Lewis B Holmes, Anne-Therese Hunt
Exposure at conception to phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ) has been associated with several different effects on the fetus, including hypoplasia of the distal phalanges, dysmorphic facial features, and structural abnormalities such as oral clefts and neural tube defects. One question is whether each of these antiepileptic drugs (AEDs) has the same effects or just similar effects. A systematic examination of the fingers of children exposed at conception to PHT, PB, or CBZ, as monotherapy, has been used to address this question...
April 26, 2024: American Journal of Medical Genetics. Part A
Aynur Küçükcongar Yavaş, Hacer Basan, Serpil Dinçer, Berrak Bilginer Gürbüz, Çiğdem Seher Kasapkara
The mitochondrial phosphate carrier is critical for adenosine triphosphate synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. Variants in the SLC25A3 gene coding mitochondrial phosphate carrier lead to failure in inorganic phosphate transport across mitochondria. The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases...
April 24, 2024: American Journal of Medical Genetics. Part A
Derya Kaya, Canan Ceylan Köse, Mehmet Berkay Akcan, Fatma Silan
Biallelic pathogenic variations in the zinc finger protein 142 (ZNF142) gene are associated with neurodevelopmental disorder with impaired speech and hyperkinetic movements (NEDISHM). This disorder is characterized by developmental delay, intellectual disability, speech delay, and movement disorders such as dystonia, tremor, ataxia, and chorea. Here, we report a patient who exhibited common neurological features and rarely reported brain MRI findings. Exome sequencing identified a novel biallelic variant in ZNF142 (c...
April 24, 2024: American Journal of Medical Genetics. Part A
Sumihito Togi, Hiroki Ura, Yo Niida
The phenotypes associated with MED12 pathogenic variants are diverse. Male patients usually have missense variants, but the effects of base substitutions on mRNA splicing have not been investigated. Here, we report a Japanese brother with intellectual disability, characteristic facial appearance with blepharophimosis, cleft palate, Fallot tetralogy, vesicoureteral reflux, and deafness. A known missense pathogenic variant was detected in MED12, NM_005120.3:c.887G>A p.(Arg296Gln), and X-linked Ohdo syndrome was diagnosed in combination with their phenotype...
April 24, 2024: American Journal of Medical Genetics. Part A
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, often associated with semilethality. Recently, pathogenic variants in GRK2, a subfamily of mammalian G protein-coupled receptor kinases, have been identified as one of the underlying causes of Jeune ATD...
April 22, 2024: American Journal of Medical Genetics. Part A
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. In this report, we performed an exome sequencing analysis of a Brazilian family with CFM. The proband was a 12-month-old boy with clinical findings consistent with the diagnostic criteria for CFM, including unilateral mandibular hypoplasia, microtia, and external auditory canal abnormalities...
April 22, 2024: American Journal of Medical Genetics. Part A
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 records of 25 current and historical patients evaluated at the National Institutes of Health. Nine patients were classified as GD1, 14 were classified as GD3, and two had an ambiguous diagnosis between GD1 and GD3...
April 22, 2024: American Journal of Medical Genetics. Part A
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 reported. Despite comprehensive workup for an acute trigger, no definite cause was identified, and pharmacological interventions were ineffective to treat PSH...
April 18, 2024: American Journal of Medical Genetics. Part A
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 were hip or knee pain and a waddling gait. All patients showed normal intelligence, normal hearing and eye examinations, and none had organomegaly...
April 18, 2024: American Journal of Medical Genetics. Part A
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 have improved. Four DS nonprofit organizations, which participated in the original study, distributed a mixed-methods survey to families who have had children with DS between 2003 and 2022...
April 15, 2024: American Journal of Medical Genetics. Part A
Takeshi Yagyu, Kazufumi Ida, Teruo Noguchi
No abstract text is available yet for this article.
April 15, 2024: American Journal of Medical Genetics. Part A
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 clefts which likely contributed to their feeding difficulties. Additional factors such as airway anomalies should be considered in patients with PWS, especially when swallowing dysfunction, dysphagia, or abnormal swallow evaluations are present...
April 15, 2024: American Journal of Medical Genetics. Part A
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 to juvenile myelomonocytic leukemia and vasculitis. Other features of the disorder include cardiac defects, postnatal growth delay, cryptorchidism, facial dysmorphisms, and predisposition to develop autoimmune disorders...
April 12, 2024: American Journal of Medical Genetics. Part A
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 a specialty. Results demonstrate that, for most, interest in genetics begins in medical school and was largely influenced by mentorship...
April 11, 2024: American Journal of Medical Genetics. Part A
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 data, but through deep phenotyping, which pointed to only one plausible candidate gene, manual inspection of genome sequencing alignment data enabled us to identify a de novo heterozygous Alu insertion in exon 8 of the ZEB2 gene...
April 11, 2024: American Journal of Medical Genetics. Part A
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 diagnosis of CHARGE syndrome and documented ophthalmic examination. Demographics, genetic testing, and ocular findings were collected...
April 10, 2024: American Journal of Medical Genetics. Part A
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