Skeletal dysplasia

Gene: SIK3

I don't know

Comment on list classification: There is one pair of siblings reported in literature affected by metaphyseal dysplasia, homozygous for a missense variant in SIK3 (PMID:30232230). SIK3 deficiency in mice affects skeletal development, resulting in a dwarfism phenotype (PMID:22318228). As reviewed by Sarah Graham, there are further clinical cases present in The Clinical Variant Ark database, where individuals with skeletal dysplasia harboured homozygous SIK3 variants. However, the variants have not been reported as causal. Hence, this gene should remain Amber for Skeletal dysplasia, until more evidence emerges to support the gene-disease association.

Created: 27 Oct 2025, 11 a.m. | Last Modified: 27 Oct 2025, 11 a.m.

Panel Version: 8.20

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondyloepimetaphyseal dysplasia, Krakow type, OMIM: 618162; spondyloepimetaphyseal dysplasia, Krakow type, MONDO:0032571

Publications

• 22318228
• 30232230

Green List (high evidence)

Two further NHS clinical cases with phenotypes consistent with published cases:

1) CVA-123533-1: Homozygous nonsense variant c.1285C>T p.(Gln429Ter) in a patient with disproportionate short stature (height Z-score -5.35); metaphyseal chondrodysplasia on radiology; bowing deformity bilaterally thigh, lower leg, forearm.
2) CVA-79484-1: Homozygous missense variant in kinase domain, p.(Leu249Arg) in patient with skeletal dysplasia, fractures, hypomineralisation and short long bones prenatally with bowing of forearms and lower tibia and fibula, pulmonary hypoplasia, patent ductus arteriosus, combined immune deficiency, chronic lung disease, recurrent respiratory viral infections, BCGosis, CD3 lymphopenia, poor vaccine responses.

Total of four families with consistent phenotypes plus supportive mouse model, sufficient for green rating.

Created: 10 Oct 2025, 11:07 a.m. | Last Modified: 10 Oct 2025, 11:07 a.m.

Panel Version: 8.17

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spondyloepimetaphyseal dysplasia, Krakow type, OMIM:618162

Publications

• 30232230
• 22318228

Comment on list classification: Promoted to amber since there is one published case plus a supportive mouse model. Following up with evidence from UK NHS cases and the rating maybe reviewed.

Created: 8 Oct 2025, 9:30 a.m. | Last Modified: 8 Oct 2025, 9:30 a.m.

Panel Version: 8.17

Comment on phenotypes: OMIM phenotype accessed on 8th October 2025

Created: 8 Oct 2025, 9:26 a.m. | Last Modified: 8 Oct 2025, 9:26 a.m.

Panel Version: 8.16

I don't know

Literature:
PMID:30232230 - 2 sibs affected with metaphyseal dysplasia, alongside other phenotypes (developmental delay with brain MRI abnormalities, a severe unclassified immunodeficiency) homozygous for NM_001366686.3(SIK3):c.559C>T p.(Arg187Cys), referred to as R129C in the publication - shown to affect kinase activity

Clinical/diagnostic testing:
Homozygous duplication (Exon 2-4 - no RNA but predicted out of frame insertion) in GMS clinical testing (off panel/untiered) in patient with with spondylometaphyseal skeletal dysplasia alongside global developmental delay, focal seizures, tetralogy of fallot (CVA-120418-1)

A possible 3rd family would provide support for green rating (details unknown- ?prenatally detected skeletal anomalies, see SIK3 review in fetal anomalies gene panel (https://panelapp.genomicsengland.co.uk/panels/478/gene/SIK3/)

Animal Model:
Association with skeletal dysplasia supported by mouse model evidence PMID:22318228
Sources: NHS GMS

Created: 30 Jan 2025, 1:03 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 30232230
• 22318228

Variants in this GENE are reported as part of current diagnostic practice