• 0
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
CNTN6 (HGNC:2176) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
contactin 6
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
NB-3
%HI
39.69(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0(Read more about gnomAD pLI score)
LOEUF
1.15(Read more about gnomAD LOEUF score)
Cytoband
3p26.3
Genomic Coordinates
GRCh37/hg19: chr3:1134708-1445901 NCBI Ensembl UCSC
GRCh38/hg38: chr3:1093024-1404217 NCBI Ensembl UCSC
MANE Select Transcript
NM_001289080.2 ENST00000446702.7 (Read more about MANE Select)
Function
Contactins mediate cell surface interactions during nervous system development. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Involved in motor coordination (By similarity). {ECO:0000250}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-24340
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
No Evidence for Haploinsufficiency (0)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/28/2022

Haploinsufficiency (HI) Score Details

HI Score:
0
HI Evidence Strength:
No Evidence for Haploinsufficiency (Disclaimer)
HI Evidence:
  • PUBMED: 25606055
    Kashevarova et al (2014) identified intragenic CNTN6 deletions predicted to result in intellectual disability (ID) and developmental delay (DD) in two siblings and an unrelated individual using the Agilent 44K and 60K arrays. A 295 kb deletion encompassing exons 3-23 of CNTN6 were detected in two siblings with DD, ID, an abnormal skull shape and facial dysmorphism. Parental studies were not available. The individual with a 271.9 kb deletion of CNTN6, involving exons 21-23, had motor DD, ID, atypical autism, and speech delay. This deletion was inherited from an apparently healthy father. In addition, the same author described a 369 kb microdeletion at 3p26.3 overlapping with CNTN6 in a patient with moderate ID, dysarthria, and attention deficit hyperactivity disorder (ADHD). Parental studies were not available (PMID: 24291026).
  • PUBMED: 26257835
    Hu et al (2015) studied 3,724 individuals with multiple congenital anomalies, heart defect, short stature, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (AS), and seizures (SZs) using NimbleGen 135K oligonucleotide array. The authors reported 3p26.3 CNVs encompassing CNTN6 in 14 individuals (0.4%). Thirteen of the 14 individuals have variable clinical manifestation of neurodevelopmental disorders (NDDs), including ASD, DD, SZs, and attention deficit order (ADHD). The remaining one individual with heart block was a newborn whose development and behavior was normal at 1 year old. In addition, seven of the 14 individuals have dysmorphic features. Family history was available for 13 of the 14 individuals. Twelve families had multiple members with NDDs and neuropsychiatric disorders including ADHD, SZs, ASD, ID, schizophrenia, depression, anxiety, learning disability, and bipolar disorder. Seven of the 14 individuals had single copy loss in the 3p26.3 region involving entire CNTN6 gene deletions (2 individuals) or intragenic CNTN6 deletions (5 unrelated individuals, involving exon 2; exons 3-7; exons 5-12; exons 8-23,and exons 2-23, respectively). Parental studies were available in only one individual. The proband and her sister with SZs had a paternally inherited intragenic deletion of CNTN6 encompassing exons 8-23. Although the father had an apparently normal phenotype, the authors suggested an incomplete penetrance. In addition, five of the 14 individuals had intragenic duplications of CNTN6 ranged from 93.95 kb to 1.23 Mb (upstream and exons 1-2; upstream and exons 1-17; exons 2-7; exons 3-23 and downstream; and exons 4-23 and downstream, respectively). No other known pathogenic CNVs or CNVs with unclear clinical significance were observed in any of these individuals. The upstream and exons 1-2 duplication was inherited from phenotypically normal mother. The exons 3–23 and downstream duplication was paternally inherited. The father had bipolar and ADHD. Parental studies were not available in the remaining individuals.
  • PUBMED: 27166760
    Mercati et al (2017) studied a cohort of 1,534 unrelated individuals with autism spectrum disorder (ASD) and 8,936 controls using Illumina SNP arrays for copy number variations (CNVs). In addition, 212 unrelated individuals with ASD and 217 controls were screened using Sanger sequencing for single nucleotide variants (SNVs) in all exons of CNTN6. Finally, replication whole genome sequencing results were analyzed in a sample of 289 individuals with ASD (200 trios and 89 sib pairs) for SNVs. The authors also accessed to the Brain & Body Genetic Resource Exchange (BBGRE version 3.0; https://bbgre.brc.iop.kcl.ac.uk/) database including 5,891 patients (776 with ASD). They identified CNTN6 deletions in 14/5891 individuals with a significant excess of CNTN6 deletions in patients with ASD (6/776; 0.77%; P = 0.02). This excess of CNTN6 deletions in ASD was even more significant when only small deletions were considered. There were small CNTN6 deletions in 7/5891 individuals listed in BBGRE version 3.0 and 6/776 in patients with ASD (P = 0.002). In this study, both deletions (6/1534 ASD (0.39%) vs 1/8936 controls (0.01%); P = 0.00006) and private coding sequence variants (18/501 ASD vs 535/33480 controls P = 0.0005) were enriched in individuals with ASD with hyperacusis. Several CNTN6 variants identified in this study were considered deleterious by at least two algorithms. All CNVs were inherited (two deletions were transmitted by fathers with ASD). Among the SNVs, one nonsense mutation (W923*) was transmitted by a mother to her two sons with ASD and one variant (P770L) was found to be de novo in an individual with ASD. Using an in vitro assay, they showed that some variants (G310S, I683S, P770S) could affect the promoting effect of CNTN6 on neuritogenesis, whereas others did not (S57L, T958I, R303Q, G678S) The authors mentioned that a total of 47 CNTN6 deletions were listed among 18 506 patients (0.25%) in Decipher database (https://decipher.sanger.ac.uk/index). In contrast to the BBGRE database, the phenotype for autism wasrarely indicated, but several patients carrying CNTN6 deletions have cognitive impairments, intellectual disability, and ASD.
  • PUBMED: 30826922
    García-Ortiz et al (2020) identified a paternally inherited, heterozygous loss-of-function truncating variant in exon 6 of CNTN6 (p.Ser189Ter), predicted in silico to be deleterious, in a patient diagnosed with autism spectrum disorder. The patient presented with clinical features including language delay, poor social interaction, stereotypic behavior, and sensory-motor and hearing problems and his father and other family members had no neuropsychological anomalies. Additional single nucleotide variants (SNVs) in a further eight known and/or potential ASD-risk genes were identified in the patient by whole-exome sequencing (WES) and these included among others, likely pathogenic variants in CNTN5, DNAH10, NEO1, and NRXN2, which were absent in his father. Furthermore, an inversion (824-bp) partially involving exon 4 of CNTN5, a closely related contactin gene, was identified in the patient when comparing his exome against four reference exome samples (including his father). The authors state that although the pathogenicity of the CNTN5 structural variant (SV) found in this patient is not clear, this could potentially produce an aberrant protein and add to the truncated CNTN6 effect.
  • PUBMED: 30836150
    Repnikova et al (2020) examined the records of 20,226 patients and revealed nineteen patients with CNVs encompassing a coding portion of the CNTN6 gene, that had been identified by microarray analysis. Six of the 19 patients had variable size deletions (from 11.7 kb to 563.6 kb) that included either the entire CNTN6 gene or at least one of its exons (including exons 1-2; exons 2-4; exons 1-12 and exon 12). No other known pathogenic CNVs were observed in this group of patients. Thirteen patients had variable size duplications (from 163.3 kb to 650.5 kb) partially including only CNTN6 (including exon 1; exons 8-23; exons 2-4; exons 1-17; exons 2-23; exons 1-11 and exons 1-2). Four of these patients with CNTN6 duplications had separate genetic aberrations that could explain their phenotypes. Parental clinical testing was completed for six families and showed that the CNTN6 CNVs were maternally inherited in five patients (entire gene deletion and 4 duplications) and paternally inherited in one patient (duplication). In three cases the CNTN6 CNV was inherited from a healthy parent and in three cases from a parent with neurodevelopmental symptoms. The authors evaluated the clinical features for the 19 patients. Most patients (79%) presented with variable clinical manifestations of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), developmental delay (DD) and intellectual disability (ID). Additional clinical features in a subset of patients including attention deficit hyperactivity disorder (ADHD), hypotonia, seizures, cardiac anomalies, low weight, microcephaly and dysmorphic features. Given the significant variability of the clinical presentations, the authors concluded it was difficult to establish genotype-phenotype correlations. The authors also attempted to identify pathogenic sequence level variants in CNTN6 by sequencing this gene in a research cohort of 94 individuals with autism spectrum disorder (ASD) and unestablished genetic etiology. They identified three non-synonymous coding variants in CNTN6, all of which were inherited from a clinically unaffected parent and there was no significant difference in the frequency of the nonsynonymous variants in CNTN6 between the cohort of ASD patients and controls in public databases (p = 0.3251).
  • PUBMED: 30508811
    Tassano et al (2018) identified CNVs involving only the CNTN6 gene in two patients with variable neurodevelopmental disorders (NDDs). Patient 1 had a 427.7kb deletion including the entire CNTN6 gene and clinical features included mild intellectual disability and autism spectrum disorder (ASD). Patient 2 had a 941.987kb duplication partially including the CNTN6 gene (exons 2-23) and clinical features included ASD, attention deficit hyperactivity disorder (ADHD), disruptive behavior disorder and hyperphagia. Parental studies showed that both patients inherited the CNTN6 CNVs from their unaffected fathers. The variants were reported to likely represent a risk factor for a variety of neurodevelopmental disorders.
HI Evidence Comments:
The CNTN6 gene encodes contactin 6, a member of the L1 immunoglobulin superfamily of proteins, that functions as a cell adhesion protein which may contribute to the formation of axon connections in the developing nervous system. It has been suggested that these genes participate in pathways that are important for correct brain development. Independent studies have suggested that CNVs involving the CNTN6 gene are associated with a wide spectrum of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID), developmental delay (DD), seizures (SZs), and attention deficit order (ADHD) [PMIDs: 30508811; 29983269; 27166760; 26257835; 25606055]. No clear genotype-phenotype correlations have been defined and many of the CNTN6 CNVs including deletions and intragenic duplications have been inherited from unaffected parents, with incomplete penetrance suggested. Family segregation is also described with variable clinical presentation. CNVs involving CNTN6 are often found in phenotypically normal individuals as shown in the Database of Genomic Variants (DGV; http://projects.tcag.ca/variation/). CNTN6 has been reported as a candidate risk factor gene for various neuropsychiatric disorders including ASD [PMID: 27166760]. It is not clear if the expression of CNTN6 has been altered in the reported individuals with CNTN6 copy number and sequence variants as there are limited published functional studies. Studies in mice show that mice lacking both copies of CNTN6 (Cntn6-/-), have impaired motor coordination and spatial learning [PMIDs: 12884264 and 30106251]. There are conflicting reports on the pathogenicity of CNVs and SNVs involving CNTN6 in the literature. A recent study has suggested that CNVs involving CNTN6 alone may be a neutral variant, or a possible modifier rather than a disease-causing variant and additional genetic testing may be warranted for a genetic diagnosis [PMID: 30836150]. Another report suggests that a loss-of-function CNTN6 variant may require the presence of concomitant likely pathogenic variants in another gene(s), possibly a closely related contactin gene, to manifest a CNTN6-related ASD phenotype (PMID: 30826922). Currently, it remains unclear whether haploinsufficiency of the CNTN6 gene alone is sufficient to cause the observed NDD phenotype in individuals with CNTN6 loss-of-function variants.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Published Evidence:
  • PUBMED: 26257835
    Hu et al (2015) studied 3,724 individuals with multiple congenital anomalies, heart defect, short stature, developmental delay (DD), intellectual disability (ID), autism spectrum disorder (AS), and seizures (SZs) using NimbleGen 135K oligonucleotide array. The authors reported 3p26.3 copy number gains encompassing CNTN6 and additional genes (CHL1/CNTN6 and CHL1/CNTN6/CNTN4, respectively) in only two individuals with NDDs. The CHL1/CNTN6 duplication detected in an individual with obesity, ADHD, and bipolar was inherited from mother with psychiatric problem. Parental study was not available for the CHL1/CNTN6/CNTN4 duplication detected in an individual with attention deficit hyperactivity disorder, obsessive–compulsive disorder, and additional physical abnormalities.
  • PUBMED: 25606055
    Kashevarova et al (2014) identified a duplication of the entire CNTN6 gene in a patient with psychomotor developmental delay, abnormal skull shape and facial dysmorphism. The duplication was detected using an Agilent 60K array and inherited from his apparently healthy father and grandmother.
  • PUBMED: 28641109
    Huang et al (2017) reported that CNTN6 duplications confer a substantial increase in risk for Tourette syndrome (TS). The authors analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. Heterozygous exonic CNTN6 duplications were identified in 12 cases (0.49%) and 2 controls (0.05%). The CNTN6 duplications were heterogeneously sized, 8 of 12 TS carriers harbored a CNTN6 duplication > 500 kb in length, while duplications in controls were < 200 kb, however only one duplication included the entire CNTN6 gene.
TS Evidence Comments:
In the literature, a limited number of individuals with various neurodevelopmental disorders have been reported with entire CNTN6 duplications, inheritance from healthy parents has been described (PMID: 25606055) and co-segregation with other rare variants in a family with psychosis (PMID: 33897758). Hu et al (2017) (PMID: 26257835) reported two individuals with variable manifestations of NDDs with CHL1/CNTN6 and CHL1/CNTN6/CNTN4, respectively. There are CNTN6 entire gene duplications in the DECIPHER database as well as in the databases of genomic variants. Given the limited published functional studies (for example, PMID: 29327201), it remains unclear whether in individuals with CNTN6 duplication the expression of CNTN6 gene has been altered.

Genomic View

Select assembly: (NC_000003.11) (NC_000003.12)