0000000000393309
AUTHOR
Mondher Chouchane
Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test
The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations a…
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.
The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, and of other patients with undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (MDA5) cause a spectrum of neuro-immunological features consistently associated with an enhanced interferon state. Cellular and biochemica…
Delineation of a new chromosome 20q11.2 duplication syndrome including the ASXL1 gene.
We report on three males with de novo overlapping 7.5, 9.8, and 10 Mb duplication of chromosome 20q11.2. Together with another patient previously published in the literature with overlapping 20q11 microduplication, we show that such patients display common clinical features including metopic ridging/trigonocephaly, developmental delay, epicanthal folds, and short hands. The duplication comprised the ASXL1 gene, in which de novo heterozygous nonsense or truncating mutations have recently been reported in patients with Borhing-Opitz syndrome. Because of craniofacial features in common with Borhing-Opitz syndrome, in particular metopic ridging/trigonocephaly, we suggest that duplication of ASX…
Les accidents vasculaires cérébraux du nouveau-né et de l’enfant
The clinical presentation, risk factors, causes, vital or functional prognosis, and acute management options for stroke occurring in neonates and children are specific, differing from those observed in young adults. Compared with the adult population, less is known about the epidemiology of stroke in the under-18 population where the disease could become more frequent because of advances in both neonatal resuscitation techniques for cerebral disorders and neuroimaging techniques enabling the diagnosis of small lesions. Clinical features are often delayed, especially in neonates, and unlike epilepsy or dystonia of the affected limb, which are frequent complications, aphasia is rather rare. T…
Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life
International audience; Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due …