Human Gene Module / Chromosome 19 / KPTN

KPTNkaptin, actin binding protein

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 10
Rare Variants / Common Variants
49 / 0
Aliases
KPTN, 2E4,  MRT41
Associated Syndromes
-
Chromosome Band
19q13.32
Associated Disorders
ASD, EPS, ID
Relevance to Autism

Biallelic variants in the KPTN gene were found to cosegregate with the disease phenotype in nine family members from four nuclear families from the Amish community of Ohio presenting with an inherited variable form of neurodevelopmental delay (most consistent features were global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of pervasive developmental disorder, such as stereotypies and/or repetitive speech) in Baple et al., 2013. A homozygous frameshift variant in the KPTN gene was identified in two adult siblings from Estonia presenting with moderate intellectual disability and macrocephaly in Pajusalu et al., 2015; the male sibling also presented with behavioral problems, including autistic features. Rawlins et al., 2026 reported the genotype and clinical phenotype of 71 individuals with KPTN-related disorder, including 48 newly identified individuals, and observed that behavioral features were a common (85%; 55/65 individuals) but variable feature and included stereotypy (51%; 30/59 individuals) and repetitive speech (34%; 17/50 individuals); in the same study, the authors found that Kptn -/- mice displayed increased cortical mTOR signaling and heterotopic neurons in the subcortical white matter.

Molecular Function

This gene encodes a filamentous-actin-associated protein, which is involved in actin dynamics and plays an important role in neuromorphogenesis. This protein is part of the KICSTOR protein complex that localizes to lysosomes. Mutations in this gene result in an autosomal recessive form of intellectual disability.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KPTN (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in KPTN cause macrocephaly, neurodevelopmental delay, and seizures Baple EL , et al. (2013) No Epilepsy/seizures, autistic features
2 Support Novel homozygous mutation in KPTN gene causing a familial intellectual disability-macrocephaly syndrome Pajusalu S , et al. (2015) No Epilepsy/seizures, autistic features
3 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Chen R , et al. (2017) Yes -
4 Support Clinical genome sequencing in an unbiased pediatric cohort Thiffault I , et al. (2018) No ASD, ID, epilepsy/seizures, macrocephaly
5 Support Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing Thiffault I et al. (2020) No ASD
6 Support Pathogenic variants in KPTN, a rare cause of macrocephaly and intellectual disability Pacio Miguez M et al. (2020) No -
7 Support - Zhou X et al. (2022) Yes -
8 Support - Horn S et al. (2023) No Autistic features, stereotypy
9 Support - Levitin MO et al. (2023) No -
10 Recent Recommendation - Lettie E Rawlins et al. () No Stereotypy, repetitive speech, epilepsy/seizures
Rare Variants   (49)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1168G>A p.Val390Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.227-79G>A - splice_site_variant Unknown - - 30008475 Thiffault I , et al. (2018)
c.1_189del - copy_number_loss Familial - Simplex 41696790 Lettie E Rawlins et al. ()
c.279G>T p.Arg93= synonymous_variant De novo - Simplex 28344757 Chen R , et al. (2017)
c.863G>A p.Arg288Gln missense_variant Unknown - Simplex 41696790 Lettie E Rawlins et al. ()
c.985G>C p.Ala329Pro missense_variant Familial - Simplex 41696790 Lettie E Rawlins et al. ()
c.431+1G>A - splice_site_variant Familial Both parents Simplex 36703628 Horn S et al. (2023)
c.429_430insTA p.Ser144Ter frameshift_variant Unknown - Simplex 36703628 Horn S et al. (2023)
c.394+1G>A - splice_site_variant Familial Paternal Simplex 41696790 Lettie E Rawlins et al. ()
c.395-2A>C - splice_site_variant Familial Maternal Simplex 41696790 Lettie E Rawlins et al. ()
c.863G>A p.Arg288Gln missense_variant Familial - Multiplex 41696790 Lettie E Rawlins et al. ()
c.431+1G>A - splice_site_variant Familial Both parents Multiplex 36703628 Horn S et al. (2023)
c.776C>A p.Ser259Ter stop_gained Familial Maternal Multiplex 24239382 Baple EL , et al. (2013)
c.776C>A p.Ser259Ter stop_gained Familial Maternal Simplex 41696790 Lettie E Rawlins et al. ()
c.227-79G>A - splice_site_variant Familial Maternal Simplex 32358097 Thiffault I et al. (2020)
c.1129G>A p.Asp377Asn missense_variant Familial - Multiplex 41696790 Lettie E Rawlins et al. ()
c.863+5G>A - splice_site_variant Familial Paternal Multiplex 41696790 Lettie E Rawlins et al. ()
c.608C>A p.Ser203Ter stop_gained Familial Both parents Simplex 24239382 Baple EL , et al. (2013)
c.776C>A p.Ser259Ter stop_gained Familial Maternal Multiplex 41696790 Lettie E Rawlins et al. ()
c.776C>A p.Ser259Ter stop_gained Familial Both parents Multiplex 24239382 Baple EL , et al. (2013)
c.418C>T p.Gln140Ter stop_gained Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.609G>A p.Trp203Ter stop_gained Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.776C>A p.Ser259Ter stop_gained Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.927C>A p.Ser309Arg missense_variant Familial Maternal Simplex 41696790 Lettie E Rawlins et al. ()
c.980T>G p.Leu327Arg missense_variant Familial Paternal Simplex 41696790 Lettie E Rawlins et al. ()
c.864_1164del - copy_number_loss Familial Both parents Multiplex 41696790 Lettie E Rawlins et al. ()
c.665dupA p.Ser223GlufsTer50 frameshift_variant Familial - Simplex 41696790 Lettie E Rawlins et al. ()
c.714_731dup p.Met241_Gln246dup inframe_insertion Unknown - Simplex 41696790 Lettie E Rawlins et al. ()
c.863G>A p.Arg288Gln missense_variant Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.985G>C p.Ala329Pro missense_variant Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.597_598dup p.Ser200IlefsTer55 frameshift_variant Familial - Simplex 41696790 Lettie E Rawlins et al. ()
c.692del p.Val231GlyfsTer23 frameshift_variant Familial Paternal Simplex 41696790 Lettie E Rawlins et al. ()
c.58_66del p.Thr20_Phe22del inframe_deletion Familial Maternal Multiplex 41696790 Lettie E Rawlins et al. ()
c.776C>A p.Ser259Ter stop_gained Familial Both parents Extended multiplex 41696790 Lettie E Rawlins et al. ()
c.714_731dup p.Met241_Gln246dup inframe_insertion Familial Maternal Simplex 41696790 Lettie E Rawlins et al. ()
c.714_731dup p.Met241_Gln246dup inframe_insertion Familial Paternal Simplex 41696790 Lettie E Rawlins et al. ()
c.862dupC p.Arg288ProfsTer9 frameshift_variant Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.597_598dup p. Ser200IlefsTer55 frameshift_variant Familial Maternal Simplex 41696790 Lettie E Rawlins et al. ()
c.714_731dup p.Met241_Gln246dup inframe_insertion Familial Paternal Multiplex 41696790 Lettie E Rawlins et al. ()
c.497dup p.Ser167GlufsTer50 frameshift_variant Familial Both parents Multiplex 25847626 Pajusalu S , et al. (2015)
c.714_731dup p.Met241_Gln246dup inframe_insertion Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.597_598dup p.Ser200IlefsTer55 frameshift_variant Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.429_430insTA p.Ser144Ter frameshift_variant Familial Both parents Multiplex 32808430 Pacio Miguez M et al. (2020)
c.714_731dup p.Met241_Gln246dup inframe_insertion Familial Both parents Multiplex 41696790 Lettie E Rawlins et al. ()
c.1129_1168dup p.Val390GlyfsTer56 frameshift_variant Familial Both parents Simplex 41696790 Lettie E Rawlins et al. ()
c.546_547insTCTGCAGATGTGGTCGGT p.Val182_Leu183insSerAlaAspValValGly inframe_insertion Unknown - - 30008475 Thiffault I , et al. (2018)
c.546_547insTCTGCAGATGTGGTCGGT p.Val182_Leu183insSerAlaAspValValGly inframe_insertion Unknown - Simplex 36703628 Horn S et al. (2023)
c.546_547insTCTGCAGATGTGGTCGGT p.Val182_Leu183insSerAlaAspValValGly inframe_insertion Familial Paternal Multiplex 24239382 Baple EL , et al. (2013)
c.546_547insTCTGCAGATGTGGTCGGT p.Val182_Leu183insSerAlaAspValValGly inframe_insertion Familial Paternal Simplex 32358097 Thiffault I et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Biallelic variants in the KPTN gene were found to cosegregate with the disease phenotype in nine family members from four nuclear families from the Amish community of Ohio presenting with an inherited variable form of neurodevelopmental delay (most consistent features were global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of pervasive developmental disorder, such as stereotypies and/or repetitive speech) in Baple et al., 2013. A homozygous frameshift variant in the KPTN gene was identified in two adult siblings from Estonia presenting with moderate intellectual disability and macrocephaly in Pajusalu et al., 2015; the male sibling also presented with behavioral problems, including autistic features.

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."

10/1/2020
S
icon
S

Score remained at S

Description

Biallelic variants in the KPTN gene were found to cosegregate with the disease phenotype in nine family members from four nuclear families from the Amish community of Ohio presenting with an inherited variable form of neurodevelopmental delay (most consistent features were global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of pervasive developmental disorder, such as stereotypies and/or repetitive speech) in Baple et al., 2013. A homozygous frameshift variant in the KPTN gene was identified in two adult siblings from Estonia presenting with moderate intellectual disability and macrocephaly in Pajusalu et al., 2015; the male sibling also presented with behavioral problems, including autistic features.

Reports Added
[Pathogenic variants in KPTN, a rare cause of macrocephaly and intellectual disability2020]
4/1/2020
S
icon
S

Score remained at S

Description

Biallelic variants in the KPTN gene were found to cosegregate with the disease phenotype in nine family members from four nuclear families from the Amish community of Ohio presenting with an inherited variable form of neurodevelopmental delay (most consistent features were global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of pervasive developmental disorder, such as stereotypies and/or repetitive speech) in Baple et al., 2013. A homozygous frameshift variant in the KPTN gene was identified in two adult siblings from Estonia presenting with moderate intellectual disability and macrocephaly in Pajusalu et al., 2015; the male sibling also presented with behavioral problems, including autistic features.

Reports Added
[Pathogenic variants in KPTN gene identified by clinical whole-genome sequencing2020]
10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Biallelic variants in the KPTN gene were found to cosegregate with the disease phenotype in nine family members from four nuclear families from the Amish community of Ohio presenting with an inherited variable form of neurodevelopmental delay (most consistent features were global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of pervasive developmental disorder, such as stereotypies and/or repetitive speech) in Baple et al., 2013. A homozygous frameshift variant in the KPTN gene was identified in two adult siblings from Estonia presenting with moderate intellectual disability and macrocephaly in Pajusalu et al., 2015; the male sibling also presented with behavioral problems, including autistic features.

Reports Added
[New Scoring Scheme]
7/1/2018
S
icon
S

Score remained at S

Description

Biallelic variants in the KPTN gene were found to cosegregate with the disease phenotype in nine family members from four nuclear families from the Amish community of Ohio presenting with an inherited variable form of neurodevelopmental delay (most consistent features were global developmental delay, macrocephaly with frontal bossing, high levels of anxiety, and some features suggestive of pervasive developmental disorder, such as stereotypies and/or repetitive speech) in Baple et al., 2013. A homozygous frameshift variant in the KPTN gene was identified in two adult siblings from Estonia presenting with moderate intellectual disability and macrocephaly in Pajusalu et al., 2015; the male sibling also presented with behavioral problems, including autistic features.

Reports Added
[Clinical genome sequencing in an unbiased pediatric cohort.2018]
Krishnan Probability Score

Score 0.41306529471567

Ranking 21938/25841 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 0.000791094717132

Ranking 11935/18225 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 0.94717587436529

Ranking 17169/18665 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 0.16710120088637

Ranking 4855/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
HSPB9 Heat shock protein beta-9 Human Protein Binding 94086 Q9BQS6
KIAA0467 seizure threshold 2 homolog (mouse) Human Protein Binding 23334 Q5T011
VWCE von Willebrand factor C and EGF domain-containing protein Human Protein Binding 220001 Q96DN2
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