ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
19346217 In 2009, Lacbawan et al. published a comprehensive literature review and case series of 77 families presenting with holoprosencephaly (HPE) and various confirmed genomic alterations impacting the SIX3 gene. Of the cases with plausible disease-causing SIX3 truncating variants in this publication, 8 were initially reported without clinical information by Domene et al. in 2008 (PMID: 18791198) as part of a functional analysis in zebrafish. Given the lack of clinical details in the original report, we used the information provided by Lacbawan et al. to assess these cases. Four different nonsense variants were identified in 5 probands with varying severities of HPE (2 of which were inherited from a parent with microform HPE) and small duplications or deletions resulting in frameshift variants were found in the remaining 3 probands (1 was inherited from a father with microform HPE). An additional 3 probands inherited a truncating variant from an apparently unaffected parent illustrating the well-recognized reduced penetrance seen in families with SIX3 variants. Larger deletions and other cytogenetic alterations were found in 15 probands, but all encompassed additional genes beyond SIX3.
20157829 Hehr et al. (2010) identified a de novo heterozygous nonsense variant [c.385G>T p.(Glu129Ter)] in a fetus with alobar HPE and evidence of schizencephaly. Complex cerebral malformations were identified by ultrasound at 27 weeks' gestation, including microbrachycephaly, and a large unilateral schizencephalic cleft of the left posterior cerebral hemisphere. The findings suggested that schizencephaly may in some cases be part of the broad HPE spectrum.
20531442 In 2010, Paulussen et al. reported SIX3 variants in 8 probands with varying degrees of HPE in a Dutch population. A de novo 4 base duplication ( c.404_407dupGCGC p.V137RfsX18) was identified in a 10 month-old female with semilobar HPE. A de novo single base deletion (c.736delA p.T245fsX5) was found in a neonate with alobar HPE, "a single nostril, flat nose, median cleft lip/palate and hypotelorism." A de novo SIX3 canonical splice site variant (c.806+1) was identified in an 8 month old male with semilobar HPE, microcephaly, epilepsy, psychomotor retardation and diabetes insipidus. Although not considered in this assessment he authors also reported a de novo 1.45 Mb deletion encompassing SIX3 as well as many other genes in a male fetus with semilobar HPE. All cases were also reported by Lacbawan et al. (2009) as part of their case series, but are only counted once towards this assessment.

Haploinsufficiency phenotype comments:

Variable expressivity and incomplete penetrance are both recognized for holoprosencephaly in general and penetrance for individuals with pathogenic variants in SIX3 is estimated to be about 60% (PMID:20104608, Solomon et al. 2010). Additional Information: PMID: 15635066 Pasquier et al. (2005) reported a 2 base duplication (c.556_557dup p.Pro187Alafs*65) in a female proband and her 2 siblings each with alobar HPE, which was inherited from their father with microform HPE. Additional cases are present in the literature, however it is worth noting that it is challenging to discern truly unique probands given that many publications include "cases from the literature" and have substantially overlapping authors. This is true of one of the more recent publications by Roessler et al. in 2012 (PMID: 22310223) where the authors include mutation analysis of 189 patients with HPE.

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