Human Gene Module / Chromosome X / PCDH19

PCDH19protocadherin 19

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
2 / 34
Rare Variants / Common Variants
206 / 0
Aliases
PCDH19, EFMR
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
Xq22.1
Associated Disorders
ADHD, DD/NDD, ASD, ID, EPS, SCZ
Relevance to Autism

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (several studies for each disease).

Molecular Function

A calcium-dependent cell-adhesion protein that is primarily expressed in the brain

Reports related to PCDH19 (34 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Dibbens LM , et al. (2008) No ID, epilepsy
2 Highly Cited Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. Depienne C , et al. (2009) No Delayed or absent speech, autistic features
3 Recent Recommendation Protocadherin-19 is essential for early steps in brain morphogenesis. Emond MR , et al. (2009) No -
4 Recent Recommendation Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families. Hynes K , et al. (2009) No -
5 Primary Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Piton A , et al. (2010) Yes SCZ
6 Recent Recommendation Protocadherin 19 mutations in girls with infantile-onset epilepsy. Marini C , et al. (2010) No -
7 Recent Recommendation Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome. Jamal SM , et al. (2010) No ID, epilepsy
8 Recent Recommendation A novel PCDH19 mutation inherited from an unaffected mother. Dimova PS , et al. (2012) No MR
9 Support Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an... Willemsen MH , et al. (2012) No ASD, ADHD
10 Support Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome. Kwong AK , et al. (2012) No ASD, ID
11 Recent Recommendation Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy. Marini C , et al. (2012) No ID, ASD
12 Support Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders. van Harssel JJ , et al. (2013) No ID, ASD
13 Support Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Carvill GL , et al. (2013) No ID, ASD, DD
14 Support PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy. Higurashi N , et al. (2013) No ID, ASD
15 Recent Recommendation Cognitive development in females with PCDH19 gene-related epilepsy. Cappelletti S , et al. (2014) No Autistic features
16 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
17 Support PCDH19-related epilepsy in two mosaic male patients. Terracciano A , et al. (2016) No -
18 Support PCDH19-related epileptic encephalopathy in a male mosaic for a truncating variant. Thiffault I , et al. (2016) No ADHD, OCD, ODD
19 Support The Clinical Spectrum of Female Epilepsy Patients with PCDH19 Mutations in a Chinese Population. Liu A , et al. (2016) No ID, autistic features
20 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No -
21 Recent Recommendation Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ER). Pham DH , et al. (2017) No -
22 Support Male patients affected by mosaic PCDH19 mutations: five new cases. de Lange IM , et al. (2017) No ID, ASD
23 Recent Recommendation The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological mat... Bassani S , et al. (2018) No -
24 Recent Recommendation PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum. Smith L , et al. (2018) No ASD or autistic features
25 Support PCDH19 regulation of neural progenitor cell differentiation suggests asynchrony of neurogenesis as a mechanism contributing to PCDH19 Girls Cluster... Homan CC , et al. (2018) No -
26 Support Chinese cases of early infantile epileptic encephalopathy: a novel mutation in the PCDH19 gene was proved in a mosaic male- case report. Tan Y , et al. (2018) No -
27 Recent Recommendation A systematic review and meta-analysis of 271 PCDH19-variant individuals identifies psychiatric comorbidities, and association of seizure onset and ... Kolc KL , et al. (2018) No -
28 Support PCDH19-related epilepsy in a male with Klinefelter syndrome: Additional evidence supporting PCDH19 cellular interference disease mechanism. Romasko EJ , et al. (2018) No -
29 Support Mosaicism and incomplete penetrance of PCDH19 mutations. Liu A , et al. (2018) No ASD
30 Recent Recommendation Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study. Trivisano M , et al. (2018) No ASD
31 Support Schizophrenia is a later-onset feature of PCDH19 Girls Clustering Epilepsy. Vlaskamp DRM , et al. (2019) No SCZ
32 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No DD
33 Support Multiplane Calcium Imaging Reveals Disrupted Development of Network Topology in Zebrafish pcdh19 Mutants. Light SEW and Jontes JD (2019) No -
34 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. Long S , et al. (2019) Yes -
Rare Variants   (206)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 30287595 Liu A , et al. (2018)
- - copy_number_loss Unknown - - 29377098 Smith L , et al. (2018)
- - copy_number_loss De novo NA - 29377098 Smith L , et al. (2018)
- - stop_gained De novo NA - 25499160 Cappelletti S , et al. (2014)
- - copy_number_loss De novo NA - 19214208 Depienne C , et al. (2009)
- - copy_number_gain Unknown - - 22796527 Willemsen MH , et al. (2012)
- p.Ile508His frameshift_variant - - - 20713952 Marini C , et al. (2010)
A>G - splice_site_variant De novo NA - 20713952 Marini C , et al. (2010)
c.6G>A p.Glu2%3D synonymous_variant - - - 19752159 Hynes K , et al. (2009)
delTTTT - frameshift_variant De novo NA - 20830798 Jamal SM , et al. (2010)
G>A p.? splice_site_variant De novo NA - 20713952 Marini C , et al. (2010)
c.1825G>T p.Glu609Ter stop_gained Unknown - - 27527380 Liu A , et al. (2016)
c.2873G>A p.Arg958Gln missense_variant - - - 19752159 Hynes K , et al. (2009)
- - copy_number_loss De novo NA Unknown 23712037 Higurashi N , et al. (2013)
c.825C>A p.Tyr275Ter stop_gained Unknown - - 29377098 Smith L , et al. (2018)
c.402C>A p.Ile134%3D synonymous_variant - - - 19752159 Hynes K , et al. (2009)
c.655C>T p.Leu219%3D synonymous_variant - - - 19752159 Hynes K , et al. (2009)
c.1375C>T p.Gln459Ter stop_gained De novo NA - 27527380 Liu A , et al. (2016)
c.1133C>G p.Ser378Ter stop_gained De novo NA - 30287595 Liu A , et al. (2018)
c.1804C>T p.Arg602Ter stop_gained De novo NA - 30287595 Liu A , et al. (2018)
c.139C>T p.Arg47Ter stop_gained De novo NA - 29377098 Smith L , et al. (2018)
c.1137C>T p.Gly379%3D synonymous_variant - - - 19752159 Hynes K , et al. (2009)
c.1627C>T p.Leu543%3D synonymous_variant - - - 19752159 Hynes K , et al. (2009)
c.1683G>A p.Pro561%3D synonymous_variant - - - 19752159 Hynes K , et al. (2009)
c.83C>A p.Ser28Ter stop_gained De novo NA - 20713952 Marini C , et al. (2010)
c.83C>A p.Ser28Ter stop_gained De novo NA - 22946748 Marini C , et al. (2012)
c.619C>T p.Arg207Ter stop_gained De novo NA - 29377098 Smith L , et al. (2018)
- p.Asp968Glu frameshift_variant De novo NA - 20713952 Marini C , et al. (2010)
c.2113C>T p.Arg705Ter stop_gained De novo NA - 29377098 Smith L , et al. (2018)
c.729C>A p.Tyr243Ter stop_gained De novo NA - 20830798 Jamal SM , et al. (2010)
c.2617-1G>A - splice_site_variant De novo NA - 22946748 Marini C , et al. (2012)
c.262G>T p.Asp88Tyr missense_variant De novo NA - 30287595 Liu A , et al. (2018)
c.1183C>T p.Arg395Ter stop_gained De novo NA - 22946748 Marini C , et al. (2012)
c.1804C>T p.Arg602Ter stop_gained De novo NA - 22946748 Marini C , et al. (2012)
c.471C>A p.Asp157Glu missense_variant De novo NA - 27527380 Liu A , et al. (2016)
c.488T>G p.Val163Gly missense_variant De novo NA - 27527380 Liu A , et al. (2016)
c.695A>G p.Asn232Ser missense_variant De novo NA - 27527380 Liu A , et al. (2016)
c.964G>C p.Gly322Arg missense_variant De novo NA - 27527380 Liu A , et al. (2016)
c.317T>A p.Met106Lys missense_variant De novo NA - 30287595 Liu A , et al. (2018)
c.471C>G p.Asp157Glu missense_variant De novo NA - 30287595 Liu A , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant De novo NA - 27527380 Liu A , et al. (2016)
c.1184G>C p.Arg395Pro missense_variant De novo NA - 27527380 Liu A , et al. (2016)
c.1681C>T p.Pro561Ser missense_variant De novo NA - 30287595 Liu A , et al. (2018)
c.798C>G p.Asp266Glu missense_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.462C>G p.Tyr154Ter stop_gained De novo NA - 28669061 de Lange IM , et al. (2017)
c.799G>T p.Glu267Ter stop_gained De novo NA - 28669061 de Lange IM , et al. (2017)
c.840C>G p.Tyr280Ter stop_gained De novo NA - 28669061 de Lange IM , et al. (2017)
c.826T>C p.Ser276Pro missense_variant De novo NA - 19752159 Hynes K , et al. (2009)
c.344T>A p.Ile115Lys missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.361G>C p.Asp121His missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.370G>T p.Asp124Tyr missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.593G>T p.Arg198Leu missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.695A>G p.Asn232Ser missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant Unknown - - 22848613 Kwong AK , et al. (2012)
c.2113C>T p.Arg705Ter stop_gained Familial Paternal - 30287595 Liu A , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.1114C>T p.Arg372Trp missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.1372T>C p.Tyr458His missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.1435G>A p.Asp479Asn missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.1441G>A p.Asp481Asn missense_variant De novo NA - 29377098 Smith L , et al. (2018)
c.608A>C p.His203Pro missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.617T>G p.Phe206Cys missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.695A>G p.Asn232Ser missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.706C>T p.Pro236Ser missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.790G>C p.Asp264His missense_variant De novo NA - 22946748 Marini C , et al. (2012)
- p.Glu900ArgfsTer8 frameshift_variant De novo NA - 20713952 Marini C , et al. (2010)
c.1339A>C p.Asn447His missense_variant Unknown - - 27864847 Parrini E , et al. (2016)
C>G p.His146Gln missense_variant Familial Maternal - 20479760 Piton A , et al. (2010)
c.991A>T p.Lys331Ter stop_gained Unknown - Multiplex 29377098 Smith L , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant De novo NA - 20713952 Marini C , et al. (2010)
c.1129G>C p.Asp377His missense_variant De novo NA - 20713952 Marini C , et al. (2010)
c.1211C>T p.Thr404Ile missense_variant De novo NA - 20713952 Marini C , et al. (2010)
c.1129G>A p.Asp377Asn missense_variant De novo NA - 22848613 Kwong AK , et al. (2012)
c.1019A>G p.Asn340Ser missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1129G>C p.Asp377His missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1211C>T p.Thr404Ile missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1298T>C p.Leu433Pro missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1537G>C p.Gly513Arg missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1700C>T p.Pro567Leu missense_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1681C>T p.Pro561Ser missense_variant Unknown - - 23708187 Carvill GL , et al. (2013)
c.416C>A p.Ser139Ter stop_gained De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.718G>T p.Glu240Ter stop_gained De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.2656C>T p.Arg886Ter stop_gained Familial Maternal - 29377098 Smith L , et al. (2018)
c.1682C>G p.Pro561Arg missense_variant Unknown - - 28669061 de Lange IM , et al. (2017)
c.2656C>T p.Arg886Ter stop_gained De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.64del p.Leu22SerfsTer8 frameshift_variant De novo NA - 30287595 Liu A , et al. (2018)
c.1192G>T p.Glu398Ter stop_gained Familial Paternal - 20713952 Marini C , et al. (2010)
c.1345_1347dup p.Asn449dup inframe_insertion De novo NA - 27527380 Liu A , et al. (2016)
c.2528T>C p.Ile843Thr splice_site_variant De novo NA - 22946748 Marini C , et al. (2012)
c.859G>T p.Glu287Ter stop_gained De novo NA Simplex 19214208 Depienne C , et al. (2009)
c.1864G>C p.Gly622Arg missense_variant De novo NA - 28669061 de Lange IM , et al. (2017)
c.91G>A p.Glu31Lys missense_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.1019A>G p.Asn340Ser missense_variant Familial Maternal - 30287595 Liu A , et al. (2018)
c.1178C>T p.Pro393Leu missense_variant Familial Paternal - 30287595 Liu A , et al. (2018)
c.1191G>C p.Gln397His missense_variant Familial Paternal - 30287595 Liu A , et al. (2018)
c.1240G>A p.Glu414Lys missense_variant Familial Maternal - 30287595 Liu A , et al. (2018)
c.158dup p.Asp54GlyfsTer35 frameshift_variant De novo NA - 30287595 Liu A , et al. (2018)
c.183dup p.Arg62SerfsTer27 frameshift_variant De novo NA - 30287595 Liu A , et al. (2018)
c.1681C>T p.Pro561Ser missense_variant De novo NA Simplex 29866057 Tan Y , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant Unknown - - 23334464 van Harssel JJ , et al. (2013)
c.1802G>A p.Gly601Asp missense_variant Unknown - - 23334464 van Harssel JJ , et al. (2013)
c.2341del p.Ser781LeufsTer6 frameshift_variant De novo NA - 30287595 Liu A , et al. (2018)
c.2222C>T p.Ser741Leu missense_variant Familial Paternal - 31139143 Long S , et al. (2019)
c.463G>A p.Asp155Asn missense_variant Familial Paternal - 29377098 Smith L , et al. (2018)
c.463G>C p.Asp155His missense_variant Familial Paternal - 29377098 Smith L , et al. (2018)
c.625A>C p.Thr209Pro missense_variant Familial Paternal - 29377098 Smith L , et al. (2018)
c.2146dup p.Arg716LysfsTer4 frameshift_variant Unknown - - 29377098 Smith L , et al. (2018)
c.1466_1468del p.Ser489del inframe_deletion De novo NA - 22946748 Marini C , et al. (2012)
c.78del p.Lys26AsnfsTer4 frameshift_variant De novo NA - 20830798 Jamal SM , et al. (2010)
c.352G>T p.Glu118Ter stop_gained De novo NA Multiplex 19214208 Depienne C , et al. (2009)
c.2656C>T p.Arg886Ter stop_gained De novo NA Unknown 23712037 Higurashi N , et al. (2013)
c.1178C>T p.Pro393Leu missense_variant De novo NA - 25499160 Cappelletti S , et al. (2014)
c.1091dup p.Tyr366LeufsTer10 frameshift_variant De novo NA - 27527380 Liu A , et al. (2016)
c.1020T>G p.Asn340Lys missense_variant Familial Paternal - 29377098 Smith L , et al. (2018)
c.1335C>A p.Asp445Glu missense_variant Familial Maternal - 29377098 Smith L , et al. (2018)
c.1748T>C p.Ile583Thr missense_variant Familial Paternal - 29377098 Smith L , et al. (2018)
c.918C>G p.Tyr306Ter stop_gained De novo NA Simplex 26765483 Terracciano A , et al. (2016)
c.1022A>G p.Asp341Gly missense_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.1031C>T p.Pro344Leu missense_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.1123G>T p.Asp375Tyr missense_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.1780G>C p.Asp594His missense_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.1663del p.Asp555ThrfsTer14 frameshift_variant De novo NA - 30945278 Jiao Q , et al. (2019)
c.434dup p.Thr146HisfsTer80 frameshift_variant De novo NA - 29377098 Smith L , et al. (2018)
c.805del p.Thr269ProfsTer36 frameshift_variant De novo NA - 29377098 Smith L , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant Familial Maternal - 20713952 Marini C , et al. (2010)
c.1240G>C p.Glu414Gln missense_variant Familial Paternal - 20713952 Marini C , et al. (2010)
c.1019A>G p.Asn340Ser missense_variant Familial Maternal - 22946748 Marini C , et al. (2012)
c.1786G>C p.Asp596His missense_variant Familial Paternal - 22946748 Marini C , et al. (2012)
c.152dup p.Ala52ArgfsTer37 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.242T>G p.Leu81Arg missense_variant De novo NA Multiplex 22946748 Marini C , et al. (2012)
c.593G>T p.Arg198Leu missense_variant Unknown - Unknown 23712037 Higurashi N , et al. (2013)
c.339C>A p.Cys113Ter stop_gained Familial - Multi-generational 27527380 Liu A , et al. (2016)
c.1091dup p.Tyr366LeufsTer10 frameshift_variant De novo NA - 29377098 Smith L , et al. (2018)
c.958dup p.Asp320GlyfsTer22 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.2200dup p.Ile734AsnfsTer3 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.2556dup p.Glu853ArgfsTer8 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.269A>T p.Asp90Val missense_variant De novo NA Unknown 23712037 Higurashi N , et al. (2013)
c.2012C>G p.Ser671Ter stop_gained Familial - Multi-generational 27527380 Liu A , et al. (2016)
A608CT617 His203Pro, Phe206Cys missense_variant De novo NA - 20713952 Marini C , et al. (2010)
c.1521dup p.Ile508HisfsTer15 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.2762dup p.Asp921GlufsTer18 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1019A>G p.Asn340Ser missense_variant De novo NA Simplex 19214208 Depienne C , et al. (2009)
c.497dup p.Tyr166Ter frameshift_variant Unknown - Unknown 23712037 Higurashi N , et al. (2013)
c.1091dupC p.Tyr366LeufsTer10 frameshift_variant De novo NA - 22946748 Marini C , et al. (2012)
c.1019A>G p.Asn340Ser missense_variant De novo NA Unknown 23712037 Higurashi N , et al. (2013)
c.1240G>A p.Glu414Lys missense_variant Familial Maternal Simplex 27527380 Liu A , et al. (2016)
c.898_899del p.Val300HisfsTer19 frameshift_variant De novo NA - 29377098 Smith L , et al. (2018)
c.706C>T p.Pro236Ser missense_variant Unknown Not maternal - 29933145 Romasko EJ , et al. (2018)
c.142G>T p.Glu48Ter stop_gained Familial Paternal Multiplex 19214208 Depienne C , et al. (2009)
c.2359C>T p.Arg787Cys missense_variant Unknown - Simplex 23334464 van Harssel JJ , et al. (2013)
c.370G>A p.Asp124Asn missense_variant Familial Paternal Multiplex 27527380 Liu A , et al. (2016)
c.790G>C p.Asp264His missense_variant Familial Paternal Multiplex 27527380 Liu A , et al. (2016)
c.370G>A p.Asp124Asn missense_variant Familial Paternal Simplex 26544041 Zhang Y , et al. (2015)
c.2156T>G p.Leu719Ter stop_gained Familial Paternal Simplex 23712037 Higurashi N , et al. (2013)
c.1048C>G p.Ser349Ter stop_gained Familial Paternal Unknown 23712037 Higurashi N , et al. (2013)
c.1352C>T p.Pro451Leu missense_variant De novo NA Simplex 26765483 Terracciano A , et al. (2016)
c.823T>A p.Tyr275Asn missense_variant Familial Maternal - 23334464 van Harssel JJ , et al. (2013)
c.1508dup p.Thr504HisfsTer19 frameshift_variant De novo NA Simplex 29866057 Tan Y , et al. (2018)
c.2851del p.Thr951LeufsTer36 splice_site_variant Familial Maternal - 30287595 Liu A , et al. (2018)
c.1095_1101del p.Tyr366SerfsTer201 frameshift_variant De novo NA - 29377098 Smith L , et al. (2018)
c.605C>A p.Ser202Ter stop_gained Unknown Not maternal Simplex 27016041 Thiffault I , et al. (2016)
c.1091dup p.Tyr366LeufsTer10 frameshift_variant De novo NA - 25499160 Cappelletti S , et al. (2014)
c.1091del p.Pro364ArgfsTer4 frameshift_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.134_135del p.Asp45GlyfsTer43 frameshift_variant Familial Paternal - 30287595 Liu A , et al. (2018)
c.497dup p.Tyr166Ter frameshift_variant Familial - Multi-generational 30287595 Liu A , et al. (2018)
c.1091dup p.Tyr366LeufsTer10 frameshift_variant Familial Paternal - 29377098 Smith L , et al. (2018)
c.357del p.Lys120ArgfsTer3 frameshift_variant Unknown - Unknown 23712037 Higurashi N , et al. (2013)
c.1863dup p.Gly622TrpfsTer18 frameshift_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.918C>G p.Tyr306Ter stop_gained Familial Paternal Multi-generational 29866057 Tan Y , et al. (2018)
c.2564dup p.Asn855LysfsTer6 frameshift_variant Familial Maternal - 22633638 Dimova PS , et al. (2012)
c.1628T>C p.Leu543Pro missense_variant Familial Paternal Simplex 19214208 Depienne C , et al. (2009)
c.2873G>A p.Arg958Gln missense_variant Familial Paternal Simplex 23708187 Carvill GL , et al. (2013)
c.416C>T p.Ser139Leu missense_variant Familial Maternal Unknown 23712037 Higurashi N , et al. (2013)
c.469G>A p.Asp157Asn missense_variant Familial Maternal Unknown 23712037 Higurashi N , et al. (2013)
c.1091dupC p.Tyr366LeufsTer10 frameshift_variant De novo NA - 23334464 van Harssel JJ , et al. (2013)
c.3319C>G p.Arg1107Gly missense_variant Familial Paternal Simplex 19214208 Depienne C , et al. (2009)
c.506del p.Thr169SerfsTer43 frameshift_variant De novo NA Simplex 19214208 Depienne C , et al. (2009)
c.361G>A p.Asp121Asn missense_variant Familial Maternal Multiplex 19214208 Depienne C , et al. (2009)
c.1019A>G p.Asn340Ser missense_variant Familial Maternal Unknown 23712037 Higurashi N , et al. (2013)
c.1787A>T p.Asp596Val missense_variant Familial Paternal Unknown 23712037 Higurashi N , et al. (2013)
c.1091dup p.Tyr366LeufsTer10 frameshift_variant Unknown - Unknown 23712037 Higurashi N , et al. (2013)
c.498C>G p.Tyr166Ter stop_gained Familial Maternal Multi-generational 29377098 Smith L , et al. (2018)
c.595G>C p.Glu199Gln missense_variant Unknown Not maternal Simplex 19214208 Depienne C , et al. (2009)
c.1671C>G p.Asn557Lys missense_variant Familial Paternal Multiplex 18469813 Dibbens LM , et al. (2008)
c.2123_2124del p.Lys708ArgfsTer11 frameshift_variant Familial Maternal - 30945278 Jiao Q , et al. (2019)
c.253C>T p.Gln85Ter stop_gained Familial Paternal Multi-generational 18469813 Dibbens LM , et al. (2008)
c.1091del p.Pro364ArgfsTer4 frameshift_variant Familial Paternal Multiplex 27527380 Liu A , et al. (2016)
c.859G>T p.Glu287Ter stop_gained Familial Paternal Multi-generational 19214208 Depienne C , et al. (2009)
c.1987del p.Ser663ProfsTer13 frameshift_variant Familial Paternal Multiplex 30287595 Liu A , et al. (2018)
c.1019A>G p.Asn340Ser missense_variant Familial Maternal Multi-generational 27527380 Liu A , et al. (2016)
c.2012C>G p.Ser671Ter stop_gained Familial Paternal Multi-generational 18469813 Dibbens LM , et al. (2008)
c.339dup p.Val114ArgfsTer112 frameshift_variant Familial - Multi-generational 30287595 Liu A , et al. (2018)
c.1091del p.Pro364ArgfsTer4 frameshift_variant Familial Paternal Multiplex 26544041 Zhang Y , et al. (2015)
c.1300_1301del p.Gln434GlufsTer11 frameshift_variant De novo NA Multiplex 22946748 Marini C , et al. (2012)
c.1004G>A p.Ser335Asn missense_variant Familial Paternal Multi-generational 29377098 Smith L , et al. (2018)
c.1342G>A p.Asp448Asn missense_variant Familial Maternal Multi-generational 29377098 Smith L , et al. (2018)
c.1873A>G p.Arg625Gly missense_variant Familial Maternal Multi-generational 29377098 Smith L , et al. (2018)
c.1408_1417del p.Ala470SerfsTer96 frameshift_variant Familial Paternal Simplex 27527380 Liu A , et al. (2016)
c.1322T>A p.Val441Glu missense_variant Familial Paternal Multi-generational 18469813 Dibbens LM , et al. (2008)
c.134_135del p.Asp45GlyfsTer43 frameshift_variant Familial Paternal Multiplex 23712037 Higurashi N , et al. (2013)
c.824A>C p.Tyr275Ser missense_variant Familial Maternal Multi-generational 23334464 van Harssel JJ , et al. (2013)
c.1017del p.Asn340MetfsTer28 frameshift_variant Familial Maternal Multi-generational 27527380 Liu A , et al. (2016)
c.359del p.Lys120ArgfsTer3 frameshift_variant Familial Maternal and paternal Multiplex 18469813 Dibbens LM , et al. (2008)
c.1036_1037insATCAA p.Ile346AsnfsTer24 frameshift_variant Familial - Multi-generational 19214208 Depienne C , et al. (2009)
c.1094dup p.Tyr366LeufsTer10 frameshift_variant Familial Maternal and paternal Multi-generational 18469813 Dibbens LM , et al. (2008)
c.2030dup p.Leu677PhefsTer43 frameshift_variant Familial Maternal and paternal Multi-generational 18469813 Dibbens LM , et al. (2008)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%). Trivisano et al., 2018 described a cohort of 61 patients with PCDH19-related epilepsy followed in 15 Italian epilepsy centers and reported that autism or autistic features was present in 31 individuals.

Score Delta: Score remained at S

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.

10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%). Trivisano et al., 2018 described a cohort of 61 patients with PCDH19-related epilepsy followed in 15 Italian epilepsy centers and reported that autism or autistic features was present in 31 individuals.

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

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%). Trivisano et al., 2018 described a cohort of 61 patients with PCDH19-related epilepsy followed in 15 Italian epilepsy centers and reported that autism or autistic features was present in 31 individuals.

4/1/2019
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%). Trivisano et al., 2018 described a cohort of 61 patients with PCDH19-related epilepsy followed in 15 Italian epilepsy centers and reported that autism or autistic features was present in 31 individuals.

1/1/2019
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%). Trivisano et al., 2018 described a cohort of 61 patients with PCDH19-related epilepsy followed in 15 Italian epilepsy centers and reported that autism or autistic features was present in 31 individuals.

10/1/2018
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%). Trivisano et al., 2018 described a cohort of 61 patients with PCDH19-related epilepsy followed in 15 Italian epilepsy centers and reported that autism or autistic features was present in 31 individuals.

7/1/2018
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies). Phenotypic characterization of 38 individuals with pathogenic or potentially pathogenic variants in the PCDH19 gene in Smith et al., 2018 revealed that autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. A systemic review and meta-analysis of 271 individuals with PCDH19 variants in Kolc et al., 2018 determined that of the 213 cases where psychiatric information was available, autistic features were most prominent (19.7%), followed by hyperactivity and/or attention deficit (11.7%), and behavioral disturbances (6.1%).

7/1/2017
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies).

4/1/2017
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies).

Reports Added
[Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.2010] [Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...2012] [X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.2008] [Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome.2010] [Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families.2009] [Protocadherin 19 mutations in girls with infantile-onset epilepsy.2010] [A novel PCDH19 mutation inherited from an unaffected mother.2012] [Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.2012] [Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy.2012] [Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders.2013] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy.2013] [Cognitive development in females with PCDH19 gene-related epilepsy.2014] [Protocadherin-19 is essential for early steps in brain morphogenesis.2009] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [The Clinical Spectrum of Female Epilepsy Patients with PCDH19 Mutations in a Chinese Population.2016] [Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes.2016] [Protocadherin 19 (PCDH19) interacts with paraspeckle protein NONO to co-regulate gene expression with estrogen receptor alpha (ER).2017]
1/1/2017
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies).

7/1/2016
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies).

1/1/2016
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies).

Reports Added
[Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.2010] [Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...2012] [X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.2008] [Novel de novo PCDH19 mutations in three unrelated females with epilepsy female restricted mental retardation syndrome.2010] [Epilepsy and mental retardation limited to females with PCDH19 mutations can present de novo or in single generation families.2009] [Protocadherin 19 mutations in girls with infantile-onset epilepsy.2010] [A novel PCDH19 mutation inherited from an unaffected mother.2012] [Identification of SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome.2012] [Focal seizures with affective symptoms are a major feature of PCDH19 gene-related epilepsy.2012] [Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders.2013] [Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1.2013] [PCDH19-related female-limited epilepsy: further details regarding early clinical features and therapeutic efficacy.2013] [Cognitive development in females with PCDH19 gene-related epilepsy.2014] [Protocadherin-19 is essential for early steps in brain morphogenesis.2009] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015]
1/1/2015
S
icon
S

Increased from S to S

Description

Rare mutations in the PCDH19 gene have been identified with autism and schizophrenia (Piton et al., 2011) as well as with epilepsy and mental retardation limited to females (EFMR) and epilepsy alone (Dibbens et al., 2008 and other studies).

Krishnan Probability Score

Score 0.57206658213999

Ranking 726/25841 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 0.97715851271551

Ranking 2208/18225 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 0.94739465444301

Ranking 17258/18665 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 0.090558776808564

Ranking 6322/20870 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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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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