ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

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Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
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).
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.
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; 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 ( 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.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.