ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000001.10) (NC_000001.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22693284 Thevenon et al (2012) report 3 unrelated families with non-progressive congenital ataxia with or without intellectual disability studied by array CGH. Family 1 had an exon 4 deletion (81 kb), Family 2 had an intragenic exon 3-5 duplication (539 kb), and family 3 had an exon 2-3 deletion (49 kb). The CNVs in Families 1 and 2 segregated with disease (8 and 3 confirmed affected carriers, respectively), while the deletion in Family 3 was de novo. All of the CNVs were intragenic and affected the 5? end of the gene that includes the CG-1 domain (required for nuclear localization). The CNVs in families 1 and 2 led to a frameshift. The deletion in Family 3 was predicted to be in-frame, and that family had ataxia without ID. Fibroblast studies of a patient from family 1 showed absent mutant mRNA, consistent with loss-of-function via NMD and haploinsufficiency.
24738973 Shinawi et al (2015) describe 3 individuals from 2 families (two unrelated probands and an affected mother) with intragenic deletions of exons 6-11 (247.7 kb and 247.9 kb) with similar features of ADHD, ID/DD, abnormal brain MRI, gastrointestinal abnormalities (constipation and/or GER), difficulties with fine motor skills, dysarthria, dysmorphic facial features and short stature. Unsteady gait was also noted in all 3 individuals, although this had since resolved in one proband. Additionally, the affected mother of Proband 1 and Proband 2 (unrelated) were both noted to have velopharyngeal insufficiency. The two deletions removed amino acids 147-971 and introduced a frameshift mutation that is predicted to result in a stop codon. Functional studies were not performed. The authors provide a review of previously reported patients as well as patients in the DECIPHER clinical database, which includes 23 patients with losses affecting CAMTA1, some of which had indications overlapping those in the literature.The authors? discussion supports CAMTA1 haploinsufficiency.

Haploinsufficiency phenotype comments:

CAMTA1 encodes a brain-specific calcium responsive transcription factor associated with non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID), a heterogeneous autosomal dominant disorder. Current evidence is sufficient to support haploinsufficiency of CAMTA1, including two independent reports of 5 unrelated families with NPCA with or without ID and intragenic copy number changes (exonic deletion or duplication) predicted or supported by functional studies to result in a loss of function. Non-focal deletion (including CAMTA1 and additional genes) has also been reported in association with similar phenotypes. Additional reports with supportive evidence are described below. PMID: 22031302 Mikhail et al (2011) summarized findings of patients referred for clinical array CGH analysis with small (<500 kb) total gene or intragenic deletions involving known or putative haploinsufficient neurodevelopmental genes. From their cohort of 8 patients with small CNVs, one patient, a boy with ataxia, ID, ADHD, LD, PDD, velopharyngeal insufficiency, and no dysmorphic features carried a 305 kb de novo deletion of the promoter region and exons 1-3 of CAMTA1 plus 3 other RefSeq genes (a non-focal deletion). The authors propose haploinsufficiency of CAMTA1 as the likely explanation for this patient?s phenotype. PMID: 26848311 Coci et al (2016) describe 2 related individuals (a 6 ? year old proband and her mother) with a paracentric inversion of the short arm of chromosome 1 with breakpoints occurring within, and resulting in separate deletions involving genes CAMTA1 and NFIA. Both individuals had non-progressive cerebellar ataxia with intellectual disability (CANPMR) syndrome believed to be due to CAMTA1 haploinsufficiency, as well as hypoplasia of the corpus callosum thought to be due to NFIA haploinsufficiency. Additional concordant findings included dysmorphic facial features, macrocephaly, mild tremor, and kidney hypoplasia. The deletion of CAMTA1 resulted in a loss of exon 5. It was predicted that exons 1-4 in CAMTA1 were disrupted by the inversion, thereby leading to mRNA decay. The inversion was de novo in the mother.

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