Galloway-Mowat Syndrome (GAMOS) via the GON7 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 or X-linked 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). GON7 is one of the minor causative genes for the disease. Inheritance of GON7 pathogenic variants is autosomal recessive.

Loss-of-function is the underlying mechanism of the GON7 gene for Galloway-Mowat syndrome.  To date, only two pathogenic truncating variants in the GON7 gene have been reported (Arrondel et al. 2019. PubMed ID: 31481669). Large deletions and duplications have not been reported in this gene. De novo variants are presumably rare.   

GON7 alongside other four genes OSGEP, TPRKB, TP53RK and LAGE3 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.

Compared with WDR73, OSGEP and NUP107, GON7 is one of the minor causative genes for Galloway-Mowat syndrome. To date, only five unrelated families with Galloway-Mowat syndrome have been reported to be caused by two pathogenic variants in GON7, one of which was suggested to be a founder variant from Algeria (Arrondel et al. 2019. PubMed ID: 31481669).

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 GON7 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).