Human Gene Module / Chromosome 1 / HNRNPU

HNRNPUheterogeneous nuclear ribonucleoprotein U

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
8 / 33
Rare Variants / Common Variants
119 / 0
Aliases
HNRNPU, EIEE54-AS1,  HNRPU,  SAF-A,  SAFA,  U21.1,  hnRNP U,  pp120, HNRNPU
Associated Syndromes
-
Chromosome Band
1q44
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017).

Molecular Function

This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBase
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to HNRNPU (33 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1 Carvill GL , et al. (2013) No ID, epilepsy/seizures
2 Support De novo mutations in epileptic encephalopathies Epi4K Consortium , et al. (2013) No ID, epilepsy/seizures, ASD
3 Support De novo mutations in moderate or severe intellectual disability Hamdan FF , et al. (2014) No ID, epilepsy/seizures, autistic features
4 Support - Zhu X et al. (2015) No -
5 Support Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients de Kovel CG , et al. (2016) No ID, epilepsy/seizures
6 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
7 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
8 Support - Depienne C et al. (2017) No ASD
9 Recent Recommendation Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability Bramswig NC , et al. (2017) No -
10 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes -
11 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No -
12 Primary Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
13 Support Clinical and molecular characterization of de novo loss of function variants in HNRNPU Leduc MS , et al. (2017) No ASD
14 Support De novo mutations in HNRNPU result in a neurodevelopmental syndrome Yates TM , et al. (2017) No Epilepsy/seizures, ASD
15 Support HRPU-2, a Homolog of Mammalian hnRNP U, Regulates Synaptic Transmission by Controlling the Expression of SLO-2 Potassium Channel in Caenorhabditis elegans Liu P , et al. (2017) No -
16 Support - Oates S et al. (2018) No -
17 Support An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a patient with a novel frameshift mutation in HNRNPU Shimada S , et al. (2018) No Epilepsy/seizures, DD, ID, autistic behavior, ster
18 Support - et al. (2019) No -
19 Support - Demos M et al. (2019) Yes -
20 Support Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability Borlot F , et al. (2019) No Autistic features
21 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
22 Support - Fernández-Marmiesse A et al. (2019) No -
23 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
24 Support Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review Durkin A et al. (2020) No -
25 Support - Johannesen KM et al. (2020) No -
26 Support Clinical and genetic characteristics of patients with Doose syndrome Hinokuma N et al. (2020) No -
27 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
28 Support - Brunet T et al. (2021) No -
29 Support - Gillentine MA et al. (2021) No ASD, DD
30 Support - Taylor J et al. (2022) No ASD or autistic features, OCD
31 Support - Chuan Z et al. (2022) No -
32 Support - Sapir T et al. (2022) No -
33 Support - Zhou X et al. (2022) Yes -
Rare Variants   (119)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 31273778 Borlot F , et al. (2019)
- - copy_number_gain Unknown - - 28393272 Bramswig NC , et al. (2017)
- - copy_number_loss De novo NA Simplex 35138025 Taylor J et al. (2022)
c.1615-1G>A - splice_site_variant De novo NA - 25590979 Zhu X et al. (2015)
c.1681C>T p.Gln561Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.1714C>T p.Arg572Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.1852C>T p.Gln618Ter stop_gained De novo NA - 33004838 Wang T et al. (2020)
c.67C>T p.Arg23Ter stop_gained Unknown - - 28554332 Bowling KM , et al. (2017)
c.508C>T p.Gln170Ter stop_gained De novo NA - 35138025 Taylor J et al. (2022)
c.2425-2A>G - splice_site_variant De novo NA - 35138025 Taylor J et al. (2022)
c.878-9T>G - intron_variant De novo NA Simplex 35138025 Taylor J et al. (2022)
- - loss_of_function_variant De novo NA Simplex 35138025 Taylor J et al. (2022)
- - loss_of_function_variant De novo NA Unknown 35138025 Taylor J et al. (2022)
c.1060+1G>A - splice_site_variant De novo NA - 28944577 Yates TM , et al. (2017)
c.1169A>C p.Asn390Thr missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.2219G>C p.Gly740Ala missense_variant Unknown - - 35571021 Chuan Z et al. (2022)
c.1681C>T p.Gln561Ter stop_gained De novo NA - 28283832 Depienne C et al. (2017)
c.508C>T p.Gln170Ter stop_gained De novo NA - 31452935 Feliciano P et al. (2019)
c.481C>T p.Gln161Ter stop_gained Unknown - - 33874999 Gillentine MA et al. (2021)
c.253dup p.Glu85GlyfsTer60 frameshift_variant Unknown - - 30951195 et al. (2019)
c.2425-3C>A - splice_region_variant De novo NA - 28283832 Depienne C et al. (2017)
c.523C>T p.Gln175Ter stop_gained De novo NA - 28393272 Bramswig NC , et al. (2017)
c.817C>T p.Gln273Ter stop_gained De novo NA - 28393272 Bramswig NC , et al. (2017)
c.1744-2del - splice_site_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.893A>G p.His298Arg missense_variant De novo NA - 35138025 Taylor J et al. (2022)
c.67C>T p.Arg23Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2425-2A>G - splice_site_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.692-1G>A - splice_site_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.418G>A p.Glu140Lys missense_variant De novo NA - 28944577 Yates TM , et al. (2017)
c.804-9_804-6del - splice_region_variant De novo NA - 35138025 Taylor J et al. (2022)
c.619C>T p.Gln207Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.575C>A p.Ser192Ter stop_gained De novo NA Unknown 33619735 Brunet T et al. (2021)
c.1686+1G>C - splice_site_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2365C>T p.Arg789Ter stop_gained De novo NA Multiplex 33004838 Wang T et al. (2020)
c.2140_2142del p.Arg714del inframe_deletion Unknown - - 29760947 Oates S et al. (2018)
c.817C>T p.Gln273Ter stop_gained De novo NA Multiplex 31164858 Demos M et al. (2019)
c.1089G>A p.Trp363Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1450C>T p.Arg484Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1801C>T p.Arg601Ter stop_gained De novo NA Simplex 32319732 Durkin A et al. (2020)
c.960G>A p.Trp320Ter stop_gained De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.325G>C p.Glu109Gln missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1089G>A p.Trp363Ter stop_gained De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.1714C>T p.Arg572Ter stop_gained De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.511C>T p.Gln171Ter stop_gained De novo NA Simplex 25356899 Hamdan FF , et al. (2014)
c.970A>G p.Arg324Gly missense_variant De novo NA - 28393272 Bramswig NC , et al. (2017)
c.1368A>C p.Glu456Asp missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1435G>A p.Val479Ile missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1516C>T p.Pro506Ser missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.2199G>T p.Arg733Ser missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.2408A>G p.Asn803Ser missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1088G>A p.Trp363Ter stop_gained De novo NA Multiplex 32319732 Durkin A et al. (2020)
c.1132T>C p.Ser378Pro missense_variant De novo NA - 28393272 Bramswig NC , et al. (2017)
c.1142A>G p.Tyr381Cys missense_variant De novo NA Simplex 35982159 Zhou X et al. (2022)
c.359C>T p.Pro120Leu missense_variant De novo NA Simplex 28714951 Lim ET , et al. (2017)
c.469G>C p.Gly157Arg missense_variant De novo NA Simplex 28714951 Lim ET , et al. (2017)
c.1834G>A p.Asp612Asn missense_variant Unknown - Simplex 35138025 Taylor J et al. (2022)
c.334dup p.Ala112GlyfsTer33 frameshift_variant De novo NA - 33004838 Wang T et al. (2020)
c.1211A>G p.Asp404Gly missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1507C>T p.Pro522Ser missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1142A>G p.Tyr381Cys missense_variant De novo NA - 31981491 Satterstrom FK et al. (2020)
c.1624del p.Gln542SerfsTer45 frameshift_variant De novo NA - 29760947 Oates S et al. (2018)
c.1561dup p.Ala521GlyfsTer4 frameshift_variant De novo NA - 35138025 Taylor J et al. (2022)
c.2167+35_*4156del p.? copy_number_loss De novo NA Simplex 32319732 Durkin A et al. (2020)
c.878A>G p.Tyr293Cys missense_variant De novo NA Simplex 32913952 Hinokuma N et al. (2020)
c.2357G>A p.Trp786Ter stop_gained Unknown Not maternal - 23708187 Carvill GL , et al. (2013)
c.1865_1867del p.Glu622del inframe_deletion Unknown - - 33874999 Gillentine MA et al. (2021)
c.1050_1051del p.Thr351LysfsTer4 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.16delinsATT p.Val6IlefsTer4 frameshift_variant De novo NA - 28708303 Chrot E , et al. (2017)
c.837_839del p.Glu279del inframe_deletion De novo NA Simplex 32319732 Durkin A et al. (2020)
c.29_30del p.Lys10ThrfsTer17 inframe_deletion Unknown - - 33874999 Gillentine MA et al. (2021)
c.673_674del p.Arg225GlyfsTer3 frameshift_variant De novo NA - 35138025 Taylor J et al. (2022)
c.1868dup p.Glu624ArgfsTer24 frameshift_variant De novo NA - 28283832 Depienne C et al. (2017)
c.1812dup p.Val605CysfsTer7 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1863del p.Phe621LeufsTer6 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.2085dup p.Gly696TrpfsTer6 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1755_1756insCCTCT p.Ala586ProfsTer22 frameshift_variant De novo NA - 28135719 et al. (2017)
c.23del p.Val8GlufsTer4 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.1755dup p.Val586CysfsTer7 frameshift_variant De novo NA - 27652284 de Kovel CG , et al. (2016)
c.198del p.Ala67LeufsTer40 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.596dup p.Pro200AlafsTer24 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.1665_1666del p.Leu556AlafsTer12 frameshift_variant De novo NA - 35138025 Taylor J et al. (2022)
c.2304_2305del p.Gly769GlufsTer83 frameshift_variant De novo NA - 35138025 Taylor J et al. (2022)
c.742dup p.Arg248LysfsTer12 frameshift_variant De novo NA Simplex 35138025 Taylor J et al. (2022)
c.1641del p.Asp548IlefsTer5 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1243del p.Asp415MetfsTer3 frameshift_variant De novo NA Simplex 35138025 Taylor J et al. (2022)
c.76del p.Ser26LeufsTer35 frameshift_variant De novo NA Simplex 29858110 Shimada S , et al. (2018)
c.1957del p.Glu653LysfsTer162 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.1687-4_1692del - splice_site_variant De novo NA Simplex 23934111 Epi4K Consortium , et al. (2013)
c.1681del p.Gln561SerfsTer45 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1836del p.Tyr613IlefsTer11 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2299_2302del p.Asn767GlufsTer66 frameshift_variant De novo NA - 28283832 Depienne C et al. (2017)
c.149_156del p.Arg50HisfsTer32 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.815_820del p.Thr273_Tyr274del inframe_deletion De novo NA - 31981491 Satterstrom FK et al. (2020)
c.1571dup p.Lys525GlufsTer25 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.1664del p.Leu555ArgfsTer51 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.324_328del p.Glu109ArgfsTer34 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.547_560del p.Ala183GlnfsTer36 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.2299_2302del p.Asn767GlufsTer66 frameshift_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.706_707del p.Glu236ThrfsTer6 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.847_857del p.Phe283SerfsTer5 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.395_401del p.Asn132ThrfsTer63 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.454_466del p.Ala152ThrfsTer41 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.16delinsATT p.Val6IlefsTer4 frameshift_variant Familial Paternal - 28283832 Depienne C et al. (2017)
c.2247_2248del p.Gly750GlufsTer83 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.2304_2305del p.Gly769GlufsTer83 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.2319_2320del p.Gly774TrpfsTer78 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.712_715del p.Lys238AlafsTer100 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.1925_1926del p.Leu642ProfsTer5 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2083_2084del p.Ser695TrpfsTer6 frameshift_variant De novo NA Simplex 32319732 Durkin A et al. (2020)
c.2213_2214del p.Pro738ArgfsTer7 frameshift_variant De novo NA Simplex 35138025 Taylor J et al. (2022)
c.1171_1172TG[1] p.Cys391_Glu392delinsTer stop_gained De novo NA - 33874999 Gillentine MA et al. (2021)
c.1846_1847insCA p.Arg616ThrfsTer9 frameshift_variant De novo NA - 33874999 Gillentine MA et al. (2021)
c.651_660del p.Gly218AlafsTer118 frameshift_variant De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.2270_2271del p.Pro757ArgfsTer7 frameshift_variant De novo NA Simplex 28815871 Leduc MS , et al. (2017)
c.706_707del p.Glu236ThrfsTer6 frameshift_variant De novo NA Not simplex 32319732 Durkin A et al. (2020)
c.1756_1757insGT p.Val586GlyfsTer2 frameshift_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.1367_1368insGA p.Phe456LeufsTer8 frameshift_variant De novo NA Simplex 28944577 Yates TM , et al. (2017)
c.914_916del p.Arg305_Ala306delinsThr inframe_indel Unknown Not paternal - 32427350 Johannesen KM et al. (2020)
c.401_402del p.Asp134GlyfsTer10 frameshift_variant De novo NA - 31780880 Fernández-Marmiesse A et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

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."

4/1/2021
1
icon
1

Score remained at 1

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios2015] [Prevalence and architecture of de novo mutations in developmental disorders2017] [Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU2017] [Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017] [Incorporating epilepsy genetics into clinical practice: a 360°evaluation2018] [The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield2019] [Diagnostic Yield and Treatment Impact of Targeted Exome Sequencing in Early-Onset Epilepsy2019] [Rare Variants in 48 Genes Account for 42% of Cases of Epilepsy With or Without Neurodevelopmental Delay in 246 Pediatric Patients2019] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Utility of genetic testing for therapeutic decision-making in adults with epilepsy2020] [Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders2021]
1/1/2021
1
icon
1

Score remained at 1

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Clinical and genetic characteristics of patients with Doose syndrome2020] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
1
icon
1

Score remained at 1

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Clinical findings of 21 previously unreported probands with HNRNPU-related syndrome and comprehensive literature review2020]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.2019]
7/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017; Yates et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder in Epi4K Consortium; Epilepsy Phenome/Genome Project 2013, Bramswig et al., 2017, Leduc et al., 2017, and Yates et al., 2017.

Reports Added
[An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a ...2018]
7/1/2017
icon
4S

Increased from to 4S

Description

Two non-synonymous postzygotic mosaic mutations (PZMs) in the HNRNPU gene were identified in ASD probands 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. 5/84,448 expected; hypergeometric P-value of 4.5E-04). Additional damaging variants in the HNRNPU gene have been identified in ASD probands (Wang et al., 2016; Bowling et al., 2017). Mutations in the HNRNPU gene have also been associated with early infantile epileptic encephalopathy-54 (EIEE54; OMIM 617391) (Carvill et al., 2013; Epi4K Consortium; Epilepsy Phenome/Genome Project 2013; Hamdan et al., 2014; de Kovel et al., 2016; Bramswig et al., 2017; Leduc et al., 2017); a diagnosis of autism or autistic features have been observed in several patients with this disorder.

Krishnan Probability Score

Score 0.57111211166452

Ranking 825/25841 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 0.99990332258243

Ranking 673/18225 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 0.7919757025084

Ranking 2076/18665 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 0.38266856349508

Ranking 1654/20870 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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