Galloway-Mowat Syndrome (GAMOS) via the WDR73 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). WDR73 is one of the major causative genes for the disease.

Loss-of-function is the underlying mechanism of the WDR73 gene for Galloway-Mowat syndrome.  To date, documented pathogenic variants in the WDR73 gene consist of missense, nonsense, and small frameshift deletion/duplication variants. Large deletions and duplications within WDR73 have not been reported in this gene. De novo variants are rare in this gene.

WDR73 encodes a WD40-repeat-containing protein, which plays a role in the regulation of the microtubule network that is crucial for the development of brain and kidney. WDR73 has been cited as a conditional gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Defects in WDR73, OSGEP and NUP107 account for ~70% of documented pathogenic variants for Galloway-Mowat syndrome in the Human Gene Mutation Database (HGMD). Biallelic WDR73 variants can explain 3 out of 51 (5.9%) patients with cerebellar atrophy (CA) and 2 out of 40 (5%) patients with Galloway-Mowat syndrome (Vodopiutz et al. 2015. PubMed ID: 26123727). In a screening of 800 children with idiopathic nephrotic syndrome, a homozygous frameshifting WDR73 variant was found in a Bulgarian child with nephrocerebellar syndrome (Jinks et al. 2015. PubMed ID: 26070982).

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 WDR73 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).