Molybdenum Cofactor Deficiency via the GPHN Gene

Molybdenum cofactor deficiency is an inborn error in metabolism caused by pathogenic variants in the enzymes responsible for molybdenum cofactor biosynthesis. As a result, several molybdenum cofactor-dependent enzymes (sulfite oxidase, xanthine dehydrogenase, and aldehyde oxidase) are nonfunctional. Patients with molybdenum cofactor deficiency excrete elevated levels of sulfite, thiosulfate, S-sulfocysteine, xanthine, and hypoxanthine while uric acid levels are low (Johnson and Duran, 2014). Clinical presentations in molybdenum cofactor deficiencies and isolated sulfite oxidase deficiency are almost indistinguishable. Considerable variability and age of onset for molybdenum cofactor deficiency exists. However, typically presentation will occur shortly after birth with severe convulsions that are difficult to suppress (Reiss et al., 2001. PubMed ID: 11095995; Reiss et al., 2011. PubMed ID: 22040219; Johnson and Duran, 2014). Patients with molybdenum cofactor deficiency also have dysmorphic features that include long face with puffy cheeks, widely spaced eyes, elongated palpebral fissures, thick lips, a long philtrum, and a small nose, which can resemble perinatal asphyxia. Patients also present with psychomotor retardation, ophthalmologic abnormalities such as lens dislocation, peripheral hypertonicity, and axial hypotonia (Johnson and Duran, 2014).

All molybdenum cofactor deficiencies are inherited in an autosomal recessive manner. Reported pathogenic variants in GPHN include a missense variant and a gross deletion of exons 2-3 (Reiss et al., 2001. PubMed ID: 11095995; Reiss et al., 2011. PubMed ID: 22040219). Copy number variants (CNVs) in GPHN in the heterozygous state have been associated with neurodevelopmental disorders such as autism, schizophrenia, and epilepsy (Lionel et al., 2013. PubMed ID: 23393157). However, these variants in the heterozygous state are not causative for molybdenum cofactor deficiency. MOCS1 and MOCS2 pathogenic variants are the more common cause of molybdenum cofactor deficiency (Reiss and Hahnewald, 2011. PubMed ID: 21031595).

The GPHN gene encodes the gephyrin protein which has surprising dual functions in cofactor synthesis as well as synaptic receptor clustering. The gephyrin protein contains two domains (E and G) that are necessary for the activation and insertion of molybdenum into molybdopterin (Reiss et al., 2001. PubMed ID: 11095995). The reported pathogenic variants for molybdenum cofactor deficiency have been observed in both domains. Gephyrin also belongs to a group of cytoskeletal elements that are critical for receptor-associated synaptic localization and organization (Reiss et al., 2001. PubMed ID: 11095995).

Clinical sensitivity cannot be estimated precisely because only a small number of patients have been reported. However, clinical sensitivity appears to be low.

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