Survival beyond the perinatal period expands the phenotypes caused by mutations in GLE1

Abstract

Mutations in GLE1 underlie Lethal Congenital Contracture syndrome and Lethal Arthrogryposis with Anterior Horn Cell Disease. Both Lethal Congenital Contracture syndrome and Lethal Arthrogryposis with Anterior Horn Cell Disease are characterized by reduced fetal movements, congenital contractures, and a severe form of motor neuron disease that results in fetal death or death in the perinatal period, respectively. We identified bi-allelic mutations in GLE1 in two unrelated individuals with motor delays, feeding difficulties and respiratory insufficiency who survived beyond the perinatal period. Each affected child had missense variants predicted to result in amino acid substitutions near the C-terminus of GLE1 that are predicted to disrupt protein-protein interaction or GLE1 protein targeting. We hypothesize that mutations that preserve function of the coiled-coil domain of GLE1 cause Lethal Arthrogryposis with Anterior Horn Cell Disease whereas mutations that abolish the function of the coiled-coil domain cause Lethal Congenital Contracture syndrome. The phenotype of Lethal Arthrogryposis with Anterior Horn Cell Disease is now expanded to include multiple individuals surviving into childhood suggesting that Lethal Arthrogryposis with Anterior Horn Cell Disease is a misnomer and should be re-named Arthrogryposis with Anterior Horn Cell Disease.

Extension of the phenotypic spectrum of GLE1‐related disorders to a mild congenital form resembling congenital myopathy

“…Indeed, GLE1 variants were initially associated with severe autosomal recessive motor neuron diseases either for lethal congenital forms (Mäkelä-Bengs et al, 1998;Nousiainen et al, 2008) or later-onset ALS forms (Aditi, Glass, Dawson, & Wente, 2016;Kaneb et al, 2015), leading in both cases to premature death. Even if the recently expanding GLE1 phenotype spectrum includes less severe clinical presentations, the case we report here, associated with a c.1808G>T [p.(Arg603Leu)] GLE1 homozygous genotype, constitutes the mildest phenotype reported to date, in comparison with previously reported congenital moderate phenotypes (Table 1) (Paakkola et al, 2018;Said et al, 2017;Smith et al, 2017;Tan et al, 2017).…”

“…The phenotype associated with this c.1808G>T homozygous GLE1 genotype, could even be considered as the mildest described to date, based on literature reports (Table 1) (Paakkola et al, 2018;Said et al, 2017;Smith et al, 2017).…”

“…Indeed, description of cases with survival beyond the perinatal period broaden the clinical spectrum and led to the nomenclature modification of LAAHD to congenital arthrogryposis with anterior horn cell disease (CAAHD, OMIM#611890) (Paakkola et al., 2018; Said et al., 2017; Smith et al, 2017; Tan et al., 2017). Therefore, it appears more accurate to define GLE1 ‐related disorders under a larger designation of arthrogryposis multiplex congenita (AMC) (Smith et al., 2017).…”

Population-level deficit of homozygosity unveils CPSF3 as an intellectual disability syndrome gene

“…Among these variants was c.1706G > A (p.Arg569His) (RefSeq NM_001003722.2) in GLE1 (MAF = 0.82%), with ten homozygous carriers expected in the population set, but none observed (Table 3 ). GLE1 p.Arg569His has been described as pathogenic when part of compound heterozygous genotypes with other variants in GLE1 , causing AR lethal congenital contracture syndrome 1 (LCCS1, MIM 253310) 8 , 23 , 24 . This severe condition, as well as the other GLE1 -related disease; congenital arthrogryposis with anterior horn cell disease (CAAHD, MIM 611890), leads to death in the perinatal period in the majority of identified cases 23 .…”