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Intellectual disability

Gene: GPHN

Red List (low evidence)

GPHN (gephyrin)
EnsemblGeneIds (GRCh38): ENSG00000171723
EnsemblGeneIds (GRCh37): ENSG00000171723
OMIM: 603930, Gene2Phenotype
GPHN is in 7 panels

4 reviews

Konstantinos Varvagiannis (Other)

I don't know

PMID 22040219 describes an patient with molybdenum cofactor deficiency (aut. recessive), born to consanguineous parents and homozygous for the Asp580Ala variant. Functional studies were performed in a subsequent publication (PMID 26613940) and demonstrated impaired molybdenium cofactor in vitro synthesis. This variant is not present in gnomAD.

PMID 26613940 reports on an individual with infantile onset epileptic encephalopathy and a de novo missense variant in GPHN. On last examination at the age of 18 years, this individual had severe intellectual disability with an IQ of 33. Functional studies of this variant suggested a dominant negative effect on the clustering of wt gephyrin leading to impaired GABAergic signaling. In addition, impaired in-vitro synthesis of the molybdenium cofactor was demonstrated.

There seems to be no other report of GPHN SNVs in the literature.

PMID 24561070 describes two families with intragenic deletions of GPHN. Probands from both families were evaluated by aCGH in the context of idiopathic generalized epilepsy (IGE). The index case from the first family, was shown to have a paternaly inherited multi-exon GPHN deletion. Apart from the IGE, this individual had presented mild deficits in motor coordination and learning difficulties, though with normal cognitive abilities at the age of 19 years. Trio exome sequencing in this family did not demonstrate any potentially causative SNVs. In the second family a further intragenic GPHN multi-exon microdeletion was demonstrated. The proband in this family had delayed cognitive development with persistent learning disability. The deletion was inherited from his father, unaffected for both phenotypes. Maternal family history was positive for seizures but not for impaired psychomotor development.

PMID 23393157 reports on individuals with heterozygous intragenic DPHN deletions and variable phenotypes (ASD, seizures or SCZ). Some of these subjects had developmental delay and one was diagnosed with ID. In three cases the deletion occurred as de novo event.
Created: 13 Aug 2018, 7:45 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Molybdenum cofactor deficiency C, 615501; Intellectual disability

Publications

Sarah Leigh (Genomics England Curator)

Associated with phenotype in OMIM. At least 2 variants reported in 2 consanguineous families. One variant (exon 2-3 deletion) was found in 3 affected infants who all 3 died (at day 12, 29, and 3, respectively). The second variant was reported in a neonate diagnosed with poor feeding, hypotonia, and intractable seizures. At age 2 years, she had spasticity and lack of psychomotor development. (PMID 22040219).

GPHN was reported as a gene linked to isolated ID and ID associated disorders (Vissers 2016 PMID 26503795) and as an ID candidate gene (Gilessen 2014 PMID 24896178).
Created: 5 Mar 2018, 4:25 p.m.

Caroline Wright (Sanger)

Red List (low evidence)

Lu Raymond (university of cambridge )

Red List (low evidence)

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Molybdenum cofactor deficiency C
Tags
treatable deletions Autism Spectrum Disorder
OMIM
603930
Clinvar variants
Variants in GPHN
Penetrance
Complete
Panels with this gene

History Filter Activity

12 Mar 2018, Gel status: 1

Panel promoted to version 2.0

Ellen McDonagh (Genomics England Curator)

12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.

12 Mar 2018, Gel status: 1

Set mode of inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene GPHN was set to BIALLELIC, autosomal or pseudoautosomal

13 Nov 2015, Gel status: 1

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 2

gel status update

GEL ()

The Gel status was updated for this whole panel

13 Nov 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

GPHN was added to Intellectual disabilitypanel. Source: Expert Review Red

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

GPHN was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen