GLE1-Related Disorders via the GLE1 Gene

Lethal congenital contracture syndrome 1 (LCCS1, OMIM 253310) and lethal arthrogryposis with anterior horn cell disease (LAAHD, OMIM 611890) are allelic disorders caused by variants in the GLE1 gene (OMIM 603371). These disorders are the most severe forms of spinal muscular atrophy. LCCS1 is characterized by complete fetal akinesia, multiple congenital contractures, low-set ears, micrognathia, pulmonary hypoplasia, muscular atrophy, abnormal positioning of hips and knees, and pterygia of the neck and elbows (Herva et al. Am J Med Genet 20:431-439, 1985; Herva et al. Am J Med Genet 29:67-76, 1988; Vuopala et al. Hum Path 26: 12-19, 1995). This phenotype closely resembles that of Pena-Shokeir type 1 (fetal akinesia deformation sequence, OMIM 208150). Findings that differentiate LCCS1 from Pena-Shokeir are fetal hydrops and generalized thinning of tubular bones. Fetal death often occurs before 32 weeks gestation. Post mortem examination of an affected spinal cord was shown to have a diminished number of anterior motor neurons (Vuopala and Herva. J Med Genet 31:521-527, 1994). LCCS1 and LAAHD are differentiated by the following criteria: LCCS1 is fatal during the fetal period and severe hydrops and intrauterine growth retardation are present. Infants with LAAHD may survive for a short period after birth, and when present, hydrops and intrauterine growth retardation are mild (Vuopala et al. Hum Path 26:12-19, 1995).

LCCS1 and LAAHD are autosomal recessive disorders.  The original cases were from northeastern Finland.  The birth incidence in Finland has been estimated to be 1:25,250 (Pakkasjarvi et al. Am J Med Genet 140A:1834-1839, 2006). Patients homozygous for the c.433-10A>G, or Fin (Major) variant, are more severely affected than compound heterozygous patients (Nousiainen et al. Nat Genet 40:155-157, 2008).  Three other variants, all amino acid substitutions within exon 16, have been reported (Nousiainen et al. 2008).  The GLE1 protein is involved with export of polyadenylated mRNA.

Outside of Finland, the prevalence of this disorder is unknown. Analytical sensitivity for the known GLE1 variants is high.

This test provides full coverage of all coding exons of the GLE1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).