ClinGen Dosage Sensitivity Curation Page

CNKSR2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22511892 Houge et al. (2012) describes a 5-year-old boy with developmental delay, well-controlled epilepsy, and microcephaly, and a 234-kb deletion of Xp22.12 detected by copy number analysis. The maternally inherited deletion removed the initial 15 of the 21 exons of CNKSR2. This child is further clinically classified as Patient 3 (Norwegian Boy) in Vaags et al. 2014.
25223753 Vaags et al. 2014 report 3 additional probands (a total of 7 additional affected individuals from 3 previously unreported families) with deletions or frameshift variants involving CNKSR2. The affected males are characterized by "intellectual disability, attention problems, and abrupt lifelong language loss following a brief early childhood epilepsy with continuous spike-waves in sleep." Two of the new probands discussed in this paper were shown to have deletions involving CNKSR2. The first, a 1.17 Mb deletion "approximated" the RPS6KA3 gene, associated with Coffin-Lowry syndrome. The authors report that fine mapping showed that the deletion does not involve this gene, and that Western blot analysis confirmed typical expression of the RPSKA3 protein product in the proband. The second deletion (0.51 Mb), involving only the CNKSR2 gene. The third family was found to have truncating frameshift variant, p.D152RfsX8. All variants are reportedly inherited from carrier mothers. Detailed descriptions of the methods used to identify these variants is not provided.
25754917 Aypar et al. (2015) described a 7-year old non-dysmorphic boy with medically intractable focal seizures and developmental delay. He had a 342 kilobase focal deletion at Xp22.12 which was maternally-inherited from an a mother who is reportedly unaffected. "The minimal deleted interval contains the entire CNKSR2 gene isoforms 3 and 4, and the majority of the CNKSR2 gene isoforms 1 and 2 with the most distal deleted probe located within the last exon of those isoforms. The interval between the most distal deleted probe, 21,670,497, and the most distal normal probe, 21,678,137, contains a hypothetical gene, KLHL34.?

Haploinsufficiency phenotype comments:

CNKSR2 (connector enhancer of KSR2) maps to Xq22.12 and is a synaptic protein. It plays an important role in neuronal proliferation, migration, and differentiation. Loss of function of CNKSR2 is associated with the epilepsy-aphasia spectrum (EAS), which is characterized by epilepsy, development delay, intellectual disability, attention deficit hyperactivity disorder (ADHD), affected speech, and continuous spike-and-slow-waves (CSWS) on EEG. There are several reports supporting haploinsufficiency of CNKSR2 via entire or partial gene deletions or loss-of-function sequence variants. The cardinal features of CNKSR2 deficiency are: (1)intellectual disability, (2) highly restricted speech (espe-cially expressive language), (3) attentional problems/hyperactivity, and (4) brief childhood epilepsy. Note: There are no overlapping copy number losses in the database of genomic variants (DGV) of the general population in this locus. Additional publications: PMID: 25644381 Hu et al. (2015) reported on X-exome sequencing of 405 unresolved families with apparent X-linked intellectual disability and seizure. They report a single family with the same p.D152RfsX8 variant described in the Vaags study. The pedigree structure of the family reported in Hu is markedly similar to the family reported in Vaags. Hu et al. do not state that this is the same family reported in Vaags et al., but this may be possible. PMID: 28098945 Damiano et al. (2017) described a maternally inherited nonsense variant (p.R712*) in a family with two affected brothers. The one brother had epileptic encephalopathy, severe with continuous spike-waves in sleep and the other one presented intermediate epilepsy aphasia disorder. The carrier sister had a childhood epilepsy and the mother had febrile seizures. The p.Arg712* variant is located toward the C-terminalof the protein and is predicted to result in a truncated proteinlacking the last 322 of 1,034 residues. PMID: 30397616 Sun et al (2018) reported a de novo nonsense variant (p.R729*) in a patient with epilepsy-aphasia spectrum PMID: 31164858 Demos et al (2019) described a maternally inherited nonsense variant (p.W595*) in a patient with early-onset epilepsy. PMID: 30776697 Wang et al. (2019) identified a de novo nonsense variant (p.Q162*) in a patient with epilepsy-aphasia spectrum. PMID: 31414730 Polla et al. (2019) identified a de novo nonsense variant (p. Trip768*) in a patient with mild intellectual and seizures. PMID: 32245427 Daoqi et al (2020) used whole exome sequencing and PCR on a family whose children had intellectual disability and seizures. Both children had a 9.5 kb deletion which occurred de novo in the proband's mother. The mother is a symptomatic carrier whose phenotype is milder. PMID: 33298018 Zhang et al (2020) used whole exome sequencing on a family with psychomotor delay, ADHD, and ID. The proband and his mother have a splice site variant in CNKSR2 with the mother's variant being de novo. PMID: 32197126 Bonardi et al (2020) used whole exome sequencing (WES), chromosomal microarray (CMA), or a 582 gene panel on 5 individuals. Patient 1 has a phenotype of developmental delay (DD), hypotonia, joint hypermobility, impaired walking, and seizures and a de novo hemizygous variant of CNKSR2. Patient 2 has a phenotype of seizures, hyperactive behaviors and mild cognitive impairment and a de novo frameshift deletion of CNKSR2. Patient 3 has a phenotype of developmental delay, seizures, and speech dyspraxia and a maternally inherited frameshift deletion of CNKSR2. The patient's mother has mosaicism and is asymptomatic. Patient 4 has a phenotype of seizures, language defects, hyperactivity, and moderate ID and a deletion of CNKSR2 with unknown inheritance. Patient 5 has a phenotype of DD, mild generalized hypotonia, language delay, attention deficit, seizures, and irritability with a de novo deletion of CNKSR2.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There is no report supporting triplosensitivity of CNKSR2

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.