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
11567216 Machinis et al (2001): Report of a G>C mutation in the invariant splice-acceptor site resulting in aberrant splicing that was found in individuals in three generations of a family. All family members with the mutation had hypopituitary function, cerebellar defects, and abnormalities of the sella turcica.
18445675 Castinetti (2008): One family with three individuals reported with a frameshift mutation (pedigree A) and functional studies indicating haploinsufficiency. Also provides update on family described by Machinis (PMID: 11567216).
18073311 Pfaeffle (2008): Report includes three families with variable pituitary hormone deficiency and missense changes. Functional studies suggest haploinsufficiency because the protein is inactive for 2/3 mutations.

Haploinsufficiency phenotype comments:

Pituitary hormone deficiency is common to all patients with variability in cerebellar or cranial structural anomalies. An additional report by Reynaud et al (PMID: 21270112) report additional affected individuals from the families reported originally by Machinis (PMID: 11567216) and Castinetti (PMID: 18445675). Tajima et al (PMID: 19856252) report a Japanese patient with the same phenotype who had a de novo missense mutation. Dateki et al, PMID: 20534763 - One patient with a de novo 522 kb deletion including LHX4 and 3 other genes; patient has combined pituitary hormone deficiency. Filges, et al, PMID: 22232309 - A neonate with unexplained heart failure and minor physical anomalies, and a clinical diagnosis of CPHD, with an identified 1.5-megabase microdeletion (13 genes total) including LHX4. The deletion was found to be maternally inherited from the clinically healthy mother, suggesting incomplete penetrance.

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