Gene Validity Curation

ANKRD11 - KBG syndrome

Gene: ANKRD11 (HGNC:21316)
Classification - 11/26/2019
Disease: KBG syndrome (MONDO_0007846)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism
Evidence Summary: ANKRD11 was reported in relation to autosomal dominant KBG syndrome as early as 2011 (Sirmaci et al., PMID: 21782149). KBG syndrome is characterized by phenotypes including neurological involvement, characteristic facial dysmorphisms, macrodontia, short stature, and hand anomalies. Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 100 affected individuals have been described in the literature; however, only 9 probands (across 8 publications: 21782149, 25543316, 30088855, 27900361, 27605097, 25424714, 25464108, 28449295) are documented here, as these probands are enough to maximize the genetic evidence score in this rubric. Eight of these probands presented with mild to moderate intellectual disability, two had formal diagnoses of autism spectrum disorder, and 1 additional proband displayed autistic behavior. Six probands had developmental delay ranging from mild to severe; however, it is possible that not all patients were evaluated for this phenotype. While the majority of cases of KBG syndrome occur de novo, variants in ANKRD11 segregated with disease in 8 additional individuals in 3 of these families (PMID: 21782149, 25424714, 25464108). The proposed mechanism of disease is dominant-negative (Walz et al. 2015, PMID: 25413698). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, ANKRD11 is definitely associated with autosomal dominant KBG syndrome.
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 5
9
9
Sirmaci A et al. 2011 Aug 12 (PMID:21782149); De Bernardi ML et al. 2018 Sep (PMID:30088855); Kleyner R et al. 2016 Nov (PMID:27900361); Goldenberg A et al. 2016 Nov (PMID:27605097); Murray N et al. 2017 Jul (PMID:28449295);
Proband with predicted or proven null variant 1.5 0-2 10 4 5.5 5.5
Sirmaci A et al. 2011 Aug 12 (PMID:21782149); Samanta D et al. 2015 Dec (PMID:25543316); Ockeloen CW et al. 2015 Sep (PMID:25424714); Kim HJ et al. 2015 Feb (PMID:25464108);
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   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 12
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 2 0.5
Sirmaci A et al. 2011 Aug 12 (PMID:21782149); Gallagher D et al. 2015 Jan 12 (PMID:25556659);
Functional Alteration Patient cells 1 0 - 2 2
1
Non-patient cells 0.5 0 - 1 2 1
Gallagher D et al. 2015 Jan 12 (PMID:25556659);
Models Non-human model organism 2 0 - 4 4 1 3 3
Barbaric I et al. 2008 Feb 19 (PMID:17986521);
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) 4.5

 


 

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 12 4.5 16.5 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
11/26/2019
EXPERT CURATION (DATE)
Definitive
11/26/2019
EVIDENCE SUMMARY
ANKRD11 was reported in relation to autosomal dominant KBG syndrome as early as 2011 (Sirmaci et al., PMID: 21782149). KBG syndrome is characterized by phenotypes including neurological involvement, characteristic facial dysmorphisms, macrodontia, short stature, and hand anomalies. Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 100 affected individuals have been described in the literature; however, only 9 probands (across 8 publications: 21782149, 25543316, 30088855, 27900361, 27605097, 25424714, 25464108, 28449295) are documented here, as these probands are enough to maximize the genetic evidence score in this rubric. Eight of these probands presented with mild to moderate intellectual disability, two had formal diagnoses of autism spectrum disorder, and 1 additional proband displayed autistic behavior. Six probands had developmental delay ranging from mild to severe; however, it is possible that not all patients were evaluated for this phenotype. While the majority of cases of KBG syndrome occur de novo, variants in ANKRD11 segregated with disease in 8 additional individuals in 3 of these families (PMID: 21782149, 25424714, 25464108). The proposed mechanism of disease is dominant-negative (Walz et al. 2015, PMID: 25413698). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, ANKRD11 is definitely associated with autosomal dominant KBG syndrome.