ClinGen Dosage Sensitivity Curation Page

1q43q44 terminal region (includes AKT3)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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).

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity 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.

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.