Galloway-Mowat Syndrome (GAMOS) via the TPRKB Gene

Galloway-Mowat syndrome (GAMOS) is an extremely rare autosomal recessive disorder characterized by neurological impairments, developmental abnormalities and early-onset nephrotic syndrome (Colin et al. 2014. PubMed ID: 25466283; Jinks et al. 2015. PubMed ID: 26070982). The primary features are infantile onset of cerebellar atrophy, microcephaly and proteinuria.

Other features include, but are not limited to, hiatal hernia, seizures, dystonia, generalized hypotonia, and visual impairment. These features are variable among patients, and have overlapping presentations with other disorders. Genetic testing is essential for differential diagnosis.

Galloway-Mowat syndrome represents a clinically and genetically heterogeneous group of autosomal recessive disorders. To date, ten genes have been associated with Galloway-Mowat syndrome: WDR73, NUP107, NUP133, WDR4, TPRKB, OSGEP, TP53RK, LAGE3, GON7, and YRDC (Colin et al. 2014. PubMed ID: 25466283; Jinks et al. 2015. PubMed ID: 26070982; Braun et al. 2017. PubMed ID: 28805828; Braun et al. 2018. PubMed ID: 30179222; Braun et al. 2018. PubMed ID: 30079490; Arrondel et al. 2019. PubMed ID: 31481669). TPRKB is one of the minor causative genes for the disease. 

Loss-of-function is the underlying mechanism of the TPRKB gene for Galloway-Mowat syndrome.  To date, only two pathogenic missense variants in the TPRKB gene have been documented. Large deletions and duplications have not been reported in this gene. De novo variants are presumably rare in this gene.  

TPRKB alongside other four genes OSGEP, TP53RK, LAGE3 and GON7 encode the subunits of the highly conserved KEOPS complex (Kinase, Endopeptidase and Other Proteins of small Size), which is essential for a universal chemical modification of tRNAs. TPRKB has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). The phenotype of microcephaly resulting in early lethality has been seen in CRISPR/Cas9 knockout in zebrafish and mice (Braun. 2017. PubMed ID: 28805828).

Compared with WDR73, OSGEP and NUP107, TPRKB is a minor causative gene for Galloway-Mowat syndrome. In a whole-exome sequencing study of patients with Galloway-Mowat syndrome, 2 of 91 (2.2%) families were found to have pathogenic variants in TPRKB (Braun et al. 2017. PubMed ID: 28805828).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the TPRKB 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).