Robin sequence (RS) has been reported in association with single gene disorders and chromosomal abnormalities; however, it has not previously been described in connection with chromosome 1q21 ...microduplication. We present the first known case of a neonate diagnosed with chromosome 1q21.1 microduplication syndrome and RS requiring surgical airway intervention. This case demonstrates the value of genetic testing in cases of RS presenting with other congenital anomalies.
Most chromosomal deletions and duplications (copy-number variants) that are associated with neurodevelopmental disorders are known to result in a wide variation of clinical phenotypes. This study ...describes a genetic mechanism for such variation.
Genomic rearrangements are an important source of genetic and phenotypic variation. Rare, recurrent copy-number variants of pathogenic significance, termed genomic disorders, were originally identified in persons with a characteristic set of clinically recognizable features, such as the Smith–Magenis syndrome, the Sotos syndrome, and the Williams–Beuren syndrome. Although unexplained phenotypic variation and differences in severity have long been recognized among patients with the same genomic disorder,
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comparatively recent discoveries of potentially pathogenic copy-number variants have broadened the phenotypic range associated with a given variant to include entirely distinct diseases. High-throughput analyses of patient populations have implicated the same copy-number variants . . .
OBJECTIVE:To identify causative genes for centronuclear myopathies (CNM), a heterogeneous group of rare inherited muscle disorders that often present in infancy or early life with weakness and ...hypotonia, using next-generation sequencing of whole exomes and genomes.
METHODS:Whole-exome or -genome sequencing was performed in a cohort of 29 unrelated patients with clinicopathologic diagnoses of CNM or related myopathy depleted for cases with mutations of MTM1, DNM2, and BIN1. Immunofluorescence analyses on muscle biopsies, splicing assays, and gel electrophoresis of patient muscle proteins were performed to determine the molecular consequences of mutations of interest.
RESULTS:Autosomal recessive compound heterozygous truncating mutations of the titin gene, TTN, were identified in 5 individuals. Biochemical analyses demonstrated increased titin degradation and truncated titin proteins in patient muscles, establishing the impact of the mutations.
CONCLUSIONS:Our study identifies truncating TTN mutations as a cause of congenital myopathy that is reported as CNM. Unlike the classic CNM genes that are all involved in excitation-contraction coupling at the triad, TTN encodes the giant sarcomeric protein titin, which forms a myofibrillar backbone for the components of the contractile machinery. This study expands the phenotypic spectrum associated with TTN mutations and indicates that TTN mutation analysis should be considered in cases of possible CNM without mutations in the classic CNM genes.
Ehlers–Danlos syndrome is a real diagnosis that is erroneously used to explain multiple fractures in suspected child abuse. This paper reviews the clinical and molecular diagnostic criteria for ...Ehlers–Danlos syndrome. This knowledge can help prevent misdiagnosis and support clinicians when evaluating infants and young children with multiple fractures.
Thousand and one amino‐acid kinase 1 (TAOK1) is a MAP3K protein kinase, regulating different mitogen‐activated protein kinase pathways, thereby modulating a multitude of processes in the cell. Given ...the recent finding of TAOK1 involvement in neurodevelopmental disorders (NDDs), we investigated the role of TAOK1 in neuronal function and collected a cohort of 23 individuals with mostly de novo variants in TAOK1 to further define the associated NDD. Here, we provide evidence for an important role for TAOK1 in neuronal function, showing that altered TAOK1 expression levels in the embryonic mouse brain affect neural migration in vivo, as well as neuronal maturation in vitro. The molecular spectrum of the identified TAOK1 variants comprises largely truncating and nonsense variants, but also missense variants, for which we provide evidence that they can have a loss of function or dominant‐negative effect on TAOK1, expanding the potential underlying causative mechanisms resulting in NDD. Taken together, our data indicate that TAOK1 activity needs to be properly controlled for normal neuronal function and that TAOK1 dysregulation leads to a neurodevelopmental disorder mainly comprising similar facial features, developmental delay/intellectual disability and/or variable learning or behavioral problems, muscular hypotonia, infant feeding difficulties, and growth problems.
In this study we expand the cohort of individuals with a neurodevelopmental disorder, carrying a de novo variant in TAOK1 (a), thereby further defining the neurodevelopmental disorder caused by TAOK1 malfunctioning. Using both in vivo (b) and in vitro (c) functional assays, we provide evidence that increased as well as decreased levels of TAOK1 cause disruption of neuronal development, showing that TAOK1 plays an important role in neuronal function. Additionally, our data suggests that both gain of function as well as loss of function mutations are potentially causative for the TAOK1‐related neurodevelopmental disorder.
Objective
Rett syndrome (RTT) and epileptic encephalopathy (EE) are devastating neurodevelopmental disorders with distinct diagnostic criteria. However, highly heterogeneous and overlapping clinical ...features often allocate patients into the boundary of the two conditions, complicating accurate diagnosis and appropriate medical interventions. Therefore, we investigated the specific molecular mechanism that allows an understanding of the pathogenesis and relationship of these two conditions.
Methods
We screened novel genetic factors from 34 RTT‐like patients without MECP2 mutations, which account for ∼90% of RTT cases, by whole‐exome sequencing. The biological function of the discovered variants was assessed in cell culture and Xenopus tropicalis models.
Results
We identified a recurring de novo variant in GABAB receptor R2 (GABBR2) that reduces the receptor function, whereas different GABBR2 variants in EE patients possess a more profound effect in reducing receptor activity and are more responsive to agonist rescue in an animal model.
Interpretation
GABBR2 is a genetic factor that determines RTT‐ or EE‐like phenotype expression depending on the variant positions. GABBR2‐mediated γ‐aminobutyric acid signaling is a crucial factor in determining the severity and nature of neurodevelopmental phenotypes. Ann Neurol 2017;82:466–478
Genetic disorders are in the differential diagnosis when young children present with unexplained fractures or intracranial hemorrhage. For medical and legal reasons, it is imperative to make the ...correct diagnosis and provide clear, evidence-based explanations of how alternative diagnoses were ruled out. A genetics consultation in cases of suspected child physical abuse should synthesize the history of present illness, medical history, family history, physical examination, and radiologic and laboratory findings in consultation with other specialists. The medical geneticist highlights how these disorders truly present. When the natural history of a genetic disorder is understood, it becomes clear that genetic disorders are not mysterious or difficult to diagnose. As highlighted in this case-based review, mainstream medical practice allows for differentiation among the intracranial and skeletal manifestations of osteogenesis imperfecta, Menkes disease, glutaric acidemia type 1 and child physical abuse. This review also highlights how a genetic disorder, Ehlers–Danlos syndrome, can be misused in a courtroom. Finally, this review summarizes when genetic testing is appropriate in cases of suspected child physical abuse.
Telemedicine is seen as a useful tool in reducing gaps in health care but this technology-enabled care can also exacerbate health inequity if not implemented with a focus on inclusivity. Though many ...studies have reported improvements as well as exacerbation of disparities in access to care in their telehealth programs, there does not exist a common evaluation tool to assess these programs. To mitigate the impact of COVID-19 on health care workers and protect medically vulnerable children, in March 2020 we expanded our pre-established specialty and subspecialty direct-to-patient pediatric telemedicine program in a high volume urban pediatric health system. Our program aimed to prevent disparities in pediatric health care. In this study, using a "Pillars of Access" approach as a model to evaluate impact and access to care of our direct-to-patient telemedicine program, we analyzed the patients that were seen pre-COVID versus post-COVID. Our study demonstrated an increase in telemedicine visits for patients from diverse socioeconomic and racial backgrounds, and geographically underserved communities. We also observed an increase in telemedicine visits for mental health complaints and for certain categories of high-risk patients. This study was not designed to identify language and cultural barriers to telemedicine. Future identification of these specific barriers is needed. The tool to evaluate telehealth impact/access to care through a "Pillars of Access" approach presented here could serve as a model for implementation of telehealth programs. Our study highlights telemedicine programs as a mechanism to address healthcare inequity and overcome barriers to care.
Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential ...treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006.
Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination.
Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease.
The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.
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