ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17478476 In 2007, Brockschmidt et al. used genome-wide array-based CGH and FISH analysis on an individual with Pitt-Hopkins Syndrome (PHS) and her family. The authors identified a de novo 0.5 Mb deletion in TCF4 in the proband, leading them to conclude that TCF4 haploinsufficiency is responsible for the proband?s phenotype.
29604340 In 2018, Liu et al. studied a child with Pitt-Hopkins Syndrome (PTHS) and her unaffected family. Using a gene panel consisting of 1,700 candidate genes for central nervous system (CNS) disorders, the authors used next generation sequencing (NGS) to identify a variant in TCF4. The identification of this deletion variant (p. Arg728Ter) was confirmed using Sanger sequencing and PCR. This variant was de novo, as it was absent in the proband?s unaffected parents and sister.
22045651 In 2012, Whalen et al. analyzed TCF4 variants in 112 individuals with Pitt-Hopkins Syndrome (PTHS). 79 of these individuals had been previously reported, while 33 were new cases. Per the authors, ?most patients were unrelated (110/112) and carried a de novo mutation.? There were 2 familial cases. 77 individuals harbored small deletions, insertions, or point variants. 53 variants resulted in premature stop codons.

Haploinsufficiency phenotype comments:

Haploinsufficiency of TCF4 has been found to cause Pitt-Hopkins syndrome. Of note: PMID: 17436254 - 1.8-Mb de novo deletion in chromosome 18q21.2, including TCF4. Additional Cases: PMID: 23528641 In 2013, Kousoulidou et al. used a variety of analyses on an individual with Pitt-Hopkins Syndrome to identify potential variants. These analyses included FISH analysis for 22q11.2, molecular analysis using 1 Mb array-CGH for conditions including Fragile X, DRPLA, Angelman syndrome, and spinocerebellar ataxias (SCA), and 400 K array-CGH. All tests returned normal results with the exception of the 400 K array-CGH; analysis identified a 263.4 kb deletion within TCF4. Analysis did not find this variant in the proband?s unaffected mother and sister, but it was discovered that the unaffected father was mosaic for the variant.

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