Human Gene Module / Chromosome X / FLNA

FLNAfilamin A

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
10 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq28
Associated Disorders
-
Relevance to Autism

Several de novo variants in the FLNA gene, including a de novo segmental duplication and two de novo missense variants, have been identified in ASD probands (Sakai et al., 2011; Takata et al., 2018; Satterstrom et al., 2020; Miyake et al., 2023), while a rare inherited missense variant in this gene was identified in a Chinese ASD proband from the ACGC cohort (Li et al, 2017). FLNA has been experimentally shown to interact with SHANK3 and NLGN3 (Sakai et al., 2011; Shen et al., 2015). Sequencing of 519 NDD-related genes in 3195 Chinese probands with neurodevelopmental phenotypes identified two individuals with hemizygous missense variants in the FLNA gene that were predicted to be deleterious (Wang et al., 2021).

Molecular Function

The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FLNA (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Sakai Y , et al. (2011) Yes -
2 Support - Shen C , et al. (2014) Yes -
3 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
4 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
5 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
6 Support - Wang T et al. (2021) No -
7 Primary - Miyake N et al. (2023) Yes -
8 Support - Tuncay IO et al. (2023) Yes -
9 Support - Sheth F et al. (2023) Yes ADHD, DD, ID
10 Support - Omri Bar et al. (2024) Yes ID, epilepsy/seizures
11 Support - Tamam Khalaf et al. (2024) No -
12 Support - Antonio Falace et al. (2024) No Epilepsy/seizures
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - Simplex 21653829 Sakai Y , et al. (2011)
c.5002G>T p.Glu1668Ter stop_gained Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.4526T>G p.Val1509Gly missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.4762G>A p.Glu1588Lys missense_variant Familial Maternal - 33994118 Wang T et al. (2021)
c.7766C>G p.Pro2589Arg missense_variant Familial Maternal - 33994118 Wang T et al. (2021)
c.4121A>G p.Asn1374Ser missense_variant Unknown - Multiplex 37543562 Sheth F et al. (2023)
c.6772G>A p.Glu2258Lys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.7553G>A p.Gly2518Asp missense_variant Familial Maternal - 37492102 Tuncay IO et al. (2023)
c.1150G>A p.Val384Met missense_variant Familial Maternal Simplex 28831199 Li J , et al. (2017)
c.1409A>G p.Tyr470Cys missense_variant Familial Maternal Simplex 38256266 Omri Bar et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
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.

7/1/2023
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.57000995944228

Ranking 984/25841 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.
Original Source
ExAC Score

Score 0.99999998760764

Ranking 139/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.95060029120849

Ranking 18556/18665 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).
Original Source
Zhang D Score

Score -0.21341622567718

Ranking 15709/20870 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.
Original Source
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