American Journal of Medical Genetics Part A最新文献

RAC1 encodes the protein RAS-related C3 Botulinum Toxin Substrate 1 (RAC1), which plays a pivotal role in various cellular functions. Pathogenic variants in RAC1 are linked to the rare intellectual developmental disorder, autosomal-dominant 48 (MRD48). We present one case with typical phenotype and two cases with a mild phenotype. This report expands the phenotypic spectrum of MRD48.

Hereditary hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder caused by biallelic variants in the transient receptor potential melastatin 6 (TRPM6) gene, typically presenting in infancy. Currently, there is a lack of reports in the literature on adult-onset cases. This case report describes a 51-year-old male with adult-onset HSH, presenting with limb weakness, muscle spasms, and electrolyte imbalances, including severe hypomagnesemia (0.28 mmol/L). Genetic testing revealed a novel heterozygous variant in the TRPM6 gene (c.4914del, p.E1638Dfs*8), classified as likely pathogenic. The patient's symptoms significantly improved following magnesium supplementation, and his electrolyte levels gradually normalized. This case highlights the importance of considering HSH in patients with unexplained hypomagnesemia and emphasizes the role of genetic testing in confirming the diagnosis. The findings also suggest that magnesium supplementation can effectively alleviate symptoms and improve the quality of life in patients with adult-onset HSH. Early recognition and treatment are crucial to prevent potential complications, such as neurological damage.

Parents of children with Down syndrome have historically reported poor experiences receiving a prenatal diagnosis. In a 2003 survey, mothers reported that their physicians pitied them, emphasized negative aspects of Down syndrome, and encouraged them to terminate the pregnancy. This study assesses whether parents' perceptions have since improved. Community-based organizations that had distributed the original 2003 survey distributed a similar survey to parents who have had a child with Down syndrome since 2003. Compared to the 2003 survey, parents continued to report dissatisfaction with their prenatal medical care (N = 60). Though subgroups became likelier to view their testing experience positively, parents' experiences worsened on certain metrics. Most parents reported dissatisfaction when providers conveyed pity or attempted to influence their decision-making about the pregnancy. Interventions to date have failed to improve parents' perceptions of their prenatal medical support, urging new strategies to improve parents' care.

Hypertrophic cardiomyopathy (HCM) is rare in childhood, but it is associated with significant morbidity and mortality. Genetic causes of HCM are mostly related to sarcomeric genes abnormalities; however, syndromic, metabolic, and mitochondrial disorders play an important role in its etiopathogenesis in pediatric patients. We here describe a new case of apparently isolated HCM due to mitochondrial assembly factor gene NDUFAF1 biallelic variants (c.631C > T and an intragenic deletion encompassing exon 3, NM_016013.4). Alterations of this nuclear gene have been associated to Mitochondrial complex I deficiency, nuclear type 11 (OMIM *618234). We here report the fourth case of a child affected by complex I deficiency due to alterations in NDUFAF1 gene. His clinical features appear simpler when compared to the other cases described in the medical literature, increasing our knowledge regarding the highly heterogeneous clinical presentation associated with this disorder.

The American Academy of Pediatrics (AAP) health supervision guidelines for children with Down syndrome are important for preventative and symptom-based care. Studies, however, have shown low overall adherence to these care recommendations due to a lack of provider familiarity, inaccessibility of a medical home, and caregiver burden. In a population of children with Down syndrome, using a retrospective chart review, we evaluated overall patient adherence to the medical components of the 2011 AAP guidelines, along with potential influencing factors, to determine if there was a difference in adherence between those who had genetic counseling and those who had not. Among 106 subjects meeting our study criteria, adherence rates were higher on average in six domains of health supervision (62% vs. 45%) in those that had genetic counseling compared with those that had not. Although adherence to supervision recommendations is likely impacted by numerous factors, genetic counseling may be one factor associated with increased adherence to medical recommendations for a pediatric population with Down syndrome. Encouraging caregivers of individuals with Down syndrome to undergo genetic counseling may lead to improved adherence to the health supervision guidelines.

Myhre syndrome is a rare disorder caused by pathogenic gain-of-function variants in the SMAD4 gene. Most of the patients have had de novo variants. There are several instances of autosomal dominant inheritance, and penetrance appears to be complete. We describe seven Brazilian patients, three of whom are siblings carrying the recurrent c.1486C>T p.(Arg496Cys) variant in SMAD4 inherited from the father. The other three patients are unrelated simplex cases. All affected individuals have clinical features commonly found in Myhre syndrome, including typical dysmorphic facial features, with intra- and interfamilial clinical heterogeneity. Five of the patients have developmental delay and/or clinical signs of intellectual disability. However, only one had neuropsychological testing. Only one patient had a diagnosis of autism spectrum disorder. As in previously reported families, this new family has the same c.1486C>T p.(Arg496Cys) variant. This is the first study describing Brazilian patients with Myhre syndrome, highlighting the clinical variability of this rare disease. We reinforce the need to investigate the parents to provide appropriate genetic counseling.

Our objectives are to report on the outcomes of adrenal insufficiency (AI) and cerebral ALD (cALD) in children diagnosed with X-linked adrenoleukodystrophy (ALD) identified by newborn screening (NBS) in Minnesota in the first 5 years following initiation of NBS in 02/2017. A retrospective chart review was conducted for children diagnosed with ALD via Minnesota NBS from 02/06/2017 through 02/06/2022. Data reviewed included newborn screening data, diagnostic very long chain fatty acid levels, ABCD1 molecular testing results, serial measurements of ACTH and cortisol, and serial brain MRI results. Thirty-two boys and 11 girls were molecularly and/or biochemically confirmed to have ALD. Of these 32 boys, six (2-7 years; median age:18 months) developed AI. Two boys developed cALD and underwent stem cell transplantation, one of whom also has been diagnosed with AI. All the pathogenic/likely pathogenic variants detected during the first 5 years had initial C26:0 lysophosphatidylcholine (C26:0 lysoPC) values over 0.3 μmol/L at the time of newborn screening. The addition of ALD to NBS in Minnesota has allowed for early detection of asymptomatic AI in six young patients and asymptomatic cALD in two patients. Data from our study shows a positive correlation between high newborn screening LysoPC levels and variant pathogenicity.

Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severity. To better characterize the course of COVID-19 infection in patients with PWS, this study analyses the outcomes of hospitalizations for COVID-19 among patients with and without PWS. The National Inpatient Sample, an all-payors administrative claims database of hospitalizations in the United States, was queried for patients with a coded diagnosis COVID-19 in 2020 and 2021. Hospitalizations for patients with PWS compared to those for patients without PWS using Augmented Inverse Propensity Weighting (AIPW). There were 295 (95% CI: 228-362) COVID-19 hospitalizations for individuals with PWS and 4,112,400 (95% CI: 4,051,497-4,173,303) for individuals without PWS. PWS patients had a median age of 33 years compared to 63 for those without PWS. Individuals with PWS had higher baseline rates of obesity (47.5% vs. 28.4%). AIPW models show that PWS diagnosis is associated with increased hospital length of stay by 7.43 days, hospital charges by $80,126, and the odds of mechanical ventilation and in-hospital death (odds ratios of 1.79 and 1.67, respectively). PWS patients hospitalized with COVID-19 experienced longer hospital stays, higher charges, and increased risk of mechanical ventilation and death. These results suggest that PWS should be considered a risk factor for severe COVID-19, warranting continued protective measures and vaccination efforts. Further research is needed to validate coding for PWS and assess the impact of evolving COVID-19 variants and population immunity on this vulnerable population.

We describe the phenotypic and genotypic spectrum of patients with vascular anomaly (VA) in a paediatric multi-disciplinary VA clinic. We measured the clinical utility of genotyping by comparing pre and posttest diagnosis and management. A 46-month retrospective analysis occurred for 250 patients offered genetic testing in the VA clinic. DNA was extracted from biopsied vascular lesions. The coding regions of 27 genes were amplified by multiplex PCR and sequenced with mean coverage depth ranging from 3005× to 66,320×, achieving >95% amplification with at least 500 reads. The limit of detection was approximately 1%. Germline confirmatory testing was arranged where phenotype and variant allele frequency (AF) were compatible with a heritable VA. A molecular diagnosis was identified for 191 of 250 (76%). A somatic cause for VA was confirmed for 70% and a germline cause for 6%. Genetic testing supported the clinical diagnosis for 55% of our patient group and revised the clinical diagnosis for 21%. For patients with a revised clinical diagnosis, a management change occurred for 62%. 33% of patients offered genetic testing for VA had a management change. 24% were referred for consideration of molecularly targeted therapy (MTT). Routine genotyping in paediatric VA improves diagnosis and management outcomes.

We report a 28-year-old G2P0 at 24 weeks 5 days who presented for evaluation secondary to suspected skeletal dysplasia in her fetus. Fetal ultrasound imaging demonstrated foreshortened long bones by 9-10 weeks, multiple bowing deformities and fractures, 11 foreshortened paired ribs with fractures, decreased skull mineralization, frontal bossing, enlarged cavum septum pellucidi, and severe fetal growth restriction (< 2%). Findings were concerning for life limiting condition with thoracic circumference < 2.5%, femur length/abdominal circumference ratio of 0.13, and the thoracic circumference/abdominal circumference ratio of 0.77 and a palliative care path was pursued. Exome sequencing through chorionic villus sampling revealed two variants SEC24D, a maternally inherited likely pathogenic variant at c.3031_3040delinsC, and a variant of uncertain significance (VUS) at c.2676 + 5del. These variants, along with the clinical overlap in the fetus were likely causative of a diagnosis of Cole-carpenter syndrome type 2 (CLCRP2). Most publications of CLCRP2 report a fairly favorable prognosis. Concern for life limiting prenatal presentation has not been reported. We report a case of CLCRP2 that phenocopies perinatally lethal type OI and that resulted in early neonatal demise from respiratory compromise.