Submission Details

STIL was first reported in relation to autosomal recessive primary microcephaly in 2009 (Kumar et al., PMID: 19215732). Thirteen variants (5 missense, 2 splice-disrupting, 2 frameshifts, and 4 premature termination codons in the last exon) that have been reported in twelve probands in eight publications (PMIDs: 19215732, 22989186, 24986681, 25218063, 25658757, 29230157, 30214071, 32677750) are included in this curation. Ten of these twelve probands were homozygous variant carriers in consanguineous families, many of which had more than one affected homozygote. Six individuals from four families in which brain imaging had been performed had a variety of brain malformations, including several cases consistent with holoprosencephaly (PMID 24986681, 25218063, 25658757, 29230157). The mechanism of pathogenicity is unknown; although an AR condition, a lack of true LoF homozygotes suggest the possibility of lethality for complete absence of gene product. This gene-disease association is also supported by a STIL -/- mouse model, which shows axial midline defects and embryonic lethality (PMID 10385121). Functional studies show STIL-/- mouse embryonic fibroblasts lack centrioles and primary cilia and are rescued by introduction of exogenous STIL; introduction of STIL carrying observed human mutations allowed partial rescue (PMID 25486474). In summary, STIL is definitively associated with autosomal recessive primary microcephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations gene curation expert panel on 28.Mar.2023.