American Journal of Medical Genetics Part A最新文献

The ability to make informed decisions about reproductive health is a cornerstone principle of the practice of prenatal medical genetics. Unfortunately, these reproductive health decisions have become entangled in the current, contentious political climate. This debate reached an inflection point in 2022 with Dobbs v. Jackson when the Supreme Court of the United States (SCOTUS) overturned the national right to abortion previously established in Roe v. Wade. This decision prompted a reassessment of the opinions of medical students on reproductive health and abortion. Our study focused on a medical school in Alabama, a conservative state that enacted a restrictive abortion ban following the Dobbs ruling. Two surveys, conducted in 2015 and 2022, explored students' viewpoints on reproductive health topics, including abortion. The comparison revealed a significant shift toward more pro-choice perspectives among medical students. Notably, religious affiliation did not consistently align with opinions, as many Christian students supported pro-choice views. Our results suggest that medical students' reproductive health opinions at our institution have shifted to a more pro-choice position over the last decade.

Pseudo-TORCH Syndrome (PTS) encompasses a heterogeneous group of genetic disorders that may clinically and radiologically resemble congenital TORCH infections. These mimickers present with overlapping features manifested as intracranial and systemic abnormalities. Collagen type IV alpha 1 chain (COL4A1)-related diseases, characterized by autosomal dominant inheritance, exhibit a diverse phenotypic spectrum involving cerebrovascular, renal, ophthalmological, cardiac, and muscular abnormalities. Cerebrovascular manifestations range from small-vessel brain disease to large vessel abnormalities, resulting in intracerebral hemorrhage, periventricular leukoencephalopathy, and ventriculomegaly. Additional features include cortical malformations, eye defects, arrhythmias, renal disease, muscular abnormalities, and hematological manifestations. Age of onset varies widely, and phenotypic variability exists even among individuals with the same variant. In this study, we present two cases of COL4A1-related disorder mimicking congenital TORCH infections, highlighting the importance of recognizing genetic mimics in clinical practice.

We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of "brain abnormalities, neurodegeneration, and dysosteosclerosis" (BANDDOS) and discuss its link with "adult leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.

RASopathies encompass a diverse set of disorders affecting genes that encode proteins within the RAS-MAPK pathway. RASA1 mutations are the cause of an autosomal dominant disorder called capillary malformation-arteriovenous malformation type 1 (CM-AVM1). Unlike other RASopathies, facial dysmorphism has not been described in these patients. We phenotypically delineated a large family of individuals with multifocal fast-flow capillary malformations, severe lymphatic anomalies of perinatal onset, and dysmorphic features not previously described. Sequencing studies were performed on probands and related family members, confirming the segregation of dysmorphic features in affected members of a novel heterozygous variant in RASA1 (NM_002890.3:c.2366G>A, p.(Arg789Gln)). In this work, we broaden the phenotypic spectrum of CM-AVM type 1 and propose a new RASA1 variant as likely pathogenic.

Haploinsufficiency of FOXP1 gene is responsible for a neurodevelopmental disorder presenting with intellectual disability (ID), autism spectrum disorder (ASD), hypotonia, mild dysmorphic features, and multiple congenital anomalies. Joint contractures are not listed as a major feature of FOXP1-related disorder. We report five unrelated individuals, each harboring likely gene disruptive de novo FOXP1 variants or whole gene microdeletion, who showed multiple joint contractures affecting at least two proximal and/or distal joints. Consistent with the phenotype of FOXP1-related disorder, all five patients showed developmental delay with moderate-to-severe speech delay, ID, ASD, and facial dysmorphic features. FOXP1 is implicated in neuronal differentiation and in organizing motor axon projections, thus providing a potential developmental basis for the joint contractures. The combination of joint contractures and neurodevelopmental disorders supports the clinical suspicion of FOXP1-related phenotype.

Ciliopathies represent a major category of rare multisystem disease. Arriving at a specific diagnosis for a given patient is challenged by the significant genetic and clinical heterogeneity of these conditions. We report the outcome of the diagnostic odyssey of a child with obesity, renal, and retinal disease. Genome sequencing identified biallelic splice site variants in sodium channel and clathrin linker 1 (SCLT1), an emerging ciliopathy gene. We review the literature on all patients reported with biallelic SCLT1 variants highlighting a frequent clinical presentation that overlaps Bardet-Biedl and Senior-Loken syndromes. We also discuss current concepts in syndrome designation in light of these data.

Low-pass whole genome sequencing (LP-WGS) has been applied as alternative method to detect copy number variants (CNVs) in the clinical setting. Compared with chromosomal microarray analysis (CMA), the sequencing-based approach provides a similar resolution of CNV detection at a lower cost. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from 15 nonprofit organizations and university centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (>50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15%-20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics.

A heterozygous gain-of-function variant in the acyl-CoA oxidase 1 (ACOX1) gene, c.710A>G (p.Asn237Ser), is known to cause Mitchell syndrome, a very rare progressive disorder characterized by episodic demyelination, sensory polyneuropathy, and hearing loss. Only eight patients have been described so far. A single patient has been treated with intravenous immunoglobulin administration, indicating clinical improvement. In this study, we describe a 10-year-old girl carrying the identical mutation, who presented with progressive sensorineural deafness, visual abnormalities, skin ichthyosis, and gait ataxia from infantile age with progressive worsening and loss of walking ability by the age of 10 years. Antioxidant therapies and monthly intravenous immunoglobulin infusions showed excellent clinical results: after 1 year of treatment, the child is now able to walk, run, and jump. We emphasize the importance of early genetic diagnosis since an effective treatment is available for this rare condition.

Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy of unknown etiology. The underlying mechanisms are highly heterogeneous, often including genetic backgrounds. Variants of LARS1, encoding the leucyl-tRNA synthetase 1, are responsible for infantile liver failure syndrome 1. We describe two siblings with ANE caused by compound heterozygous variants of LARS1. Patient 1 was a 17-month-old girl. She presented with generalized seizure and liver dysfunction due to influenza type A infection. Brain magnetic resonance imaging on day 4 of onset showed diffuse high-intensity signals consistent with ANE. She died on day 10. Patient 2, a younger male sibling of patient 1, had mild to moderate developmental delay and growth failure at the age of 18 months. He showed a markedly elevated level of transaminases triggered by infection with human herpesvirus 6. On day 4 of onset, he had generalized seizures. Brain computed tomography showed a diffuse symmetrical hypodensity consistent with ANE. He died on day 7. Whole exome sequencing identified the compound heterozygous variants in LARS1 (NM_020117.11) as c.83_88delinsAATGGGATA, p.(Arg28_Phe30delinsLysTryAspIle) and c.1283C>T, p.(Pro428Leu) in both siblings. The severe neurologic phenotype, found in our patients, reflects the complicated pathogenesis of LARS1-related disorder.

Although next-generation sequencing has enabled diagnoses for many patients with Mendelian disorders, the majority remain undiagnosed. Here, we present a sibling pair who were clinically diagnosed with Escobar syndrome, however targeted gene testing was negative. Exome sequencing (ES), and later genome sequencing (GS), revealed compound heterozygous TTN variants in both siblings, a maternally inherited frameshift variant [(NM_133378.4):c.36812del; p.(Asp12271Valfs*10)], and a paternally inherited missense variant [(NM_133378.4):c.12322G > A; p.(Asp4108Asn)]. This result was considered nondiagnostic due to poor clinical fit and limited pathogenicity evidence for the missense variant of uncertain significance (VUS). Following initial nondiagnostic RNA sequencing (RNAseq) on muscle and further pursuit of other variants detected on the ES/GS, a reanalysis of noncanonical splice sites in the muscle transcriptome identified an out-of-frame exon retraction in TTN, near the known VUS. Interim literature included reports of patients with similar TTN variants who had phenotypic concordance with the siblings, and a diagnosis of a congenital titinopathy was given 4 years after the TTN variants had been initially reported. This report highlights the value of reanalysis of RNAseq with a different approach, expands the phenotypic spectrum of congenital titinopathy and also illustrates how a perceived phenotypic mismatch, and failure to consider known variants, can result in a prolongation of the diagnostic journey.