ClinGen Dosage Sensitivity Curation Page

1q43q44 terminal region (includes AKT3)

  • Curation Status: Complete
  • id: ISCA-37493
  • Date last evaluated: 2016-10-12
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 0


Location Information

  • 1q43-q44
  • GRCh37/hg19 chr1: 243,287,730-245,318,287
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr1: 243,124,428-245,154,985
  • View: NCBI | Ensembl | UCSC
Select assembly: () ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
17603806 The authors mapped the deleted regions in seven patients with terminal deletions of chromosome 1q to define a 2.0-Mb microcephaly critical region including the 1q43-1q44 boundary and no more than 11 genes.
21800092 Baliff et al. characterized pure interstitial or terminal microdeletions of the 1q43q44 region in 22 patients. They found a 2Mb genomic critical region at 1q43q44 (241.5-243.5, hg18; liftover 243.4-245.4 Mb, hg19) for the microcephaly (MIC), agenesis of the corpus callosum (ACC) and seizure (SZR) phenotypes. This region contains 12 genes, including candidate genes for MIC (AKT3), and ACC (ZNF238). The authors narrowed down the SZR phenotype to three genes within a small region of overlap (SRO): FAM36A (now known as COX20), C1orf199 (now known as HNRNPU-AS1) and HNRNPU.
22678713 Eleven unrelated patients with 1q43q44 deletions were studied by Thierry et al. All patients presented with seizures, intellectual disability (ID) and craniofacial abnormalities. The authors found a phenotype/genotype correlation of ID, seizures and craniofacial anomalies with the same SRO as that found by Ballif et al. (2012).

Haploinsufficiency phenotype comments:

Chromosome 1q43-q44 deletion syndrome is characterized by moderate to severe mental retardation, limited or no speech, and variable but characteristic facial features, including round face, prominent forehead, flat nasal bridge, hypertelorism, epicanthal folds, and low-set ears. Other features may include hypotonia, poor growth, microcephaly, agenesis of the corpus callosum, and seizures. The phenotype is variable, and not all features are observed in all patients, which may be explained in some cases by incomplete penetrance or variable expressivity (OMIM description). Breakpoints are highly variable. Primary candidate genes for the brain anomalies are: AKT3, ZBTB18, HNRNPU and HNRNPU-AS. Please note: The coordinates chosen here take into consideration the boundaries created by LCRs near the CEP170 locus on the proximal side and on the distal side, a minor segmental duplication that follows HNRNPU. This region was chosen to minimally include the candidate genes for the brain anomalies. Outer LCRs likely contribute to the larger deletions.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
23794269 Wang et al (2013) provide a single case report of a child with a de novo 3 Mb duplication at 1q43q44 (hg19 chr 1 242.1-245.1 Mb), which largely overlaps the critical region for 1q43q44 microdeletions. The patient had moderate developmental delays in gross motor movements and speech, macrocephaly and craniofacial anomalies. The 3 Mb duplicated region contained 15 genes including AKT3. The authors propose triplosensitivity of AKT3 as causal for the macrocephaly phenotype.

Triplosensitivity phenotype comment:

Reports of 1q43q44 duplications are scarce and as a result, there is insufficient evidence to indicate a triplosensitivity score.