The mRNA export factor GLE1 protein plays critical yet enigmatic functions in RNA processing and has been linked with multiple developmental disorders, including lethal congenital contracture syndrome 1 (LCCS1). Using in vivo genetic engineering to study disturbed GLE1 functions under physiological conditions, we demonstrate that total inactivation of GLE1 results in disorganization of the blastocyst inner cell mass and early embryonic lethality due to defects in lineage specification. In contrast, the knock-in mice genocopying the LCCS1-associated GLE1FinMajor variant (Gle1PFQ/PFQ) survive the prenatal period but die suddenly at midadulthood. Gle1PFQ/PFQ mice present an irregular count and distribution of spinal motor neurons as well as impaired development of neural crest-derived tissues, as demonstrated by defects in the sympathetic innervation of heart ventricles, irregularities in the paravertebral sympathetic ganglia volume, and decreased adrenal chromaffin cell counts. Unlike previously reported for yeast and HeLa cells, analysis of the molecular consequences of the GLE1FinMajor variant identified normal poly(A) + RNA distribution in Gle1PFQ/PFQ cells; however, cells were impaired in RNA and protein synthesis and simultaneously showed severely disturbed formation of G3BP stress granule assembly factor 1 (G3BP1)-positive stress granules. Intriguingly, stressed Gle1PFQ/PFQ cells show microRNA profiles indicative of impaired transcription, protein metabolism, nervous system development, and axon guidance, further corroborating our functional findings. Our results show the necessity of functional GLE1 for life and indicate that LCCS1 etiology is a result of the pathogenic GLE1FinMajor variant impinging differentiation of neural crest derivatives and leading to complex multiorgan defects.

Custodial suspects must be informed of their Miranda rights (Miranda v. Arizona, 1966) prior to police questioning. Since this landmark decision, scholars have rigorously studied Miranda comprehension and reasoning among vulnerable groups including those with intellectual disabilities (ID). However, the focus on ID has left arrestees with limited cognitive capacities (i.e., LCCs with IQs between 70 and 85) entirely overlooked. The current dataset addressed this oversight using a large (N = 820) sample of pretrial defendants who had completed the Standardized Assessment of Miranda Abilities (SAMA). Traditional (i.e., ID and no-ID) criterion groups were first analyzed with the standard error of measurement (SEM) removed. Second, a nuanced three-group framework included defendants with LCCs. Results indicate that LCC defendants are vulnerable to impaired Miranda comprehension (i.e., limited recall of the Miranda warning and deficits in Miranda-related vocabulary knowledge). Not surprisingly, their waiver decisions were often impaired by crucial misconceptions (e.g., seeing the investigating officers as beneficently on their side). The practical implications of these findings were underscored with respect to Constitutional safeguards for this critically important group, who have appeared to fall through the cracks in the criminal justice system.

Arthrogryposis multiplex congenita (AMC) is defined as congenital, non-progressive contractures in more than two joints and in multiple body areas, resulting from reduced fetal mobility. So far, more than 400 causative genes for AMC have been identified. Some isolated AMC phenotypes arise as a result of mutations in genes encoding components required for motor neuron structure, function, and myelination, as in the case of ADCY6 encoding the enzyme adenylyl cyclase type 6. ADCY6 inactivation, due to biallelic variants, have been previously associated with the lethal congenital contracture syndrome 8 (LCCS8). So far, only four LCCS8 patients, from two families, have been reported. Here, we describe a new patient affected by a severe form of AMC, harboring two novel compound heterozygous variants in ADCY6. Our findings expand the clinical and mutational spectrum of LCCS8, showing a possible correlation between the impact of the ADCY6 missense variants reported to date, predicted by molecular modeling, and the severity of the phenotype.

GLE1 (GLE1, RNA Export Mediator, OMIM#603371) variants are associated with severe autosomal recessive motor neuron diseases, that are lethal congenital contracture syndrome 1 (LCCS1, OMIM#253310) and congenital arthrogryposis with anterior horn cell disease (CAAHD, OMIM#611890). The clinical spectrum of GLE1-related disorders has been expanding these past years, including with adult-onset amyotrophic lateral sclerosis (ALS) GLE1-related forms, especially through the new molecular diagnosis strategies associated with the emergence of next-generation sequencing (NGS) technologies. However, despite this phenotypic variability, reported congenital or ALS adult-onset forms remain severe, leading to premature death. Through multidisciplinary interactions between our Neuropediatric and Medical Genetics departments, we were able to diagnose two siblings presenting with congenital disorder, using an NGS approach accordingly to the novel French national recommendations. Two siblings with very similar clinical features, meaning neuromuscular disorder of neonatal onset with progressive improvement, were examined in our Neuropediatrics department. The clinical presentation evoked initially congenital myopathy with autosomal recessive inheritance. However, additional symptoms such as mild dysmorphic features including high anterior hairline, downslanted palpebral fissures, anteverted nares, smooth philtrum with thin upper-lip, narrow mouth and microretrognathia or delayed expressive language and postnatal growth retardation were suggestive of a more complex clinical presentation and molecular diagnosis. Our NGS approach revealed an unexpected molecular diagnosis for these two siblings, meaning the presence of the homozygous c.1808G>T GLE1 variant. We here report the mildest phenotype ever described, in two siblings carrying the homozygous c.1808G>T GLE1 variant, further widening the clinical spectrum of GLE1-related diseases. Moreover, by reflecting current medical practice, this case report confirms the importance of establishing regular multidisciplinary meetings, essential for discussing such difficult clinical presentations to finally enable molecular diagnosis, especially when NGS technologies are used.