Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FOXG1 : FOXG1 disorder

HGNC:3811 | MONDO_0100040
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Rett Angelman EP
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 5

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Ariani F et al. 2008 Jul (PMID:18571142); Kortüm F et al. 2011 Jun (PMID:21441262);
Proband with predicted or proven null variant 1.5 0-2 10 1.5 1.5
Kortüm F et al. 2011 Jun (PMID:21441262);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence Evidence of segregation in one or more families   Sequencing Method 0-3 3
Total LOD Score Canditate Gene Sequencing Exome/Genome or all genes sequenced in linkage region  
2-2.99 0.5 1
3-4.99 1 2
≥5 1.5 3
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Total Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Total Counted
Function Biochemical Function 0.5 0 - 2 2
Protein Interaction 0.5 0 - 2 1.5
Orlic-Milacic M et al. 2014 Apr 3 (PMID:24699272); Dastidar SG et al. 2012 Feb 22 (PMID:22357867);
Expression 0.5 0 - 2 0.5
Shen L et al. 2006 (PMID:16941454);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 4.5 4
Xuan S et al. 1995 Jun (PMID:7605629); Tian C et al. 2012 Feb 29 (PMID:22378868); Yang Y et al. 2017 Jan 1 (PMID:26620267); Shen L et al. 2006 (PMID:16941454);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 0.5
Fimiani C et al. 2016 Dec 20 (PMID:27995975);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
Haploinsufficiency of the FOXG1 gene causes FOXG1 disorder, a condition sometimes referred to as the congenital variant of Rett syndrome. FOXG1 disorder, however, is a clinically distinct entity characterized by onset of neurodevelopmental impairment congenitally or during early infancy, in contrast to typical Rett syndrome in which symptoms appear after a period of normal development. Patients with FOXG1 disorder can also have epilepsy, motor dysfunction, stereotypic hand movements, abnormal breathing, lack of speech development, and corpus callosum hypoplasia on MRI. Variants in FOXG1 were first reported in patients with this disorder by Ariani et al. (2008). Males and females are equally affected, and the mechanism of disease is loss of function. Both sequence and copy number loss variants have been reported in patients with FOXG1 disorder. All reported variants are presumed to have arisen de novo. Experimental evidence, including mouse models with neurological phenotypes consistent with FOXG1 disorder (Xuan et al 1995, Shen et al. 2006, Tian et al. 2012) as well as interaction with MECP2, the causative gene of classical Rett syndrome (Dastidar et al 2012, Orlic-Milacic et al 2014) support the role of FOXG1 in this disease. This disease association is not accounted for in this assessment. In summary, the association between FOXG1 and FOXG1 disorder has been classified as definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Approved by the ClinGen Rett/Angelman Expert Panel 4/30/2018.