GPHN was first reported in relation to autosomal recessive molybdenum cofactor deficiency type C in 2001 (Reiss et al., PMID: 11095995). Molybdenum cofactor deficiency type C (MOCODC) is characterized by refractory neonatal seizures, dysmorphic features, ocular lens dislocation, and a characteristic urinary profile indicative of an underlying biochemical dysfunction (PMID: 33017596). The underlying mechanism is a failure to synthesize molybdenum cofactor, leading to loss of function of the enzymes sulfite oxidase, xanthine oxidase, and aldehyde oxidase (PMID: 33017596).
Lumping and Splitting:
GPHN encodes the gephyrin protein, which has two catalytically active domains that both participate in molybdenum cofactor biosynthesis. This protein also forms oligomeric clusters that act as scaffolds to promote the clustering of glycine and GABA type A receptors at the postsynaptic membrane of inhibitory neurons, a process that occurs independent of enzymatic activity. Heterozygous GPHN variants have been reported in individuals with complex neurodevelopmental disorders, but it is unclear at this time whether these variants are truly causative. Conversely, MOCODC is an autosomal recessive disease driven by loss of gephyrin enzyme activity. Therefore, this split curation only includes cases of confirmed molybdenum cofactor deficiency type C.
Variants in this gene have been reported in two probands in two publications (PMID: 11095995, 22040219). Co-segregation with disease has not been observed in the literature. The mechanism of disease is biallelic loss of function.
This gene-disease association is also supported by in vitro functional assays and an animal model (PMID: 9812897, 11095995, 33017596). Molybdenum cofactor synthesis was completely absent in fibroblasts from a MOCODC patient homozygous for a predicted null GPHN allele. Homozygous knock-out of the homologous gene in mice leads to the combined loss of sulfite oxidase and xanthine reductase. Further, these mice fail to thrive, have a significantly reduced lifespan, and exhibit spasticity reminiscent of the seizures observed in MOCODC patients.
In summary, there is moderate evidence to support the gene-disease relationship between GPHN and autosomal recessive molybdenum cofactor deficiency type C. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has yet emerged. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 5/12/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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