Human Gene Module / Chromosome 6 / PHIP

PHIPpleckstrin homology domain interacting protein

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
8 / 25
Rare Variants / Common Variants
129 / 0
Aliases
PHIP, BRWD2,  DCAF14,  WDR11,  ndrp
Associated Syndromes
Chung-Jansen syndrome, DD, Chung-Jansen syndrome, DD, ID, Chung-Jansen syndrome
Chromosome Band
6q14.1
Associated Disorders
DD/NDD, ADHD, ASD, EPS
Relevance to Autism

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016).

Molecular Function

Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization.

SFARI Genomic Platforms
Reports related to PHIP (25 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
3 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies Redin C , et al. (2016) No PDD, epilepsy/seizures
4 Recent Recommendation De novo PHIP-predicted deleterious variants are associated with developmental delay, intellectual disability, obesity, and dysmorphic features Webster E , et al. (2016) No Anxiety, hypotonia, obesity
5 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
6 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
7 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 -
8 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No -
9 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
10 Recent Recommendation A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency Jansen S , et al. (2017) No ASD or autistic features
11 Support Clinical and genetic characterization of individuals with predicted deleterious PHIP variants Craddock KE , et al. (2019) No ASD or autistic features, ADHD
12 Recent Recommendation Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription Marenne G et al. (2020) No Autistic features, behavioral abnormalities
13 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
14 Support - Rodin RE et al. (2021) Yes -
15 Support - Kritioti E et al. (2021) No -
16 Support - Álvarez-Mora MI et al. (2022) No -
17 Support - Woodbury-Smith M et al. (2022) Yes -
18 Support - Brea-Fernández AJ et al. (2022) No -
19 Support - Hu C et al. (2022) Yes -
20 Support - Tirado-Class N et al. (2022) No ASD
21 Support - Zhou X et al. (2022) Yes -
22 Recent Recommendation - Kampmeier A et al. (2023) No ASD, ADHD, epilepsy/seizures
23 Support - Spataro N et al. (2023) No ADHD, dyslexia
24 Support - et al. () No -
25 Support - et al. () No ASD
Rare Variants   (129)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation - - - 29209020 Jansen S , et al. (2017)
- - copy_number_loss - - - 29209020 Jansen S , et al. (2017)
- - copy_number_loss De novo - - 27841880 Redin C , et al. (2016)
- - copy_number_loss De novo - - 36726590 Kampmeier A et al. (2023)
- - copy_number_loss Unknown - - 36726590 Kampmeier A et al. (2023)
- p.Arg250Ter stop_gained De novo - - 32492392 Marenne G et al. (2020)
- p.Arg721Ter stop_gained Unknown - - 32492392 Marenne G et al. (2020)
- p.Gln1343Ter stop_gained Unknown - - 32492392 Marenne G et al. (2020)
c.50T>G p.Phe17Cys missense_variant De novo - Simplex 37788244 et al. ()
c.748C>T p.Arg250Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1880-2dup - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
- - copy_number_loss Familial Maternal - 36726590 Kampmeier A et al. (2023)
- - copy_number_loss Familial Paternal - 36726590 Kampmeier A et al. (2023)
c.1186C>T p.Arg396Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1663C>T p.Gln555Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2854C>T p.Arg952Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1186C>T p.Arg396Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
- p.Arg1718Ser missense_variant Unknown - - 32492392 Marenne G et al. (2020)
c.3193C>T p.Arg1065Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4276A>T p.Lys1426Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.5227C>T p.Arg1743Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3536-7A>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.823-2A>G - splice_site_variant Unknown - - 32492392 Marenne G et al. (2020)
c.820C>T p.Gln274Ter stop_gained De novo - - 29209020 Jansen S , et al. (2017)
c.894G>A p.Trp298Ter stop_gained Unknown - - 36980980 Spataro N et al. (2023)
c.1524+1G>T - splice_site_variant Unknown - - 32492392 Marenne G et al. (2020)
- - copy_number_loss Unknown Not maternal - 36726590 Kampmeier A et al. (2023)
c.235T>C p.Cys79Arg missense_variant De novo - - 33004838 Wang T et al. (2020)
c.3892C>T p.Arg1298Ter stop_gained De novo - - 28708303 Chrot E , et al. (2017)
c.20G>A p.Gly7Asp missense_variant De novo - - 33432195 Rodin RE et al. (2021)
c.2902C>T p.Arg968Ter stop_gained De novo - - 29209020 Jansen S , et al. (2017)
c.3433A>G p.Arg1145Gly missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.589C>T p.Arg197Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.694G>A p.Ala232Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.749G>A p.Arg250Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.868G>A p.Gly290Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.949C>T p.Arg317Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3447T>G p.Tyr1149Ter stop_gained De novo - - 29209020 Jansen S , et al. (2017)
c.3571C>T p.Gln1191Ter stop_gained De novo - - 29209020 Jansen S , et al. (2017)
c.3892C>T p.Arg1298Ter stop_gained De novo - - 29209020 Jansen S , et al. (2017)
c.4060A>T p.Arg1354Ter stop_gained Unknown - - 29209020 Jansen S , et al. (2017)
c.1013C>T p.Thr338Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1471G>A p.Val491Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2071C>T p.Arg691Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2903G>A p.Arg968Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2903G>C p.Arg968Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2935C>T p.Arg979Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3139G>A p.Asp1047Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3611C>T p.Thr1204Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3764T>A p.Leu1255His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3928C>T p.Arg1310Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3929G>A p.Arg1310His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4759C>T p.Arg1587Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4760G>A p.Arg1587His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.50T>C p.Phe17Ser missense_variant De novo - - 27900362 Webster E , et al. (2016)
c.3706C>T p.Arg1236Ter stop_gained Unknown - - 36726590 Kampmeier A et al. (2023)
c.1362C>A p.Tyr454Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.328C>A p.Arg110Ser missense_variant De novo - - 29209020 Jansen S , et al. (2017)
c.328C>T p.Arg110Cys missense_variant De novo - - 29209020 Jansen S , et al. (2017)
c.865A>C p.Thr289Pro missense_variant Unknown - - 32492392 Marenne G et al. (2020)
c.3536-4_3540del - splice_site_variant De novo - - 32492392 Marenne G et al. (2020)
c.3161del p.Leu1054Ter stop_gained De novo - - 31167805 Craddock KE , et al. (2019)
c.3595del p.Val1199Ter stop_gained De novo - - 31167805 Craddock KE , et al. (2019)
c.577C>T p.Arg193Ter stop_gained De novo - Simplex 28940097 Anazi S , et al. (2017)
c.91G>T p.Ala31Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.92C>T p.Ala31Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- p.Thr1506Ala missense_variant Familial Paternal - 32492392 Marenne G et al. (2020)
c.3787C>G p.Gln1263Glu missense_variant De novo - - 29209020 Jansen S , et al. (2017)
c.4241T>C p.Phe1414Ser missense_variant De novo - - 32492392 Marenne G et al. (2020)
- p.Lys1443ThrfsTer11 frameshift_variant Unknown - - 32492392 Marenne G et al. (2020)
c.439+1G>T - splice_site_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.686C>T p.Ser229Leu missense_variant De novo - - 31167805 Craddock KE , et al. (2019)
c.860C>A p.Ser287Tyr missense_variant De novo - - 31167805 Craddock KE , et al. (2019)
c.328C>T p.Arg110Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.921_923+2del - frameshift_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1562A>G p.Lys521Arg missense_variant De novo - - 31167805 Craddock KE , et al. (2019)
c.1046T>A p.Phe349Tyr missense_variant Familial Paternal - 35741772 Hu C et al. (2022)
c.1507C>T p.Arg503Ter stop_gained De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.3790A>G p.Thr1264Ala missense_variant Familial Paternal - 35741772 Hu C et al. (2022)
c.779del p.Leu260TrpfsTer48 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.3947dup p.Tyr1316Ter frameshift_variant Unknown - - 36726590 Kampmeier A et al. (2023)
c.1463A>T p.Asp488Val missense_variant De novo - - 35863899 Tirado-Class N et al. (2022)
c.2888A>G p.Glu963Gly missense_variant De novo - - 35863899 Tirado-Class N et al. (2022)
c.2304del p.Thr770LeufsTer43 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1050dup p.Gly351TrpfsTer16 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2925C>T p.Val975%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2995C>A p.Arg999%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1653+1G>A - splice_site_variant Unknown Not maternal - 29209020 Jansen S , et al. (2017)
c.3440del p.Leu1147GlnfsTer26 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1900C>T p.Gln634Ter stop_gained Unknown Not maternal - 29209020 Jansen S , et al. (2017)
c.774dup p.Pro259ThrfsTer9 frameshift_variant Unknown - - 29209020 Jansen S , et al. (2017)
c.1139_1142del p.Phe380Ter frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.3274C>T p.Gln1092Ter stop_gained Familial Paternal - 36726590 Kampmeier A et al. (2023)
c.4513C>T p.Arg1505Ter stop_gained Familial Paternal - 36726590 Kampmeier A et al. (2023)
c.860C>A p.Ser287Tyr missense_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.3311A>T p.Asn1104Ile missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1165G>A p.Ala389Thr missense_variant Familial Paternal - 32492392 Marenne G et al. (2020)
c.1225C>T p.Arg409Cys missense_variant Familial Paternal - 32492392 Marenne G et al. (2020)
c.779del p.Leu260TrpfsTer48 frameshift_variant De novo - - 27900362 Webster E , et al. (2016)
c.3787C>G p.Gln1263Glu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1043A>C p.Tyr348Ser missense_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.1525A>T p.Ile509Phe missense_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.2888A>G p.Glu963Gly missense_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.4516A>G p.Thr1506Ala missense_variant Familial Paternal - 32492392 Marenne G et al. (2020)
c.5300_5301del p.Arg1767AsnfsTer2 frameshift_variant De novo - - 27824329 Wang T , et al. (2016)
c.298_299del p.Leu100IlefsTer13 frameshift_variant De novo - - 29209020 Jansen S , et al. (2017)
c.919_923del p.Ile307ProfsTer22 frameshift_variant De novo - - 29209020 Jansen S , et al. (2017)
c.5317C>T p.Arg1773Ter stop_gained De novo - Simplex 35183220 Álvarez-Mora MI et al. (2022)
c.5072C>T p.Thr1691Ile missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1663C>T p.Gln555Ter stop_gained Familial Paternal Multiplex 29209020 Jansen S , et al. (2017)
c.4570del p.Ser1524LeufsTer22 frameshift_variant Unknown - - 31167805 Craddock KE , et al. (2019)
c.3801_3805del p.Ile1268SerfsTer4 frameshift_variant De novo - - 29209020 Jansen S , et al. (2017)
c.340+2T>C - splice_site_variant Unknown Not maternal Multiplex 29209020 Jansen S , et al. (2017)
c.919_923del p.Ile307ProfsTer22 frameshift_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.4415_4418del p.Glu1472AlafsTer22 frameshift_variant De novo - - 29209020 Jansen S , et al. (2017)
c.2231_2232insGAG p.Gly744_Glu745insArg inframe_insertion De novo - - 35982159 Zhou X et al. (2022)
c.3631_3634del p.Gln1211AspfsTer13 frameshift_variant De novo - - 34324503 Kritioti E et al. (2021)
c.3782+3_3782+6del - splice_site_variant Unknown Not maternal - 31167805 Craddock KE , et al. (2019)
c.3947dup p.Tyr1316Ter frameshift_variant Unknown Not maternal - 36726590 Kampmeier A et al. (2023)
c.2744_2747del p.Lys915SerfsTer15 frameshift_variant De novo - - 31167805 Craddock KE , et al. (2019)
c.180_182del p.Tyr60_Gln61delinsTer frameshift_variant Unknown - - 36726590 Kampmeier A et al. (2023)
c.2048C>A p.Ser683Ter stop_gained Unknown Not maternal Multiplex 36726590 Kampmeier A et al. (2023)
c.1050del p.Phe350LeufsTer32 frameshift_variant Unknown Not maternal - 29209020 Jansen S , et al. (2017)
c.2306_2309del p.Pro769LeufsTer43 frameshift_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.3631_3634del p.Gln1211AspfsTer13 frameshift_variant De novo - Simplex 36726590 Kampmeier A et al. (2023)
c.598_599delinsT p.Thr200LeufsTer8 frameshift_variant Unknown Not paternal - 31167805 Craddock KE , et al. (2019)
c.540_541insA p.Gly181ArgfsTer12 frameshift_variant Familial Paternal Unknown 31167805 Craddock KE , et al. (2019)
c.2521_2522insCACACACA p.Ser841ThrfsTer65 frameshift_variant Familial Maternal - 36726590 Kampmeier A et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

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.

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."

1/1/2021
1
icon
1

Score remained at 1

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo loss-of-function (LoF) variant in PHIP was identified in an ASD proband from the Simons Simplex Collection in Turner et al., 2017. De novo variants in this gene have also been identified in patients presenting with developmental delay/intellectual disability in multiple reports (Webster et al., 2016; Redin et al., 2017; Stessman et al. ,2017; Vissers et al., 2017; Cherot et al., 2017). A clinical evaluation of 23 individuals with PHIP variants in Jansen et al., 2017 identified a syndromic form of developmental delay/intellectual disability in which most individuals (17/23, 74%) were overweight or obese; behavioral problems, including autistic features, were observed in 18 out of 23 individuals (78%). Craddock et al., 2019 described 10 novel individuals with PHIP-related DIDOD syndrome; all ten individuals presented with developmental delay/intellectual disability, and ASD or autistic features were observed in 6/9 individuals.

10/1/2020
1
icon
1

Score remained at 1

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo loss-of-function (LoF) variant in PHIP was identified in an ASD proband from the Simons Simplex Collection in Turner et al., 2017. De novo variants in this gene have also been identified in patients presenting with developmental delay/intellectual disability in multiple reports (Webster et al., 2016; Redin et al., 2017; Stessman et al. ,2017; Vissers et al., 2017; Cherot et al., 2017). A clinical evaluation of 23 individuals with PHIP variants in Jansen et al., 2017 identified a syndromic form of developmental delay/intellectual disability in which most individuals (17/23, 74%) were overweight or obese; behavioral problems, including autistic features, were observed in 18 out of 23 individuals (78%). Craddock et al., 2019 described 10 novel individuals with PHIP-related DIDOD syndrome; all ten individuals presented with developmental delay/intellectual disability, and ASD or autistic features were observed in 6/9 individuals.

7/1/2020
1
icon
1

Score remained at 1

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo loss-of-function (LoF) variant in PHIP was identified in an ASD proband from the Simons Simplex Collection in Turner et al., 2017. De novo variants in this gene have also been identified in patients presenting with developmental delay/intellectual disability in multiple reports (Webster et al., 2016; Redin et al., 2017; Stessman et al. ,2017; Vissers et al., 2017; Cherot et al., 2017). A clinical evaluation of 23 individuals with PHIP variants in Jansen et al., 2017 identified a syndromic form of developmental delay/intellectual disability in which most individuals (17/23, 74%) were overweight or obese; behavioral problems, including autistic features, were observed in 18 out of 23 individuals (78%). Craddock et al., 2019 described 10 novel individuals with PHIP-related DIDOD syndrome; all ten individuals presented with developmental delay/intellectual disability, and ASD or autistic features were observed in 6/9 individuals.

10/1/2019
3S
icon
1

Decreased from 3S to 1

New Scoring Scheme
Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo loss-of-function (LoF) variant in PHIP was identified in an ASD proband from the Simons Simplex Collection in Turner et al., 2017. De novo variants in this gene have also been identified in patients presenting with developmental delay/intellectual disability in multiple reports (Webster et al., 2016; Redin et al., 2017; Stessman et al. ,2017; Vissers et al., 2017; Cherot et al., 2017). A clinical evaluation of 23 individuals with PHIP variants in Jansen et al., 2017 identified a syndromic form of developmental delay/intellectual disability in which most individuals (17/23, 74%) were overweight or obese; behavioral problems, including autistic features, were observed in 18 out of 23 individuals (78%). Craddock et al., 2019 described 10 novel individuals with PHIP-related DIDOD syndrome; all ten individuals presented with developmental delay/intellectual disability, and ASD or autistic features were observed in 6/9 individuals.

Reports Added
[New Scoring Scheme]
7/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo loss-of-function (LoF) variant in PHIP was identified in an ASD proband from the Simons Simplex Collection in Turner et al., 2017. De novo variants in this gene have also been identified in patients presenting with developmental delay/intellectual disability in multiple reports (Webster et al., 2016; Redin et al., 2017; Stessman et al. ,2017; Vissers et al., 2017; Cherot et al., 2017). A clinical evaluation of 23 individuals with PHIP variants in Jansen et al., 2017 identified a syndromic form of developmental delay/intellectual disability in which most individuals (17/23, 74%) were overweight or obese; behavioral problems, including autistic features, were observed in 18 out of 23 individuals (78%). Craddock et al., 2019 described 10 novel individuals with PHIP-related DIDOD syndrome; all ten individuals presented with developmental delay/intellectual disability, and ASD or autistic features were observed in 6/9 individuals.

10/1/2017
4
icon
3

Decreased from 4 to 3

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). A second de novo loss-of-function (LoF) variant in PHIP was identified in an ASD proband from the Simons Simplex Collection in Turner et al., 2017. De novo variants in this gene have also been identified in patients presenting with developmental delay/intellectual disability in multiple reports (Webster et al., 2016; Redin et al., 2017; Stessman et al. ,2017; Vissers et al., 2017; Cherot et al., 2017).

7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016).

10/1/2016
icon
4

Increased from to 4

Description

A de novo potentially damaging missense variant in the PHIP gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); a de novo frameshift variant in this gene was identified in an ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016).

Krishnan Probability Score

Score 0.44718601258811

Ranking 13849/25841 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.
ExAC Score

Score 0.99999994770165

Ranking 173/18225 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
Sanders TADA Score

Score 0.94685804943982

Ranking 17040/18665 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 0.60580098224821

Ranking 71/20870 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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