Homozygous variants in ZSWIM6 cause severe syndromic short stature and developmental delay
Authors' conclusion
We report the first-ever homozygous ZSWIM6 variant, causing a novel phenotype of severe syndromic short stature with biochemical features consistent with GH deficiency and developmental delay. Our findings demonstrate that ZSWIM6 is a key transcriptional regulator and that allele-specific disturbances drive the marked clinical heterogeneity of ZSWIM6-related disorders.
Study context
- Population
- Two siblings from a consanguineous Kurdish family with specific facial phenotype, severe short stature with biochemical features of growth hormone (GH) deficiency, microcephaly and developmental delay
- Participants
- 2 siblings
- Comparison
- p.Arg1040His vs p.Arg1163Trp vs p.Arg913Ter
- Outcome
- Transcriptional activity of ZSWIM6 variants on HECW2 and ZIC2 promoters (HEK293 cells)
Methodological detailscase report of two siblings, whole-exome sequencing, dual-luciferase reporter assays, in silico 3D structural modelling (AlphaFold)
- Case report of two siblings
- Whole-exome sequencing
- Dual-luciferase reporter assays
- In silico 3D structural modelling (AlphaFold)
Main finding
As reported in the abstract
- ZSWIM6 is a transcriptional regulator of the HECW2 and ZIC2 promoters
- p.Arg1040His reduced ZIC2 activation (loss-of-function)
- p.Arg1163Trp enhanced ZIC2 activation (gain-of-function)
- p.Arg913Ter specifically increased HECW2 activation (derepression)
Further findings
3D structural modelling
- p.Arg1040His and p.Arg1163Trp predicted to alter local surface charge without disrupting overall fold
- p.Arg913Ter truncates ZSWIM6, potentially affecting DNA binding interactions
Clinical phenotype
- Siblings shared partial overlap with prior ZSWIM6-associated phenotypes but had a distinct clinical presentation
Original publication
Homozygous variants in ZSWIM6 cause severe syndromic short stature and developmental delay. Horm Res Paediatr. Published 12 September 2026. doi:10.
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