Gene Validity Classification Summary

Gene/Disease Pair:

OFD1 : ciliopathy

HGNC:2567 | MONDO_0005308
Mode of Inheritance: X-linked inheritance (HP:0001417)
Expert Panel: Autism and Intellectual Disability 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
Thauvin-Robinet C et al. 2006 Jan (PMID:16397067); Coene KL et al. 2009 Oct (PMID:19800048);
Proband with predicted or proven null variant 1.5 0-2 10
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
Tang Z et al. 2013 Oct 10 (PMID:24089205);
Protein Interaction 0.5 0 - 2 1
Coene KL et al. 2009 Oct (PMID:19800048);
Expression 0.5 0 - 2 0.5
Coene KL et al. 2009 Oct (PMID:19800048);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1
Coene KL et al. 2009 Oct (PMID:19800048); Tang Z et al. 2013 Oct 10 (PMID:24089205);
Models Non-human model organism 2 0 - 4 4 2 3
Ferrante MI et al. 2006 Jan (PMID:16311594);
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 1
Tang Z et al. 2013 Oct 10 (PMID:24089205);
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)*
OFD1 (Oro-facial-difital syndrome 1) is a gene that codes for a suppressor of primary ciliogenesis in human cells. It localizes at centrioles and centriolar satellites and is involved in primary cilium biogenesis. Most reported OFD1 mutations are loss of function (indels with frameshift) and are inherited in an X-linked dominant manner. OFD1 has been associated with 4 different diseases: Retinitis pigmentosa 23, Joubert syndrome 10 (XL-JS), Orofaciodigital syndrome I (OFD1), and Simpson-Golabi-Behmel syndrome, type 2 (SGBS2). Intra-familial variability within these diseases has been reported and X inactivation studies have shown that skewed X inactivation could be partially involved in the pathogenesis of intrafamilial clinical variability. OFD1 interacts with the LCA5-encoded protein lebercilin. Mutations in LCA5 cause the Leber's congenital amaurosis (LCA), a rare inherited eye disease. The destabilization of lebercilin in conditions of OFD1 deficiency might be the basis of Retinitis pigmentosa 23 diagnoses in these patients. There is an inverse correlation between OFD1 mutant protein length and phenotypic severity, which could be explained by differences in binding to functionally interacting proteins and disruption of ciliary localization. All mutations before amino acid residue 631 are lethal for males and cause OFD1 syndrome in females. The SGBS2-associated p.E709fs mutation causes macroencephaly and early death in males but it leaves females unaffected. Male patients with the p.K948fs and p.E923fs mutations have JS and may live beyond the age of 30 years, whereas carrier females are not affected. Based on this data, the ID/Autism EP decided to lump together the OFD1, SGBS2, and XL-JS disease assertions under Ciliopathy, a MONDO Disease Ontology that is inclusive of all three assertions. This decision has been made as OFD1 mutations cause Ciliopathy with differing severity of phenotype (OFD1 > SGBS2 > XL-JS, OFD1 being the most severe); the phenotype depends on the OFD1 mutant protein length left. Regarding the correlation of OFD1 and XLID, in Del Giudice et al. 2014 (PMID: 24884629) the authors identified patients displaying neurological symptoms and/or cognitive/behavioral abnormalities, brain structural anomalies in 88.7%, cognitive impairment in 68%, and associated neurological disorders and signs in 53% of cases. The most frequently observed structural brain anomalies included agenesis of the corpus callosum, neuronal migration/organization disorders, intracerebral cysts, porencephaly, and cerebellar malformations. The results from Del Giudice et al. 2014 support recently published findings indicating that CNS involvement in this condition is found in more than 60% of cases. Additionally, the authors described specific neuropsychological aspects such as reduced ability processing verbal information, slow thought process, difficulties in attention and concentration, and notably, long-term memory deficits which may indicate a specific role of OFD1 and/or primary cilia in higher brain functions. Thus the association of ODF1 and XLID is definitive.