• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SIX3 (HGNC:10889) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
SIX homeobox 3
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
HPE2
Alias symbols
No aliases found
%HI
12.2(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.95(Read more about gnomAD pLI score)
LOEUF
0.32(Read more about gnomAD LOEUF score)
Cytoband
2p21
Genomic Coordinates
GRCh37/hg19: chr2:45168841-45173210 NCBI Ensembl UCSC
GRCh38/hg38: chr2:44941702-44946071 NCBI Ensembl UCSC
MANE Select Transcript
NM_005413.4 ENST00000260653.5 (Read more about MANE Select)
Function
Transcriptional regulator which can act as both a transcriptional repressor and activator by binding a ATTA homeodomain core recognition sequence on these target genes. During forebrain development represses WNT1 expression allowing zona limitans intrathalamica formation and thereby ensuring proper anterio-posterior patterning of the diencephalon and formation of the rostral diencephalon. Acts as a direct upstream activator of SHH expression in the rostral diencephalon ventral midline and that i... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-3496
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/23/2020

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 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.
  • PUBMED: 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.
  • PUBMED: 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.
HI Evidence 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 (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000002.11) (NC_000002.12)