Intellectual disabilityGene: GPHN Red List (low evidence)
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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
Molybdenum cofactor deficiency C, 615501; Intellectual disability
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.
Red List (low evidence)
Red List (low evidence)
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.
Model of inheritance for gene GPHN was set to BIALLELIC, autosomal or pseudoautosomal
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
GPHN was added to Intellectual disabilitypanel. Source: Expert Review Red
GPHN was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.