Gene Validity Curation

HOXA1 - complex neurodevelopmental disorder

Gene: HOXA1 (HGNC:5099)
Classification - 06/19/2019
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism EP
Evidence Summary: Variants in HOXA1 were first reported in humans with autosomal recessive complex neurodevelopmental disorder as early as 2003 (Holve et al., 12833395). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 variants (e.g. nonsense and frameshift) have been reported in humans. Variants in this gene have been reported in at least 16 probands in 3 publications (12833395, 16155570, 18412118). Variants in this gene segregated with disease in 8 additional family members. All affected individuals identified thus far are Saudi Arabian, Turkish, or Native American, and the authors asserted that the variants associated were likely founder variants. The mechanism for disease is homozygous loss of function. Of note, this gene has also been implicated in brain malformation. This will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, HOXA1 is definitively associated with autosomal recessive complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (SOP Version 6).
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
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 4
8
8
Tischfield MA et al. 2005 Oct (PMID:16155570); Holve S et al. 2003 Jul 15 (PMID:12833395); Bosley TM et al. 2008 May 15 (PMID:18412118);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 7.7 1
Tischfield MA et al. 2005 Oct (PMID:16155570);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 7.7    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points 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) 9.5
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2
0.5
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Murphy P et al. 1991 Jan (PMID:1673098);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 2
Lufkin T et al. 1991 Sep 20 (PMID:1680563);
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
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
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
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 9.5 2.5 12 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
09/26/2019
EXPERT CURATION (DATE)
Definitive
06/19/2019
EVIDENCE SUMMARY
Variants in HOXA1 were first reported in humans with autosomal recessive complex neurodevelopmental disorder as early as 2003 (Holve et al., 12833395). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 4 variants (e.g. nonsense and frameshift) have been reported in humans. Variants in this gene have been reported in at least 16 probands in 3 publications (12833395, 16155570, 18412118). Variants in this gene segregated with disease in 8 additional family members. All affected individuals identified thus far are Saudi Arabian, Turkish, or Native American, and the authors asserted that the variants associated were likely founder variants. The mechanism for disease is homozygous loss of function. Of note, this gene has also been implicated in brain malformation. This will be assessed separately. This gene-disease association is supported by expression studies and animal models. In summary, HOXA1 is definitively associated with autosomal recessive complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (SOP Version 6).