ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 14q23.3-q24.1
  • GRCh37/hg19 chr14: 66,974,125-67,648,525
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr14: 66,507,934-67,181,805
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000014.8) (NC_000014.9)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
23393157 Lionel et al. 2013: Rare de novo or inherited hemizygous microdeletions overlapping exons of GPHN at chromosome 14q23.3 were detected in 6 unrelated patients with a range of neurodevelopmental diagnoses including ASD, schizophrenia or seizures. From the description of this article in OMIM entry 603930: "The deletions ranged in size from 183 to 357 kb; 1 breakpoint was shared by 3 patients. No exonic deletions at the GPHN locus were reported in the Database of Genomic Variants (DGV), and CNVs at this locus were only found in 3 of 27,019 controls. The frequency of deletions was significantly greater in patients (6 of 8,775) compared to controls (3 of 27,019, p = 0.009). Three of the deletions were proven to occur de novo in patients with ASD, ASD with seizures, and schizophrenia, respectively. Parental information was not available from the fourth patient, who had seizures. A deletion found in a fifth patient, who had ASD, was inherited from a father with subclinical social skills; there was significant psychiatric history on both sides of the family. The sixth patient, who had schizophrenia, inherited the deletion from an unaffected mother whose mother reportedly had schizophrenia. The common region of overlap encompassed exons 3 to 5 of the GPHN gene, corresponding to the coding segment of the G domain, which is vital to the formation of gephyrin scaffolds." Of note, the authors mention the association between homozygous null mutations in GPHN and molybdenum cofactor (MoCo) deficiency, an extremely rare severe autosomal recessive metabolic condition. At the time of publication, the authors report that two families have been reported with MoCo deficiency as the result of homozygous GPHN mutations, and that they had tried to contact both for information regarding neuropsychiatric phenotypes of unaffected heterozygous carriers, but were unable to receive additional information. Since the time this paper was originally submitted for publication (fall 2012), several exonic deletions at the GPHN locus have been reported in the DGV. However, the majority of these deletions were reported within the context of a single study (Xu et al. 2011). Per personal communication with the Lionel et al. authors (and DGV curators) in February 2014, the Xu et al. study is being reviewed and reprocessed by DGV staff; it is thought that some of the calls reported within this study could actually represent false positives, due to issues such as use of a single algorithm and low size filters for CNV calling and lack of experimental validation.
24561070 Dejanovic et al. 2014: 1469 unrelated patients of North-Western European ancestry with idiopathic generalized epilepsy (IGE) and 2256 German population controls underwent what the authors describe as "CNV screening of the genomic GPHN sequence" ("genome-wide CNV screening beyond this locus was restricted to CNVs with a segment size >500 kb and a minimum of 50 markers"). They identified "two hemizygous exonic GPHN microdeletions in the IGE cohort: [one] 129 kb microdeletion... affecting GPHN exons 5? a German male patient with juvenile myoclonic epilepsy [Family 1]... and [one] 158 kb microdeletion...encompassing GPHN exons 2? a German male patient with myoclonic astatic epilepsy (Doose syndrome)[Family 2]... Genome-wide screening for large CNVs revealed no additional known pathogenic CNVs previously associated with epilepsy in both index patients...None of the 2256 German controls carried a microdeletion at the GPHN locus." The microdeletions in both cases were paternally inherited. In Family 1, the proband was described as having "mild deficits in motor coordination,hyperactivity, and learning difficulties during childhood. Neuropsychological testing at the age of 19 years showed normal cognitive abilities with average performance scores. Recurrent episodes of major depression with suicide attempts started at the age of 16 years, accompanied by generalized anxiety, panic attacks and phobic vertigo. Non-epileptic psychogenic attacks became evident since the age of 32 years. The patient's father experienced three unprovoked events of loss of consciousness between 4 and 6 years of age." Both the patient and his father "exhibited an impaired cortical inhibition leading to neuronal hyperexcitability" by transcranial magnetic stimulation. The proband in Family 2 is described as having "normal physical but delayed cognitive development with persistent learning disability." His father (who carries the same microdeletion) is described as having "no history of seizures and a normal psychomotor development" while his mother (who does not carry the microdeletion) was said to have had "three seizures during infancy with spontaneous remission and normal psychomotor development." A full brother (who does not have the microdeletion) also experienced 2 febrile seizures during childhood. The authors conclude that "molecular characterization of the GPHN ?5?9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of ?2-subunit containing GABAARs. GPHN ?2?3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haploinsufficiency of the gene."
24643514 Egger et al. 2014: 245 family members from 73 Austrian autism spectrum disorder (ASD) families were genotyped with Affymetrix SNP 6.0 microarrays, and a list of "stringent calls was compared to existing CNV data from over 2,357 controls of European ancestry." A de novo 357-kb loss of 10 exons of GPHN was identified. Per the authors, this CNV was validated by qPCR and was not present in their control population, but did have a 56% overlap with an area represented in DGV.

Haploinsufficiency phenotype comments:

The evidence presented here relates to the potential association between GPHN haploinsufficiency and neuropsychiatric phenotypes, such as autism spectrum disorders, seizures, and schizophrenia. Because of some of the family data represented above, questions about reduced penetrance and variable expressivity, and questions regarding mechanism, it is the decision of the committee to give this gene a haploinsufficiency score of 2 at this time. Of note, homozygous mutations of GPHN have also been observed in molybdenum cofactor (MoCo) deficiency, a rare autosomal recessive metabolic disorder. A single missense mutation has also been reported in an individual with hyperekplexia (PMID: 12684523). From the OMIM description of this article (12684523): "This variant is classified as a variant of unknown significance because its contribution to hyperekplexia has not been confirmed. In 1 of 38 unrelated patients with hyperekplexia (see 149400), Rees et al. (2003) detected a heterozygous 28A-T transversion in exon 1 of the GPHN gene, resulting in an asn10-to-tyr (N10Y) substitution at the extreme N terminus. The N10Y variant was not found in 94 controls. The GPHN gene was chosen for sequencing after it was shown to interact with the GLRB (138492) subunit. The N10Y substitution is located 5 residues upstream from a putative region important for protein interactions; however, in vitro functional expression studies in HEK293 cells suggested that the variant did not affect the structural lattices formed by gephyrin or interrupt its interactions with GLRB. The variant protein did not interrupt cell surface clustering. Thus, the functional effect of the variant remained elusive."

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity