Human Gene Module / Chromosome 17 / DNAH17

DNAH17dynein axonemal heavy chain 17

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
6 / 0
Aliases
DNAH17, DNAHL1,  DNEL2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
17q25.3
Associated Disorders
-
Relevance to Autism

A de novo nonsense variant in the DNAH17 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 40/84,448 expected; hypergeometric P-value of 0.030). Additional missense variants in DNAH17 that are predicted to be damaging have been identifed in ASD probands from the Simons Simplex Collection (O'Roak et al., 2012; Iossifov et al., 2014), although these variants are also present in external databases such as dbSNP.

Molecular Function

Dyneins are microtubule-associated motor protein complexes composed of several heavy, light, and intermediate chains. DNAH17 is a heavy chain associated with axonemal dynein.

Reports related to DNAH17 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
2 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Recent Recommendation Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
5 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.7979C>T p.Ser2660Phe missense_variant De novo NA - 28714951 Lim ET , et al. (2017)
c.3799A>T p.Lys1267Ter stop_gained De novo NA - 25363760 De Rubeis S , et al. (2014)
c.3114+1G>T - splice_site_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.13202C>T p.Pro4401Leu missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.13294C>T p.Arg4432Cys missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.11163del p.Leu3722SerfsTer20 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

A de novo nonsense variant in the DNAH17 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 40/84,448 expected; hypergeometric P-value of 0.030). Additional missense variants in DNAH17 that are predicted to be damaging have been identifed in ASD probands from the Simons Simplex Collection (O'Roak et al., 2012; Iossifov et al., 2014), although these variants are also present in external databases such as dbSNP.

Score Delta: Decreased from 4 to 3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo nonsense variant in the DNAH17 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 40/84,448 expected; hypergeometric P-value of 0.030). Additional missense variants in DNAH17 that are predicted to be damaging have been identifed in ASD probands from the Simons Simplex Collection (O'Roak et al., 2012; Iossifov et al., 2014), although these variants are also present in external databases such as dbSNP.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A de novo nonsense variant in the DNAH17 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 40/84,448 expected; hypergeometric P-value of 0.030). Additional missense variants in DNAH17 that are predicted to be damaging have been identifed in ASD probands from the Simons Simplex Collection (O'Roak et al., 2012; Iossifov et al., 2014), although these variants are also present in external databases such as dbSNP.

7/1/2017
icon
4

Increased from to 4

Description

A de novo nonsense variant in the DNAH17 gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014; this variant was later determined to be a postzygotic mosaic mutation (PZM) in Lim et al., 2017. A second non-synonymous PZM in this gene was identified in an ASD proband in Lim et al., 2017; comparison with a background set of 84,448 privately inherited variants demonstrated that this gene harbored more PZMs than expected based on background rates (2/571 observed vs. 40/84,448 expected; hypergeometric P-value of 0.030). Additional missense variants in DNAH17 that are predicted to be damaging have been identifed in ASD probands from the Simons Simplex Collection (O'Roak et al., 2012; Iossifov et al., 2014), although these variants are also present in external databases such as dbSNP.

Krishnan Probability Score

Score 0.49679428677125

Ranking 2514/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Sanders TADA Score

Score 0.83344057160657

Ranking 2943/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score

Score 0.027700330718849

Ranking 7853/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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