ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000017.10) (NC_000017.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
15106123 Bongers et al., 2004 report sequence mutations in TBX4 as the cause of Small patella syndrome (SPS). They sequenced TBX4 in patients with SPS and found 6 heterozygous mutations that were pathogenic, but not found in 100 control chromosomes. Two mutations from this paper as evidence: one nonsense change (Q62X) that cosegregated with the disease; one frameshift mutation (1112_1113insC).
23592887 Kerstjens-Frederikse et al., 2013 report sequence variants and contiguous gene deletions in 6 of 20 patients in cohort of patients with childhood onset pulmonary arterial hypertension (PAH). Two of these nonsense point mutations counted as evidence were inherited from parents with features consistent with small patella syndrome but without PAH.
29120062 Vanlerberghe et al., 2017 report analysis of 10 families with small patella syndrome. Seven families found to have sequence variants that are predicted to be loss of function or haploinsufficiency, confirming the clinical diagnosis of SPS.

Haploinsufficiency phenotype comments:

Literature indicates that haploinsufficiency of TBX4 is highly penetrant for small patella syndrome (SPS). Several cohorts of patients with childhood onset pulmonary arterial hypertension (PAH) have been identified to have sequence variants, then to be found to have features of SPS. Carrier parents of those children with PAH are typically found to have SPS but typically do not have features of PAH, suggesting decreased penetrance and variable expressivity for PAH. Oda 2018 (PMID 29854702) identified a patient with small patella syndrome with a paternally inherited frameshift mutation. The father was reportedly unaffected but it was not indicated how extensive his clinical evaluation was and therefore not clear if this is an example of incomplete penetrance.

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

Triplosensitivity phenotype comment:

Lu et al. 2012 (PMID 22678995) found a 350 kb duplication including TBX4 and 2 additional genes in a large family with clubfoot. The duplication was only found in patients with abnormal feet. Peterson et al. 2014 (PMID 24592505) report 2.15Mb duplicaiton including TBX4 in mother, daughter, two sons, both sons had clubfoot, one with additional congenital malformations, seizures, delays. Both mother and daughter were phenotypically normal. Alvarado et al. 2010 (PMID 20598276) analyzed 66 probands with isolated clubfoot with at least one affected first degree relative. Three probands were found to have microduplications including multiple genes, which segreated with clubfoot in the families. Seven of the 10 individuals among the families with the microduplications had clubfoot. No focal gene duplications appear to be reported.