Human Gene Module / Chromosome X / FRMPD4

FRMPD4FERM and PDZ domain containing 4

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
14 / 0
Aliases
FRMPD4, MRX104,  PDZD10,  PDZK10
Associated Syndromes
-
Chromosome Band
Xp22.2
Associated Disorders
SCZ, ID, EP, EPS, ASD
Relevance to Autism

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011). X-exome sequencing of 405 unresolved families with X-linked intellectual disability (XLID) in Hu et al., 2016 identified a maternally-transmitted frameshift variant in the FRMPD4 gene that segregated with XLID in a family in which affected males presented with variable seizures, poor or absent speech, and behavioral problems; a de novo missense variant in FRMPD4 was also identified in an unrelated male proband presenting with ASD, developmental delay, and absent speech in this study. Piard et al., 2017 presented two novel families with four affected males carrying FRMPD4 mutations; three of these affected males presented with ASD in addition to intellectual disability, gross motor delay, and speech delay. Frmpd4-knockout mice were also shown to display hippocampal-dependent spatial learning and memory deficits in Piard et al., 2017.

Molecular Function

This gene encodes a multi-domain (WW, PDZ, FERM) containing protein. Through its interaction with other proteins (such as PSD-95), it functions as a positive regulator of dendritic spine morphogenesis and density, and is required for the maintenance of excitatory synaptic transmission.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to FRMPD4 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Recent Recommendation Preso, a novel PSD-95-interacting FERM and PDZ domain protein that regulates dendritic spine morphogenesis Lee HW , et al. (2009) No -
2 Primary Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia Piton A , et al. (2010) Yes SCZ
3 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No Epilepsy, ASD
4 Support X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes Hu H et al. (2016) No ASD
5 Recent Recommendation FRMPD4 mutations cause X-linked intellectual disability and disrupt dendritic spine morphogenesis Piard J , et al. (2017) No ASD, epilepsy/seizures
6 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
7 Support - Levchenko O et al. (2022) No Autistic features
8 Support - Zhou X et al. (2022) Yes -
9 Support - Omri Bar et al. (2024) Yes ID, epilepsy/seizures
10 Support - Axel Schmidt et al. (2024) Yes DD
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1657T>C p.Cys553Arg missense_variant De novo - - 25644381 Hu H et al. (2016)
- - copy_number_loss Familial Maternal Multiplex 29267967 Piard J , et al. (2017)
c.213C>G p.Ile71Met missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.608C>T p.Ala203Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1405A>G p.Arg469Gly missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1535A>G p.Tyr512Cys missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.2425G>A p.Ala809Thr missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1411G>T p.Glu471Ter stop_gained De novo - Simplex 35887114 Levchenko O et al. (2022)
c.3440G>A p.Gly1147Glu missense_variant Familial Maternal - 20479760 Piton A , et al. (2010)
c.3271C>G p.Gln1091Glu missense_variant Familial Maternal - 31031587 Xiong J , et al. (2019)
c.856C>T p.Leu286= stop_gained Familial Maternal Multiplex 29267967 Piard J , et al. (2017)
c.2854G>A p.Glu952Lys missense_variant Familial Maternal Simplex 23020937 Rauch A , et al. (2012)
c.1924G>A p.Ala642Thr missense_variant Familial Maternal Simplex 38256266 Omri Bar et al. (2024)
c.1851del p.Cys618ValfsTer8 frameshift_variant Familial Maternal Extended multiplex 25644381 Hu H et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011). X-exome sequencing of 405 unresolved families with X-linked intellectual disability (XLID) in Hu et al., 2016 identified a maternally-transmitted frameshift variant in the FRMPD4 gene that segregated with XLID in a family in which affected males presented with variable seizures, poor or absent speech, and behavioral problems; a de novo missense variant in FRMPD4 was also identified in an unrelated male proband presenting with ASD, developmental delay, and absent speech in this study. Piard et al., 2017 presented two novel families with four affected males carrying FRMPD4 mutations; three of these affected males presented with ASD in addition to intellectual disability, gross motor delay, and speech delay. Frmpd4-knockout mice were also shown to display hippocampal-dependent spatial learning and memory deficits in Piard et al., 2017.

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011). X-exome sequencing of 405 unresolved families with X-linked intellectual disability (XLID) in Hu et al., 2016 identified a maternally-transmitted frameshift variant in the FRMPD4 gene that segregated with XLID in a family in which affected males presented with variable seizures, poor or absent speech, and behavioral problems; a de novo missense variant in FRMPD4 was also identified in an unrelated male proband presenting with ASD, developmental delay, and absent speech in this study. Piard et al., 2017 presented two novel families with four affected males carrying FRMPD4 mutations; three of these affected males presented with ASD in addition to intellectual disability, gross motor delay, and speech delay. Frmpd4-knockout mice were also shown to display hippocampal-dependent spatial learning and memory deficits in Piard et al., 2017.

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

Score remained at S

Description

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011). X-exome sequencing of 405 unresolved families with X-linked intellectual disability (XLID) in Hu et al., 2016 identified a maternally-transmitted frameshift variant in the FRMPD4 gene that segregated with XLID in a family in which affected males presented with variable seizures, poor or absent speech, and behavioral problems; a de novo missense variant in FRMPD4 was also identified in an unrelated male proband presenting with ASD, developmental delay, and absent speech in this study. Piard et al., 2017 presented two novel families with four affected males carrying FRMPD4 mutations; three of these affected males presented with ASD in addition to intellectual disability, gross motor delay, and speech delay. Frmpd4-knockout mice were also shown to display hippocampal-dependent spatial learning and memory deficits in Piard et al., 2017.

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
7/1/2018
5
icon
S

Decreased from 5 to S

Description

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011). X-exome sequencing of 405 unresolved families with X-linked intellectual disability (XLID) in Hu et al., 2016 identified a maternally-transmitted frameshift variant in the FRMPD4 gene that segregated with XLID in a family in which affected males presented with variable seizures, poor or absent speech, and behavioral problems; a de novo missense variant in FRMPD4 was also identified in an unrelated male proband presenting with ASD, developmental delay, and absent speech in this study. Piard et al., 2017 presented two novel families with four affected males carrying FRMPD4 mutations; three of these affected males presented with ASD in addition to intellectual disability, gross motor delay, and speech delay. Frmpd4-knockout mice were also shown to display hippocampal-dependent spatial learning and memory deficits in Piard et al., 2017.

7/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the FRMPD4 gene have been identified with autism and schizophrenia (Piton et al., 2011).

Krishnan Probability Score

Score 0.50023424258246

Ranking 2091/25841 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 0.99719082898636

Ranking 1342/18225 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 0.94841684676952

Ranking 17675/18665 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
Larsen Cumulative Evidence Score

Score 0

Ranking 447/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
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